Genes and Disease

Genes and Disease Blood and Lymph Diseases

1

Blood and Lymph Diseases


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As most of the cells in the human body are not in direct contact with the external environment, thecirculatory system acts as a transport system for these cells. Two distinct fluids move through thecirculatory system: blood and lymph. Blood carries oxygen and nutrients to the body's cells, andcarries waste materials away. Blood also carries hormones, which control body processes, andantibodies, to fight invading germs. The heart is the pump that keeps this transport system moving.Together, the blood, heart, and blood vessels form the circulatory system.

The lymphatic system (lymph, lymph nodes and lymph vessels) supports the circulatory systemby draining excess fluids and proteins from tissues back into the bloodstream, thereby preventingtissue swelling. It also serves as a defense system for the body, filtering out organisms that causedisease, producing white blood cells, and generating antibodies.

The biochemical make up of lymph the fluid found in the lymphatic vessels varies with thesite of origin. For example, lymph from bone marrow, spleen, and thymus have high concentrationsof white blood cells for fighting infection, while lymph from intestines is high in fat that has beenabsorbed during digestion. Damage to the lymphatic and circulatory systems leaves the body moresusceptible to sickness and infection, as well as to serious conditions such as cancer.


3

Anemia, sickle cell

Sickle cell anemia is the most common inheritedblood disorder in the United States, affecting about72,000 Americans or 1 in 500 African Americans.SCA is characterized by episodes of pain, chronichemolytic anemia and severe infections, usuallybeginning in early childhood.

SCA is an autosomal recessive disease causedby a point mutation in the hemoglobin beta gene(HBB) found on chromosome 11p15.4. Carrier fre-quency of HBB varies significantly around the world,with high rates associated with zones of high malariaincidence, since carriers are somewhat protectedagainst malaria. About 8% of the African Americanpopulation are carriers. A mutation in HBB results inthe production of a structurally abnormal hemoglobin(Hb), called HbS. Hb is an oxygen carrying proteinthat gives red blood cells (RBC) their characteristiccolor. Under certain conditions, like low oxygen lev-els or high hemoglobin concentrations, in individualswho are homozygous for HbS, the abnormal HbSclusters together, distorting the RBCs into sickledshapes. These deformed and rigid RBCs becometrapped within small blood vessels and block them,producing pain and eventually damaging organs.

Though, as yet, there is no cure for SCA, acombination of fluids, painkillers, antibiotics andtransfusions are used to treat symptoms and compli-cations. Hydroxyurea, an antitumor drug, has been

shown to be effective in preventing painful crises.Hydroxyurea induces the formation of fetal Hb (HbF)a Hb normally found in the fetus or newbornwhich, when present in individuals with SCA, pre-vents sickling. A mouse model of SCA has beendeveloped and is being used to evaluate the effec-tiveness of potential new therapies for SCA.

Important Links

Gene sequenceGenome view see gene locationsEntrez Gene collection of gene-related informationBLink [www.ncbi.nlm.nih.gov/sutils/blink.cgi?pid=4504349&org=1] related sequences in different organisms

The literatureResearch articles online full textBooks online books sectionOMIM catalog of human genes and disorders

WebsitesFact Sheet [http://www.nhlbi.nih.gov/health/dci/Diseases/Sca/SCA_WhatIs.html] from the National Heart, Lung and Blood Institute,NIHSCDAA [www.sicklecelldisease.org] Sickle Cell Disease Association of America


4

Burkitt lymphoma

Burkitt lymphoma is a rare form of cancer predomi-nantly affecting young children in Central Africa, butthe disease has also been reported in other areas.The form seen in Africa seems to be associated withinfection by the EpsteinBarr virus, although thepathogenic mechanism is unclear.

Burkitt lymphoma results from chromosometranslocations that involve the Myc gene. A chromo-some translocation means that a chromosome isbroken, which allows it to associate with parts ofother chromosomes. The classic chromosometranslocation in Burkitt lymophoma involves chromo-some 8, the site of the Myc gene. This changes thepattern of Myc's expression, thereby disrupting itsusual function in controlling cell growth and prolifera-tion.

We are still not sure what causes chromosometranslocation. However, research in model organ-isms such as mice is leading us toward a betterunderstanding of how translocations occur and,hopefully, how this process contributes to Burkittlymphoma and other cancers such as leukemia.

Important Links



WebsitesCancerNet [cancernet.nci.nih.gov/] from the National Cancer Institute, NIHAmerican Cancer Society [www.cancer.org/] research and patient supportOncolink [oncolink.upenn.edu/] comprehensive cancer information from the University of Pennsylvania


5

Gaucher disease

Gaucher (pronounced "go-SHAY") disease is aninherited illness caused by a gene mutation. Nor-mally, this gene is responsible for an enzyme calledglucocerebrosidase that the body needs to breakdown a particular kind of fat called glucocerebroside.In people with Gaucher disease, the body is not ableto properly produce this enzyme, and the fat can notbe broken down. It then accumulates, mostly in theliver, spleen, and bone marrow. Gaucher diseasecan result in pain, fatigue, jaundice, bone damage,anemia, and even death.

Gaucher disease is considerably more commonin the descendants of Jewish people from EasternEurope (Ashkenazi), although individuals from anyethnic group may be affected. Among the AshkenaziJewish population, Gaucher disease is the mostcommon genetic disorder, with an incidence ofapproximately 1 in 450 persons. In the general pub-lic, Gaucher disease affects approximately 1 in100,000 persons. According to the National GaucherFoundation, 2500 Americans suffer from Gaucherdisease.

In 1991, enzyme replacement therapy becameavailable as the first effective treatment for Gaucherdisease. The treatment consists of a modified formof the glucocerebrosidase enzyme given intra-venously. Performed on an outpatient basis, thetreatment takes about 12 h and is given every 2weeks. Enzyme replacement therapy can stop andoften reverse the symptoms of Gaucher disease,allowing patients to enjoy a better quality of life.

Important Links

Gene sequenceGenome view see gene locationsEntrez Gene collection of gene-related informationBLink [www.ncbi.nlm.nih.gov/sutils/blink.cgi?pid=54607043&all=1] related sequences in different organisms


WebsitesNational Gaucher Foundation [www.gaucherdisease.org/] supporting research into the causes of Gaucher disease


6

Hemophilia A

Hemophilia A is a hereditary blood disorder, pri-marily affecting males, characterized by a deficiencyof the blood clotting protein known as Factor VIII thatresults in abnormal bleeding. Babylonian Jews firstdescribed hemophilia more than 1700 years ago; thedisease first drew widespread public attention whenQueen Victoria transmitted it to several Europeanroyal families. Mutation of the HEMA gene on the Xchromosome causes Hemophilia A. Normally,females have two X chromosomes, whereas maleshave one X and one Y chromosome. Since maleshave only a single copy of any gene located on the Xchromosome, they cannot offset damage to that

gene with an additional copy as can females. Con-sequently, X-linked disorders such as Hemophilia Aare far more common in males. The HEMA genecodes for Factor VIII, which is synthesized mainly inthe liver, and is one of many factors involved inblood coagulation; its loss alone is enough to causeHemophilia A even if all the other coagulation factorsare still present.

Treatment of Hemophilia A has progressedrapidly since the middle of the last century whenpatients were infused with plasma or processedplasma products to replace Factor VIII. HIV contam-ination of human blood supplies and the consequentHIV infection of most hemophiliacs in the mid-1980sforced the development of alternate Factor VIIIsources for replacement therapy, including mono-clonal antibody purified Factor VIII and recombinantFactor VIII, both of which are used in replacementtherapies today.

Development of a gene replacement therapy forHemophilia A has reached the clinical trial stage,and results so far have been encouraging. Investiga-tors are still evaluating the long-term safety of thesetherapies, and it is hoped that a genetic cure forhemophilia will be generally available in the future.

Important Links



WebsitesNational Hemophilia Foundation [www.hemophilia.org/] a nonprofit organization dedicated to finding cures for inherited bleedingdisorders


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8

Leukemia, chronic myeloid

Chronic myeloid leukemia (CML) is a cancer ofblood cells, characterized by replacement of thebone marrow with malignant, leukemic cells. Many ofthese leukemic cells can be found circulating in theblood and can cause enlargement of the spleen,liver, and other organs.

CML is usually diagnosed by finding a specificchromosomal abnormality called the Philadelphia(Ph) chromosome (see figure), named after the citywhere it was first recorded. The Ph chromosome isthe result of a translocationor exchange of geneticmaterialbetween the long arms of chromosomes 9and 22 . This exchange brings together two genes:the BCR (breakpoint cluster region) gene on chro-mosome 22 and the proto-oncogene ABL (Ablesonleukemia virus) on chromosome 9. The resultinghybrid gene BCR-ABL codes for a fusion protein withtyrosine kinase activity, which activates signal trans-duction pathways, leading to uncontrolled cellgrowth.

A mouse model has been created that developsa CML-like disease when given bone marrow cellsinfected with a virus containing the BCR-ABL gene.In other animal models, the fusion proteins havebeen shown to transform normal blood precursor

cells to malignant cells. To research the human dis-ease, antisense oligomers (short DNA segments)that block BCR-ABL were developed that specificallysuppressed the formation of leukemic cells while notaffecting the normal bone marrow cell development.These and other experimental techniques may leadto future treatments for CML.

Important Links



WebsitesCancer.gov [http://www.cancer.gov/cancerinfo/wyntk/leukemia] from the National Cancer Institute, NIH


9

NiemannPick disease

In 1914, German pediatrician Albert Niemanndescribed a young child with brain and nervous sys-tem impairment. Later, in the 1920's, Luddwick Pickstudied tissues after the death of such children andprovided evidence of a new disorder, distinct fromthose storage disorders previously described.

Today, there are three separate diseases thatcarry the name NiemannPick: Type A is the acuteinfantile form, Type B is a less common, chronic,non-neurological form, while Type C is a biochemi-cally and genetically distinct form of the disease.Recently, the major locus responsible for NiemannPick type C (NP-C) was cloned from chromosome18, and found to be similar to proteins that play arole in cholesterol homeostasis.

Usually, cellular cholesterol is imported intolysosomes'bags of enzymes' in the cellfor pro-cessing, after which it is released. Cells taken fromNP-C patients have been shown to be defective in

releasing cholesterol from lysosomes. This leads toan excessive build-up of cholesterol inside lyso-somes, causing processing errors. NPC1 was foundto have known sterol-sensing regions similar tothose in other proteins, which suggests it plays arole in regulating cholesterol traffic.

Important Links


The literatureResearch articles online full textBooks online books sectionOMIM [www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=257200] catalog of human genes and disorders

WebsitesFact sheet [www.ninds.nih.gov/health_and_medical/disorders/niemann.doc.htm] from the National Institute of NeurologicalDisorders and Stroke, NIHNational Niemann-Pick Disease Foundation [www.nnpdf.org] an educational, support and fund-raising organization


10

Paroxysmal nocturnal hemoglobinuria

The distinct and rather peculiar characteristics ofparoxysmal nocturnal hemoglobinuria (PNH) havepuzzled hematologists for more than a century. PNHis characterized by a decreased number of red bloodcells (anemia), and the presence of blood in theurine (hemoglobinuria) and plasma (hemoglobine-mia), which is evident after sleeping. PNH is associ-ated with a high risk of major thrombotic events,most commonly thrombosis of large intra-abdominalveins. Most patients who die of their disease die ofthrombosis.

PNH blood cells are deficient in an enzymeknown as PIG-A, which is required for the biosyn-thesis of cellular anchors. Proteins that are partly onthe outside of cells are often attached to the cellmembrane by a glycosylphosphatidylinositol (GPI)anchor, and PIG-A is required for the synthesis of akey anchor component. If PIG-A is defective, surfaceproteins that protect the cell from destructive com-ponents in the blood (complement) are not anchoredand therefore absent, so the blood cells are brokendown.

The PIG-A gene is found on the X chromosome.Although not an inherited disease, PNH is a geneticdisorder, known as an acquired genetic disorder.The affected blood cell clone passes the alteredPIG-A to all its descendantsred cells, leukocytes(including lymphocytes), and platelets. The propor-tion of abnormal red blood cells in the blood deter-mines the severity of the disease.

Important Links




11

Porphyria

Porphyria is a diverse group of diseases inwhich production of heme is disrupted. Porphyria isderived from the Greek word "porphyra", whichmeans purple. When heme production is faulty, por-phyrins are overproduced and lend a reddish-purplecolor to urine.

Heme is composed of porphyrin, a large circularmolecule made from four rings linked together withan iron atom at its center. Heme is the oxygen-binding part of hemoglobin, giving red blood cellstheir color. It is also a component of several vitalenzymes in the liver including the group known as

cytochrome P450. This enzyme family is important inconverting potentially harmful substances such asdrugs to inactive products destined for excretion.

Heme synthesis takes place in several steps,each of which requires a specific enzyme of whichthere are 8 in total. The genes that encode theseenzymes are located on different chromosomes, andmutations of these genes can be inherited in eitheran autosomal dominant or autosomal recessive fash-ion, depending on the gene concerned. Affectedindividuals are unable to complete heme synthesis,and intermediate products, porphyrin or its precur-sors, accumulate.

Environmental triggers are important in manyattacks of porphyria. Example triggers include cer-tain medications, fasting, or hormonal changes.Genetic carriers who avoid a triggering exposuremay never experience symptoms.

The cutaneous porphyrias cause sun sensitivity,with blistering typically on the face, back of thehands, and other sun-exposed areas. The mostcommon of these is porphyria cutanea tarda (PCT).Triggering factors are alcohol use, estrogen, iron,and liver disease, particularly hepatitis C.

The acute porphyrias typically cause abdominalpain and nausea. Some patients have personalitychanges and seizures at the outset. With time theillness can involve weakness in many different mus-cles.

The cutaneous and acute forms are treated dif-ferently. Cure of these genetic diseases awaits theresults of ongoing research on the safest and mosteffective means of gene transfer or correction.

Important Links



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WebsitesFact sheet [http://digestive.niddk.nih.gov/ddiseases/pubs/porphyria/]from National Institute of Diabetes and Digestive and KidneyDiseases (NIDDK), NIHMedlinePlus [http://www.nlm.nih.gov/medlineplus/ency/article/001208.htm]a medical encyclopedia from the National Library ofMedicine, NIH


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Thalassemia

Thalassemia is an inherited disease of faulty synthe-sis of hemoglobin. The name is derived from theGreek word "thalassa" meaning "the sea" becausethe condition was first described in populations livingnear the Mediterranean Sea; however, the diseaseis also prevalent in Africa, the Middle East, and Asia.

Thalassemia consists of a group of disordersthat may range from a barely detectable abnormalityof blood, to severe or fatal anemia. Adult hemoglobinis composed of two alpha () and two beta ()polypeptide chains. There are two copies of thehemoglobin alpha gene (HBA1 and HBA2), whicheach encode an -chain, and both genes are locatedon chromosome 16. The hemoglobin beta gene(HBB) encodes the -chain and is located on chro-mosome 11.

In -thalassemia, there is deficient synthesis of-chains. The resulting excess of -chains bind oxy-gen poorly, leading to a low concentration of oxygenin tissues (hypoxemia). Similarly, in -thalassemiathere is a lack of -chains. However, the excess -chains can form insoluble aggregates inside redblood cells. These aggregates cause the death ofred blood cells and their precursors, causing a verysevere anemia. The spleen becomes enlarged as itremoves damaged red blood cells from the circula-tion.

Deletions of HBA1 and/or HBA2 tend to underliemost cases of -thalassemia. The severity of symp-toms depends on how many of these genes are lost.Loss of one or two genes is usually asymptomatic,whereas deletion of all four genes is fatal to theunborn child.

In contrast, over 100 types of mutations affectHBB, and deletion mutations are rare. Splice muta-tions and mutations that occur in the HBB genepromoter region tend to cause a reduction, ratherthan a complete absence, of -globin chains and soresult in milder disease. Nonsense mutations andframeshift mutations tend to not produce any -globin chains leading to severe disease.

Currently, severe thalassemia is treated byblood transfusions, and a minority of patients arecured by bone marrow transplantation. Mouse mod-els are proving to be useful in assessing the poten-tial of gene therapy.

Important Links

Gene sequenceGenome view see gene locationsEntrez Gene collection of gene-related informationBLink -chain [www.ncbi.nlm.nih.gov/sutils/blink.cgi?pid=122412&org=1]BLink -chain [www.ncbi.nlm.nih.gov/sutils/blink.cgi?pid=4504349&all=1] related sequences in different organisms


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WebsitesCooley's Anemia Foundation [www.cooleysanemia.org/]Further information for patients and familiesThalassemia.Com [www.thalassemia.com]Further information for patients and health care workers

Genes and Disease Cancers

1

Cancers

Cancer occurs when cell division gets out of control. Usually, the timing of cell division is under strictconstraint, involving a network of signals that work together to say when a cell can divide, how oftenit should happen and how errors can be fixed. Mutations in one or more of the nodes in this networkcan trigger cancer, be it through exposure to some environmental factor (e.g. tobacco smoke) orbecause of a genetic predisposition, or both. Usually, several cancer-promoting factors have to addup before a person will develop a malignant growth: with some exceptions, no one risk alone issufficient.

The predominant mechanisms for the cancers featured here are (i) impairment of a DNA repairpathway (ii) the transformation of a normal gene into an oncogene and (iii) the malfunction of atumor supressor gene.


2

Breast and ovarian cancer

Breast cancer is the second major cause of cancerdeath in American women, with an estimated 44,190lives lost (290 men and 43,900 women) in the US in1997. While ovarian cancer accounts for fewerdeaths than breast cancer, it still represents 4% ofall female cancers. For some of the cases of bothtypes of cancer, there is also a clear genetic link.

In 1994, two breast cancer susceptibility geneswere identified: BRCA1 on chromosome 17 andBRCA2 on chromosome 13. When an individual car-ries a mutation in either BRCA1 or BRCA2, they areat an increased risk of being diagnosed with breastor ovarian cancer at some point in their lives. Untilrecently, it was not clear what the function of thesegenes was, until studies on a related protein in yeastrevealed their normal role: they participate in repair-ing radiation-induced breaks in double-strandedDNA. It is though that mutations in BRCA1 orBRCA2 might disable this mechanism, leading tomore errors in DNA replication and ultimately to can-cerous growth.

So far, the best opportunity to reduce mortality isthrough early detection (general screening of thepopulation for BRCA1 and BRCA2 is not yet recom-mended). However, new strategies to find anticancerdrugs are constantly being developed. The latest,called "synthetic lethal screening" looks for new drug

targets in organisms such as yeast and fruit flies. Inthe same way that studies in yeast recently helpedto identify the functions of BRCA1 and BRCA2, it isthought that drugs that work in more primative organ-isms will also be applicable to humans.

Important Links



WebsitesCancerNet [cancernet.nci.nih.gov/] from the National Cancer Institute, NIHOncolink [oncolink.upenn.edu/] comprehensive cancer information from the University of PennsylvaniaGeneReviews [www.geneclinics.org/profiles/brca1/index.html] a medical genetics resource


3

Burkitt lymphoma

Burkitt lymphoma is a rare form of cancer predomi-nantly affecting young children in Central Africa, butthe disease has also been reported in other areas.The form seen in Africa seems to be associated withinfection by the EpsteinBarr virus, although thepathogenic mechanism is unclear.

Burkitt lymphoma results from chromosometranslocations that involve the Myc gene. A chromo-some translocation means that a chromosome isbroken, which allows it to associate with parts ofother chromosomes. The classic chromosometranslocation in Burkitt lymophoma involves chromo-some 8, the site of the Myc gene. This changes thepattern of Myc's expression, thereby disrupting itsusual function in controlling cell growth and prolifera-tion.

We are still not sure what causes chromosometranslocation. However, research in model organ-isms such as mice is leading us toward a betterunderstanding of how translocations occur and,hopefully, how this process contributes to Burkittlymphoma and other cancers such as leukemia.

Important Links



WebsitesCancerNet [cancernet.nci.nih.gov/] from the National Cancer Institute, NIHAmerican Cancer Society [www.cancer.org/] research and patient supportOncolink [oncolink.upenn.edu/] comprehensive cancer information from the University of Pennsylvania


4

Colon cancer

The American Cancer Society estimates that therewill be 93,800 new cases of colon cancer diagnosedin the US in 2000, with 47,700 resulting deaths. Allkinds of cancer occur when cell division, normally avery highly regulated process, gets out of control.While environmental factors can certainly contributeto a person's risk of cancer (e.g. smoking, diet, andexercise), most cancers have a genetic basis too.Literally hundreds of genes and proteins areinvolved in monitoring the process of cell divisionand DNA replication; a mutation in one or more ofthese genes or proteins can sometimes lead touncontrolled cancerous growth.

Colon cancer is one of the most common inher-ited cancer syndromes known. Among the genesfound to be involved in colorectal cancer are: MSH2and MSH6 both on chromosome 2 and MLH1, onchromosome 3. Normally, the protein products ofthese genes help to repair mistakes made in DNAreplication. If the MSH2, MSH6, and MLH1 proteinsare mutated and therefore don't work properly, thereplication mistakes are not repaired, leading todamaged DNA and, in this case, colon cancer.

It is not clear why mutations in genes that areessential in all tissues preferentially cause cancer inthe colon. However, studies on the equivalent genesin mice and brewer's yeast are helping to further ourunderstanding of the mechanisms of DNA repair andthe role that environmental factors might play incolon cancer incidence.

Important Links



WebsitesCancerNet [cancernet.nci.nih.gov/] from the National Cancer Institute, NIHAmerican Cancer Society [www.cancer.org] research and patient supportOncolink [oncolink.upenn.edu/] comprehensive cancer information from the University of Pennsylvania


5

Leukemia, chronic myeloid

Chronic myeloid leukemia (CML) is a cancer ofblood cells, characterized by replacement of thebone marrow with malignant, leukemic cells. Many ofthese leukemic cells can be found circulating in theblood and can cause enlargement of the spleen,liver, and other organs.

CML is usually diagnosed by finding a specificchromosomal abnormality called the Philadelphia(Ph) chromosome (see figure), named after the citywhere it was first recorded. The Ph chromosome isthe result of a translocationor exchange of geneticmaterialbetween the long arms of chromosomes 9and 22 . This exchange brings together two genes:the BCR (breakpoint cluster region) gene on chro-mosome 22 and the proto-oncogene ABL (Ablesonleukemia virus) on chromosome 9. The resultinghybrid gene BCR-ABL codes for a fusion protein withtyrosine kinase activity, which activates signal trans-duction pathways, leading to uncontrolled cellgrowth.

A mouse model has been created that developsa CML-like disease when given bone marrow cellsinfected with a virus containing the BCR-ABL gene.In other animal models, the fusion proteins havebeen shown to transform normal blood precursor

cells to malignant cells. To research the human dis-ease, antisense oligomers (short DNA segments)that block BCR-ABL were developed that specificallysuppressed the formation of leukemic cells while notaffecting the normal bone marrow cell development.These and other experimental techniques may leadto future treatments for CML.

Important Links



WebsitesCancer.gov [http://www.cancer.gov/cancerinfo/wyntk/leukemia] from the National Cancer Institute, NIH


6

Lung carcinoma, small cell

In the US, lung cancer is the most common cause ofcancer deaths among both men and women. In fact,North Americans have the highest rates of lung can-cer in the world. In 1997, some 178,100 new caseswere diagnosed, and roughly 160,400 deathsoccurred from the disease. Sadly, the 5-year survivalrate for persons with lung cancer is only 14%. Sincethe 1940s, the increase in lung cancer mortality bygender has followed historic patterns of smoking,with a 20-year time lag. About 90% of male lungcancer deaths and 80% of female lung cancerdeaths are attributable to cigarette smoking.Although smoking is by far the major risk factor forlung cancer, certain industrial substances, such asasbestos, and environmental factors can contribute.

Small cell lung carcinoma is distinctive fromother kinds of lung cancer (metastases are alreadypresent at the time of discovery) and accounts forapproximately 110,000 cancer diagnoses annually.A deletion of part of chromosome 3 was firstobserved in 1982 in small cell lung carcinoma celllines.

As with other cancers, mutations in a variety ofmolecules (oncogenes and tumor-suppressor genes)that control cell growth and division are observed,and no one mutation is likely to result in cancerousgrowth. Basic research into the function of thesemoleculeshow and when they play their roleshould help the fight against lung, and other, can-cers and give clues to find appropriate therapies.

Important Links





7

Malignant melanoma

In 1997, it was expected that about 40,300 Ameri-cans would be diagnosed with malignant melanoma,the most aggressive kind of skin cancer. Melanomasare more common in people with lightly pigmentedskin, and people who have had melanoma oncehave a high risk of developing new melanomas.

In some cases, the risk of developing melanomaruns in families, where a mutation in the CDKN2gene on chromosome 9 can underlie susceptibility tomelanoma. CDKN2 codes for a protein called p16that is an important regulator of the cell divisioncycle; it stops the cell from synthesizing DNA beforeit divides. If p16 is not working properly, the skin celldoes not have this brake on the cell division cycleand so can go on to proliferate unchecked. At somepoint this proliferation can be seen as a suddenchange in skin growth or the appearance of a mole.

The most powerful weapons against melanomaare therefore 1) prevention, by using protective cloth-ing and sun screen and 2) early detection, by recog-

nizing changes in skin growths or the appearance ofnew growths. Insight may also be drawn for othercancer types by studying the molecular biology ofp16, since the malfunction of other components ofthe p16 pathway have also been implicated in othercancers.

Important Links



WebsitesCancerNet [cancernet.nci.nih.gov/] from the National Cancer Institute, NIHAmerican Cancer Society [www.cancer.org] research and patient supportMEDLINE plus [www.nlm.nih.gov/medlineplus/melanoma.html] links on melanoma compiled by the National Library of Medicine


8

Multiple endocrine neoplasia

Multiple endocrine neoplasia (MEN) is a group ofrare diseases caused by genetic defects that lead tohyperplasia (abnormal multiplication or increase inthe number of normal cells in normal arrangement ina tissue) and hyperfunction (excessive functioning)of two or more components of the endocrine system.

Endocrine glands are different from other organsin the body because they release hormones into thebloodstream. Hormones are powerful chemicals thattravel through the blood, controlling and instructingthe functions of various organs. Normally, the hor-mones released by endocrine glands are carefully

balanced to met the body's needs. When a personhas MEN, specific endocrine glands, such as theparathyroid glands, the pancreas gland, and the pitu-itary gland, tend to become overactive. When theseglands go into overdrive, the result can be: exces-sive calcium in the bloodstream (resulting in kidneystones or kidney damage); fatigue; weakness; mus-cle or bone pain; constipation; indigestion; andthinning of bones.

The MEN1 gene, which has been known forseveral years to be found on chromosome 11, wasmore finely mapped in 1997.

Important Links



WebsitesFact sheet [www.niddk.nih.gov/health/endo/pubs/fmen1/fmen1.htm] from the National Institute of Diabetes and Digestive and KidneyDiseases, NIH


9

Neurofibromatosis

Neurofibromatosis, type 2, (NF-2) is a rare inheriteddisorder characterized by the development of benigntumors on both auditory nerves (acoustic neuromas).The disease is also characterized by the develop-ment of malignant central nervous system tumors aswell.

The NF2 gene has been mapped to chromo-some 22 and is thought to be a so-called 'tumor-suppressor gene'. Like other tumor suppressorgenes (such as p53 and Rb), the normal function ofNF2 is to act as a brake on cell growth and division,ensuring that cells do not divide uncontrollably, asthey do in tumors. A mutation in NF2 impairs itsfunction, and accounts for the clinical symptomsobserved in neurofibromatosis sufferers. NF-2 is anautosomal dominant genetic trait, meaning it affectsboth genders equally and that each child of anaffected parent has a 50% chance of inheriting thegene.

We are learning more about the function of theNF2 gene through studies of families with neurofi-bromatosis type 2 and through work in model organ-

isms, particularly mice. The exact molecular functionof NF2 in the cell is still unknown, although the pro-tein is similar to the ERM family of cytoskeleton-membrane linker proteins. Further work on thebinding partners of NF2 would help to identify poten-tial specific targets for future drug therapies.

Important Links




10

The p53 tumor suppressor protein

The p53 gene like the Rb gene, is a tumor suppres-sor gene, i.e., its activity stops the formation oftumors. If a person inherits only one functional copyof the p53 gene from their parents, they are predis-posed to cancer and usually develop several inde-pendent tumors in a variety of tissues in earlyadulthood. This condition is rare, and is known as Li-Fraumeni syndrome. However, mutations in p53 arefound in most tumor types, and so contribute to thecomplex network of molecular events leading totumor formation.

The p53 gene has been mapped to chromosome17. In the cell, p53 protein binds DNA, which in turnstimulates another gene to produce a protein calledp21 that interacts with a cell division-stimulating pro-tein (cdk2). When p21 is complexed with cdk2 thecell cannot pass through to the next stage of celldivision. Mutant p53 can no longer bind DNA in aneffective way, and as a consequence the p21 proteinis not made available to act as the 'stop signal' forcell division. Thus cells divide uncontrollably, andform tumors.

Help with unraveling the molecular mechanismsof cancerous growth has come from the use of miceas models for human cancer, in which powerful

'gene knockout' techniques can be used. Theamount of information that exists on all aspects ofp53 normal function and mutant expression inhuman cancers is now vast, reflecting its key role inthe pathogenesis of human cancers. It is clear thatp53 is just one component of a network of eventsthat culminate in tumor formation.

Important Links



WebsitesCancerNet [cancernet.nci.nih.gov/] from the National Cancer Institute, NIHOncolink [oncolink.upenn.edu/] comprehensive cancer information from the University of PennsylvaniaAmerican Cancer Society [www.cancer.org] research and patient support


11

Pancreatic cancer

The pancreas is responsible for producing the hor-mone insulin, along with other substances. It alsoplays a key role in the digestion of protein. Therewere an estimated 27,000 new cases of pancreaticcancer in the US in 1997, with 28,100 deaths fromthe disease.

About 90% of human pancreatic carcinomasshow a loss of part of chromosome 18. In 1996, apossible tumor suppressor gene, DPC4 (Smad4),was discovered from the section that is lost in pan-creatic cancer, so may play a role in pancreaticcancer. There is a whole family of Smad proteins invertebrates, all involved in signal transduction oftransforming growth factor (TGF) related path-ways. Other tumor suppressor genes include p53and Rb, which, if mutated or absent from thegenome can contribute to cancerous growth in avariety of tissues.

DPC4 (Smad4) homologs exist in the worm(Caenorhabditis elegans), mouse and the fly(Drosophila). In Drosophila, when the gene is notpresent, there a number of developmental defects.

Likewise, homozygous Smad4 mutant mouseembryos die before embryonic day 7.5, and havereduced size because of reduced cell proliferation.Research on these model organisms should helpelucidate the role of Smad4 and related proteins inhumans.

Important Links



WebsitesCancerNet [cancernet.nci.nih.gov/] from the National Cancer Institute, NIHOncolink [oncolink.upenn.edu/] comprehensive cancer information from the University of PennsylvaniaAmerican Cancer Society [www.cancer.org] research and patient supportMEDLINEplus [www.nlm.nih.gov/medlineplus/pancreaticcancer.html] links on pancreatic cancer compiled by the National Library ofMedicine


12

Polycystic kidney disease

Adult polycystic kidney disease (APKD) is character-ized by large cysts in one or both kidneys and agradual loss of normal kidney tissue which can leadto chronic renal failure. The role of the kidneys in thebody is to filter the blood, excreting the end-productsof metabolism in the form of urine and regulating theconcentrations of hydrogen, sodium, potassium,phosphate and other ions in the extracellular fluid.

In 1994 the European Polycystic Kidney DiseaseConsortium isolated a gene from chromosome 16that was disrupted in a family with APCD. The pro-tein encoded by the PKD1 gene is an integral mem-brane protein involved in cell-cell interactions andcell-matrix interactions. The role of PKD1 in thenormal cell may be linked to microtubule-mediatedfunctions, such as the placement of Na(+), K(+)-ATPase ion pumps in the membrane. Programmedcell death, or apoptosis, may also be invoked inAPKD. Further clarification of the pathogenesis ofthe disease await further research.

The so-called 'cpk mouse' is a well known modelfor the human disease. Studying the molecular basisof the disease in the mouse is expected to provide abetter understanding of the human disease, and ishoped to lead to more effective therapies.

Important Links



WebsitesFact sheet [www.niddk.nih.gov/health/kidney/pubs/polycyst/polycyst.htm] from the National Institute of Diabetes and Digestive andKidney Diseases, NIH


13

Prostate cancer

The second leading cause of cancer death in Ameri-can men, prostate cancer will be diagnosed in anestimated 184,500 American men in 1998 and willclaim the lives of an estimated 39,200. Prostate can-cer mortality rates are more than two times higherfor African-American men than white men. The inci-dence of prostate cancer increases with age; morethan 75% of all prostate cancers are diagnosed inmen over age 65.

Despite the high prevalence of prostate cancer,little is known about the genetic predisposition ofsome men to the disease. Numerous studies point toa family history being a major risk factor, which maybe responsible for an estimated 5-10% of all prostatecancers.

One of the most promising recent breakthroughsmay be the discovery of a susceptibility locus forprostate cancer on chromosome 1, called HPC1,which may account for about 1 in 500 cases ofprostate cancer. The next step will be to clone thegene. Once researchers have the sequence, theywill be able to search the databases to compare the

HPC1 sequence to previously characterized proteinsfrom both humans and other animals. This shouldprovide clues as to the function of HPC1 in the cell,and suggest potential starting points to find drugtargets.

Important Links

Gene sequenceGenome view see gene locationsEntrez Gene collection of gene-related information


WebsitesFact sheet [www.nhgri.nih.gov/DIR/LCG/PROSTATE/pros_home.html] from the National Human Genome Research Institute, NIHCancerNet [cancernet.nci.nih.gov/] from the National Cancer Institute, NIHOncolink [oncolink.upenn.edu/] comprehensive cancer information from the University of Pennsylvania


14

Harvey Ras oncogene

Cancer occurs when the growth and differentiation ofcells in a body tissue become uncontrolled andderanged. While no two cancers are geneticallyidentical (even in the same tissue type), there arerelatively few ways in which normal cell growth cango wrong. One of these is to make a gene that stimu-lates cell growth hyperactive; this altered gene isknown as an 'oncogene'.

Ras is one such oncogene product that is foundon chromosome 11. It is found in normal cells, whereit helps to relay signals by acting as a switch. Whenreceptors on the cell surface are stimulated (by ahormone, for example), Ras is switched on andtransduces signals that tell the cell to grow. If thecell-surface receptor is not stimulated, Ras is notactivated and so the pathway that results in cellgrowth is not initiated. In about 30% of human can-cers, Ras is mutated so that it is permanentlyswitched on, telling the cell to grow regardless ofwhether receptors on the cell surface are activatedor not.

Usually, a single oncogene is not enough to turna normal cell into a cancer cell, and many mutationsin a number of different genes may be required to

make a cell cancerous. To help unravel the intricatenetwork of events that lead to cancer, mice arebeing used to model the human disease, which willfurther our understanding and help to identify possi-ble targets for new drugs and therapies.

Important Links

Gene sequenceGenome view see gene locationsLocusLink collection of gene-related informationBLink [www.ncbi.nlm.nih.gov/sutils/blink.cgi?pid=4885425&org=1] related sequences in different organisms



15

Retinoblastoma

Retinoblastoma occurs in early childhood and affectsabout 1 child in 20,000. The tumor develops from theimmature retina - the part of the eye responsible fordetecting light and color. There are both hereditaryand non-hereditary forms of retinoblastoma. IN thehereditary form, multiple tumors are found in botheyes, while in the non-hereditary form only one eyeis effected and by only one tumor.

In the hereditary form, a gene called Rb is lostfrom chromosome 13. Since the absence of Rbseemed to be linked to retinoblastoma, it has beensuggested that the role of Rb in normal cells is tosuppress tumor formation. Rb is found in all cells ofthe body, where under normal conditions it acts as abrake on the cell division cycle by preventing certainregulatory proteins from triggering DNA replication. IfRb is missing, a cell can replicate itself over andover in an uncontrolled manner, resulting in tumorformation.

Untreated, retinoblastoma is almost uniformlyfatal, but with early diagnosis and modern methodsof treatment the survival rate is over 90%. Since the

Rb gene is found in all cell types, studying themolecular mechanism of tumor suppression by Rbwill give insight into the progression of many types ofcancer, not just retinoblastoma.

Important Links



WebsitesThe National Eye Institute, NIH [www.nei.nih.gov/] research and patient information


16

Tuberous sclerosis

Tuberous sclerosis is an hereditary disorder charac-terized by benign, tumor-like nodules of the brainand/or retinas, skin lesions, seizures and/or mentalretardation. Patients may experience a few or all ofthe symptoms with varying degrees of severity.

Two loci for tuberous sclerosis have been found:TSC1 on chromosome 9, and TSC2 on chromosome16. It took four years to pin down a specific genefrom the TSC1 region of chromosome 9: in 1997, apromising candidate was found. Called hamartin bythe discoverers, it is similar to a yeast protein ofunknown function, and appears to act as a tumorsuppressor: without TSC1, growth of cells proceedsin an unregulated fashion, resulting in tumor forma-tion. TSC2 codes for a protein called tuberin, which,through database searches, was found to have aregion of homology to a protein found in pathwaysthat regulate the cell (GAP3, a GTPase-activationprotein).

SC1 has a homolog in yeast, which provides asystem in which to model the human disease.

Important Links



WebsitesCancerNet [cancernet.nci.nih.gov/] from the National Cancer Institute, NIHOncolink [oncolink.upenn.edu/] comprehensive cancer information from the University of PennsylvaniaGeneClinics [www.geneclinics.org/profiles/tuberous-sclerosis/index.html] a medical genetics resource


17

Von Hippel-Lindau syndrome

Von Hippel-Lindau syndrome is an inherited multi-system disorder characterized by abnormal growthof blood vessels. While blood vessels normally growlike trees, in people with VHL little knots of bloodcapillaries sometimes occur. These knots are calledangiomas or hemangioblastomas. Growths maydevelop in the retina, certain areas of the brain, thespinal cord, the adrenal glands and other parts of thebody.

The gene for Von-Hippel Lindau disease (VHL)is found on chromosome 3, and is inherited in adominant fashion. If one parent has a dominantgene, each child has a 50-50 chance of inheritingthat gene. The VHL gene is a tumor suppressorgene. This means that its role in a normal cell is tostop uncontrolled growth and proliferation. If thegene is lost or mutated, then its inhibitory effect oncell growth is lost or diminished, which, in combina-tion with defects in other regulatory proteins, canlead to cancerous growth. LIke the Rb tumor sup-pressor gene, VHL seems to act as a 'gatekeeper' tothe multistep process of tumorigenesis.

Although unrelated to any other known family ofhuman proteins, homologs to human VHL are foundin mice and rats. Experiments using these animals

as model organisms for the human disease are help-ing researchers discover the normal physiologicalrole of VHL, which will shed light on its mechanismof pathogenesis. Initial results suggest that VHL mayplay a role in regulating exit form the cell cycle.

Important Links


The literatureResearch articles online full textBooks online books sectionOMIM [193300] catalog of human genes and disorders

WebsitesFact sheet [www.ninds.nih.gov/health_and_medical/disorders/vonhippe_doc.htm] from the National Institute of NeurologicalDisorders and Stroke, NIH

Genes and Disease The Digestive System

1

The Digestive System

Digestion is the process of turning food into fuel for energy, and for maintenance of the bodystructure. The digestive tract is a series of hollow organs joined in a long, twisting tube from themouth to the anus. Inside this tube is a lining called the mucosa. In the mouth, stomach, and smallintestine, the mucosa contains tiny glands that produce enzymes to help digest food. There are alsotwo solid digestive organs, the liver and the pancreas, which produce enzymes that reach theintestine through small tubes.

During the digestive process, food passes down the throat, through the esophagus, and into thestomach, where food continues to be broken down. The partially digested food passes into a shorttube called the duodenum the first part of the small intestine. The jejunum and ileum are alsopart of the small intestine. The liver, the gallbladder, and the pancreas produce enzymes andsubstances to help with digestion in the small intestine. After the digestive process is complete, the


2

resulting waste travels downstream to the colon. The colon and rectum are parts of the body'sdigestive system, which removes nutrients from food and stores waste until it passes out of thebody. Together, the colon and rectum form a long, muscular tube called the large intestine.

The health of your digestive system has a lot to do with lifestyle the food you eat, the amountof exercise you get, and the pace and stress level of your day. However, some digestive diseases,such as those discussed here, are thought to be hereditary or stem from an infection. For others,there is no known cause.


3

Colon cancer

The American Cancer Society estimates that therewill be 93,800 new cases of colon cancer diagnosedin the US in 2000, with 47,700 resulting deaths. Allkinds of cancer occur when cell division, normally avery highly regulated process, gets out of control.While environmental factors can certainly contributeto a person's risk of cancer (e.g. smoking, diet, andexercise), most cancers have a genetic basis too.Literally hundreds of genes and proteins areinvolved in monitoring the process of cell divisionand DNA replication; a mutation in one or more ofthese genes or proteins can sometimes lead touncontrolled cancerous growth.

Colon cancer is one of the most common inher-ited cancer syndromes known. Among the genesfound to be involved in colorectal cancer are: MSH2and MSH6 both on chromosome 2 and MLH1, onchromosome 3. Normally, the protein products ofthese genes help to repair mistakes made in DNAreplication. If the MSH2, MSH6, and MLH1 proteinsare mutated and therefore don't work properly, thereplication mistakes are not repaired, leading todamaged DNA and, in this case, colon cancer.

It is not clear why mutations in genes that areessential in all tissues preferentially cause cancer inthe colon. However, studies on the equivalent genesin mice and brewer's yeast are helping to further ourunderstanding of the mechanisms of DNA repair andthe role that environmental factors might play incolon cancer incidence.

Important Links





4

Crohn's disease

Inflammatory bowel disease (IBD) is a group ofchronic disorders that causes inflammation or ulcera-tion in the small and large intestines. Most often, IBDis classified either as ulcerative colitis or Crohn'sdisease. While ulcerative colitis affects the inner lin-ing of the colon and rectum, Crohn's diseaseextends into the deeper layers of the intestinal wall.It is a chronic condition and may recur at varioustimes over a lifetime.

About 20% of cases of Crohn's disease appearto run in families. It is a "complex trait," which meansthat several genes at different locations in thegenome may contribute to the disease. A susceptibil-ity locus for the disease was recently mapped tochromosome 16. Candidate genes found in thisregion include several involved in the inflamatoryresponse, including: CD19, involved in B-lymphocytefunction; sialophorin, involved in leukocyte adhesion;the CD11 integrin cluster, involved in microbacterialcell adhesion; and the interleukin-4 receptor, whichis interesting, as IL-4-mediated functions are alteredin IBDs.

Because some of the genetic factors involved inCrohn's disease may also contribute to ulcerativecolitis susceptibility, research into Crohn's diseasemay assist in further understanding both types ofIBD.

Important Links



WebsitesFact sheet [www.niddk.nih.gov/health/digest/pubs/crohns/crohns.htm] from the National Institute for Diabetes and Digestive andKidney Diseases, NIHThe Crohn's disease web page [www.healingwell.com/ibd/] information and linksMEDLINEplus [www.nlm.nih.gov/medlineplus/crohnsdisease.html] links on Crohn's disease compiled by the National Library ofMedicine


5

Cystic fibrosis

Cystic fibrosis (CF) is the most common fatal geneticdisease in the United States today. It causes thebody to produce a thick, sticky mucus that clogs thelungs, leading to infection, and blocks the pancreas,stopping digestive enzymes from reaching theintestines where they are required to digest food.

CF is caused by a defective gene, which codesfor a chloride transporter found on the surface of theepithelial cells that line the lungs and other organs.Several hundred mutations have been found in thisgene, all of which result in defective transport ofchloride, and secondarily sodium, by epithelial cells.As a result, the amount of sodium chloride (salt) isincreased in bodily secretions. The severity of thedisease symptoms of CF is directly related to thecharacteristic effects of the particular mutation(s)that have been inherited by the sufferer.

CF research has accelerated sharply since thediscovery of CFTR in 1989. In 1990, scientists suc-cessfully cloned the normal gene and added it to CFcells in the laboratory, which corrected the defectivechloride transport mechanism. This techniquegene

therapywas then tried on a limited number of CFpatients. However, this treatment may not be assuccessful as originally hoped. Further research willbe required before gene therapy, and other experi-mental treatments, prove useful in combating CF.

Important Links



WebsitesFact sheet [www.nhlbi.nih.gov/health/public/lung/other/cystfib.htm] from the National Heart, Lung and Blood Institute, NIHThe Cystic Fibrosis Foundation [www.cff.org/] information and links


6

Diabetes, type 1

Diabetes is a chronic metabolic disorder thatadversely affects the body's ability to manufactureand use insulin, a hormone necessary for the con-version of food into energy. The disease greatlyincreases the risk of blindness, heart disease, kidneyfailure, neurological disease, and other conditions forthe approximately 16 million Americans who areaffected by it. Type 1, or juvenile onset diabetes, isthe more severe form of the illness.

Type 1 diabetes is what is known as a 'complextrait', which means that mutations in several geneslikely contribute to the disease. For example, it isnow known that the insulin-dependent diabetes mel-litus (IDDM1) locus on chromosome 6 may harbor atleast one susceptibility gene for Type 1 diabetes.Exactly how a mutation at this locus adds to patientrisk is not clear, although a gene maps to the regionof chromosome 6 that also has genes for antigens(the molecules that normally tell the immune systemnot to attack itself). In Type 1 diabetes, the body'simmune system mounts an immunological assaulton its own insulin and the pancreatic cells that manu-facture it. However, the mechanism of how thishappens is not yet understood.

About 10 loci in the human genome have nowbeen found that seem to confer susceptibility to Type1 diabetes. Among these are 1) a gene at the locus

IDDM2 on chromosome 11 and 2) the gene for glu-cokinase (GCK), an enzyme that is key to glucosemetabolism which helps modulate insulin secretion,on chromosome 7.

Conscientious patient care and daily insulindosages can keep patients comparatively healthy.But in order to prevent the immunoresponses thatoften cause diabetes, we will need to experimentfurther with mouse models of the disease andadvance our understanding of how genes on otherchromosomes might add to a patient's risk of dia-betes.

Important Links

Gene sequenceGenome view see gene locationsLocusLink collection of gene-related informationBLink [www.ncbi.nlm.nih.gov/sutils/blink.cgi?pid=4503951&org=1] related sequences in different organisms


WebsitesPatient information on diabetes [www.niddk.nih.gov/health/diabetes/diabetes.htm] from the National Institute of Diabetes andDigestive and Kidney Diseases, NIHJuvenile Diabetes Research Foundation International [http://www.jdf.org/] 'dedicated to finding a cure'American Diabetes Association [www.diabetes.org/default.htm] research and information


7

Glucose galactose malabsorption

Glucose Galactose Malabsorption (GGM) is a raremetabolic disorder caused by a defect in glucoseand galactose transport across the intestinal lining.GGM is characterized by severe diarrhea and dehy-dration as early as the first day of life and can resultin rapid death if lactose (milk sugar), sucrose (tablesugar), glucose, and galactose are not removedfrom the diet. Half of the 200 severe GGM casesfound worldwide result from familial intermarriage. Atleast 10% of the general population has glucoseintolerance, however, and it is possible that thesepeople may have milder forms of the disease.

GGM is an autosomal recessive disorder inwhich affected individuals inherit two defectivecopies of the SGLT1 gene, located on chromosome22. Normally within the space enclosed by the smallintestine (called the lumen), lactose is broken downinto glucose and galactose by an enzyme called lac-tase, while sucrose is broken down into glucose andfructose by an enzyme called sucrase. The proteinproduct of SGLT1 then moves the glucose and thegalactose from the lumen of the small intestine intointestinal cells. Usually the mutations carried byGGM individuals result in nonfunctional truncatedSGLT1 proteins or in the improper placement of theproteins such that they can not transport glucoseand galactose out of the intestinal lumen. The glu-cose and galactose, if left untransported, draw waterout of the body into the intestinal lumen, resulting indiarrhea.

Although no cure exists for GGM, patients cancontrol their symptoms (diarrhea) by removing lac-tose, sucrose, and glucose from their diets. Infants

showing a prenatal diagnosis of GGM will thrive on afructose-based replacement formula and will latercontinue their "normal" physical development on afructose-based solid diet. Older children and adultswith severe GGM can also manage their symptomson a fructose-based diet and may show improvedglucose tolerance and even clinical remission asthey age.

Important Links



8


WebsitesNational Digestive Diseases Information Clearinghouse [www.niddk.nih.gov/health/digest/nddic.htm] from the National Institute ofDiabetes and Digestive and Kidney Diseases, NIH


9

Pancreatic cancer

The pancreas is responsible for producing the hor-mone insulin, along with other substances. It alsoplays a key role in the digestion of protein. Therewere an estimated 27,000 new cases of pancreaticcancer in the US in 1997, with 28,100 deaths fromthe disease.

About 90% of human pancreatic carcinomasshow a loss of part of chromosome 18. In 1996, apossible tumor suppressor gene, DPC4 (Smad4),was discovered from the section that is lost in pan-creatic cancer, so may play a role in pancreaticcancer. There is a whole family of Smad proteins invertebrates, all involved in signal transduction oftransforming growth factor (TGF) related path-ways. Other tumor suppressor genes include p53and Rb, which, if mutated or absent from thegenome can contribute to cancerous growth in avariety of tissues.

DPC4 (Smad4) homologs exist in the worm(Caenorhabditis elegans), mouse and the fly(Drosophila). In Drosophila, when the gene is notpresent, there a number of developmental defects.

Likewise, homozygous Smad4 mutant mouseembryos die before embryonic day 7.5, and havereduced size because of reduced cell proliferation.Research on these model organisms should helpelucidate the role of Smad4 and related proteins inhumans.

Important Links



WebsitesCancerNet [cancernet.nci.nih.gov/] from the National Cancer Institute, NIHOncolink [oncolink.upenn.edu/] comprehensive cancer information from the University of PennsylvaniaAmerican Cancer Society [www.cancer.org] research and patient supportMEDLINEplus [www.nlm.nih.gov/medlineplus/pancreaticcancer.html] links on pancreatic cancer compiled by the National Library ofMedicine


10

Wilson's disease

Wilson's Disease is a rare autosomal recessive dis-order of copper transport, resulting in copper accu-mulation and toxicity to the liver and brain. Liverdisease is the most common symptom in children;neurological disease is most common in youngadults. The cornea of the eye can also be affected:the 'Kayser-Fleischer ring' is a deep copper-coloredring at the periphery of the cornea, and is thought torepresent copper deposits.

The gene for Wilson's disease (ATP7B) wasmapped to chromosome 13. The sequence of thegene was found to be similar to sections of the genedefective in Menkes disease, another diseasecaused by defects in copper transport. The similarsequences code for copper-binding regions, whichare part of a transmembrane pump called a P-typeATPase that is very similar to the Menkes diseaseprotein.

A homolog to the human ATP7B gene has beenmapped to mouse chromosome 8, and an authenticmodel of the human disease in rat is also available

(called the Long-Evans Cinnamon [LEC][ rat). Thesesystems will be useful for studying copper transportand liver pathophysiology, and should help in thedevelopment of a therapy for Wilson disease.

Important Links



WebsitesFact sheet [www.ninds.nih.gov/health_and_medical/disorders/wilsons_doc.htm] from the National Institute of Neurological Disordersand Stroke, NIHGeneClinics [www.geneclinics.org/profiles/wilson/] a medical genetics resource


11

Zellweger syndrome

Zellweger syndrome is a rare hereditary disorderaffecting infants, and usually results in death.Unusual problems in prenatal development, anenlarged liver, high levels of iron and copper in theblood, and vision disturbances are among the majormanifestations of Zellweger syndrome.

The PXR1 gene has been mapped to chromo-some 12; mutations in this gene cause Zellwegersyndrome. The PXR1 gene product is a receptorfound on the surface of peroxisomes - microbodiesfound in animal cells, especially liver, kidney andbrain cells. The function of peroxisomes is not fullyunderstood, although the enzymes they containcarry out a number of metabolically important reac-tions. The PXR1 receptor is vital for the import ofthese enzymes into the peroxisomes: without it func-tioning properly, the peroxisomes can not use theenzymes to carry out their important functions, suchas cellular lipid metabolism and metabolic oxida-tions.

There is a yeast homolog to human PXR1,which should allow powerful molecular genetic tech-niques to be used in the investigation of the normalrole of peroxisomes in cells, as well as the molecularevents that occur in disease states.

Important Links



WebsitesFact sheet [www.ninds.nih.gov/health_and_medical/disorders/zellwege_doc.htm] from the National Institute of NeurologicalDisorders and Stroke, NIH

Genes and Disease Ear, Nose, and Throat

1

Ear, Nose, and Throat

Within the structures of the ear, nose and throat are complex and interrelated mechanisms thatallow a person to make sound, hear, maintain balance, smell, breathe, and swallow. Traditionally,treatment of the ear otology was associated with that of the eye in medical practice. With thedevelopment of laryngology the study of the throat in the late 19th century, the connectionbetween the ear and throat became known. Thus the birth of a discipline called otolaryngology.

Many people associate otolaryngologists with the treatment of ear infections, hearing loss andsinus problems. Otolaryngology actually encompasses the treatment of many diverse conditions,including: dizziness, facial plastic and reconstructive surgery, head and neck cancer, hearing loss,problems of the larynx and sinus, difficulties swallowing, tumors of the auditory nerve, and voiceproduction.


2

When diagnosing ear, nose, and throat disorders, it is important to differentiate geneticdisorders from those due to environmental influences. This is often difficult as similar clinicalfeatures may be produced by different environmental factors or by different genes or groups ofgenes.


3

Deafness

Hearing loss is extremely common and can presentat any time from infancy to old age. About 1 in 1000infants has profound hearing impairment, with halfthought to be of genetic origin. Many deafnessgenes exist, but the most common cause of hearingloss in American and European populations is amutation in the connexin 26 (Cx26) gene. Cx26 hasa carrier rate of 3%, similar to that for cystic fibrosis,and it causes about 20% of childhood deafness.

Mutations in Cx26 cause congenital syndromicand nonsyndromic deafnessthat is, the deafnessis not accompanied by other symptoms, such asblindness. Cx26 is located on chromosome 13q11-12 and codes for a gap junction protein called con-nexin 26. Gap junctions are plasma membranechannels that allow the movement of smallmolecules and ions between adjacent cells. Gapjunctions of the inner ear may play a role in maintain-ing potassium homeostasis, which is important forinner-ear function and, thus, hearing. It has beenproposed that mutations in Cx26 may disrupt potas-sium circulation and result in deafness.

The discovery that Cx26 mutations are a causeof congenital hearing loss can help in the early diag-nosis of hearing impairment. Early identification andmanagement of deafness is important for the devel-opment of language and social skills.

Important Links



WebsitesNIDCD [http://www.nidcd.nih.gov/] National Institute on Deafness and Other Communication DisordersInfo to Go [clerccenter.gallaudet.edu/InfoToGo/index.html] from Gallaudet UniversityGeneClinics [www.geneclinics.org/profiles/dfnb1/] a medical genetics resourceMEDLINEplus [www.nlm.nih.gov/medlineplus/hearingdisordersdeafness.html] links compiled by the National Library of Medicine


4

Neurofibromatosis

Neurofibromatosis, type 2, (NF-2) is a rare inheriteddisorder characterized by the development of benigntumors on both auditory nerves (acoustic neuromas).The disease is also characterized by the develop-ment of malignant central nervous system tumors aswell.

The NF2 gene has been mapped to chromo-some 22 and is thought to be a so-called 'tumor-suppressor gene'. Like other tumor suppressorgenes (such as p53 and Rb), the normal function ofNF2 is to act as a brake on cell growth and division,ensuring that cells do not divide uncontrollably, asthey do in tumors. A mutation in NF2 impairs itsfunction, and accounts for the clinical symptomsobserved in neurofibromatosis sufferers. NF-2 is anautosomal dominant genetic trait, meaning it affectsboth genders equally and that each child of anaffected parent has a 50% chance of inheriting thegene.

We are learning more about the function of theNF2 gene through studies of families with neurofi-bromatosis type 2 and through work in model organ-

isms, particularly mice. The exact molecular functionof NF2 in the cell is still unknown, although the pro-tein is similar to the ERM family of cytoskeleton-membrane linker proteins. Further work on thebinding partners of NF2 would help to identify poten-tial specific targets for future drug therapies.

Important Links




5

Pendred syndrome

Pendred syndrome is an inherited disorder thataccounts for as much as 10% of hereditary deaf-ness. Patients usually also suffer from thyroid goiter.The recent discovery of the gene for Pendred syn-drome illuminates a disorder that has confoundedscientists for more than a century.

In December of 1997, scientists at NIH'sNational Human Genome Research Institute usedthe physical map of human chromosome 7 to helpidentify an altered gene, PDS, thought to causependred syndrome. The normal gene makes a pro-tein, called pendrin, that is found at significant levelsonly in the thyroid and is closely related to a numberof sulfate transporters. When the gene for this pro-tein is mutated, the person carrying it will exhibit thesymptoms of Pendred syndrome.

Because goiter is not always found in Pendredsyndrome patients, it is possible that a defectivependrin gene will turn out to be responsible for some

cases of deafness that had not previously beenattributed to this disorder. The discovery of pendrinshould also stimulate new angles of research intothyroid physiology and the role of altered sulfurtransport in human disease.

Important Links



WebsitesResearch News [www.nhgri.nih.gov/NEWS/Pendred/] from the National Human Genome Research Institute, NIHGeneClinics [www.geneclinics.org/profiles/pendred/] a medical genetics resource

Genes and Disease Diseases of the Eye

1

Diseases of the Eye

The function of our eyes is to allow us to see the objects in our surroundings at variable distancesand under various conditions of lights. This function is achieved by a very complex arrangement oflayers and structures found in the eye. In addition, two pockets of transparent fluid the aqueousand vitreous humors nourish eye tissues and help maintain constant eye shape.

The eye is comprised of three layers: an outer protective white coating called the sclera; amiddle layer (choroid) containing blood vessels which nourish the eye; and an inner layer (retina)which contains the nerves that bear information to the brain for processing.


2

The cornea is the clear portion found at the front of the eye and serves to bend light rays. Theiris, an extension of the choroid, is the colored portion of the eye and is made up of a spongy tissue.The pupil (black) is an opening in the iris that allows light into the eye. The lens then helps focus thelight rays onto photoreceptors, which absorb and convert the light into electrical signals that carryinformation. The optic nerve contains fibers that transmit these signals to the brain for interpretationof the objects seen.

With the recent advances in molecular genetic techniques, new genes that cause eye diseaseare rapidly being identified, such as for those diseases discussed here. In many instances, thesefindings allow researchers to develop innovative strategies for preventing or slowing the progress ofgenetic eye diseases.


3

Best disease

Best disease, also known as Vitelliform Macular Dys-trophy type 2 (VMD2), is a heritable disorder occur-ring primarily in European Caucasians. Individualswith Best disease generally show a gradual loss ofvisual acuity starting in their teenage years, althoughthe frequency with which an affected individual mayshow symptoms and the severity of those symptomsare highly variable.

Best disease is autosomal dominant; in otherwords, a mutation in only one copy of the VMD2gene located on chromosome 11 may result indevelopment of the disease. Prior to their vision loss,individuals with Best disease accumulate a mass offat-like material that resembles an egg yolk (vitellineis a word that means yolk-like) in the area of theretina responsible for central vision. Surprisingly, it isthe breakup of this mass rather than its formationthat is associated with the gradual vision loss char-acteristic of Best disease.

Little is known about the protein product of theVMD2 gene, although its function seems to berestricted to an area of the eye known as the retinal

pigment epithelium. There is speculation that theprotein encoded by VMD2 may be involved in theremoval and/or processing of photoreceptor compo-nents. Determination of the VMD2 protein functionand development of an animal model will be the nextcrucial steps toward a better understanding of Bestdisease.

Important Links



WebsitesFoundation Fighting Blindness [www.blindness.org/] searching for treatments and cures for retinal degenerative diseases


4

Glaucoma

"Glaucoma" is a term used for a group of diseasesthat can lead to damage to the eye's optic nerve andresult in blindness. The most common form of thedisease is open-angle glaucoma, which affectsabout 3 million Americans, half of whom don't knowthey have it. Glaucoma has no symptoms at first butover the years can steal its victims' sight, with sidevision being affected first.

It is estimated that nearly 100,000 individuals inthe US suffer from glaucoma due to a mutation inthe GLC1A gene, found on chromosome 1. Therehas been some speculation as to the role of thegene product in the eye. As it is found in the struc-tures of the eye involved in pressure regulation, itmay cause increased pressure in the eye byobstructing the aqueous outflow.

With early treatment, serious loss of vision andblindness can be prevented. The cloning of theGLCA1 gene is the first step toward an understand-

ing of the pathology of glaucoma at the molecularlevel and may help in the development of tests forthe early detection of the disease, as well as provid-ing a basis for research into effective therapies.

Important Links



WebsitesFact sheet [http://www.nei.nih.gov/health/glaucoma/glaucoma_facts.htm] for patients and the public from the National Eye Institute,NIHThe Glaucoma Foundation [www.glaucoma-foundation.org/info/] an international not-for-profit organizationThe Glaucoma Research Foundation [www.glaucoma.org/] a US national not-for-profit organization


5

Gyrate atrophy of the choroid and retina

People suffering from gyrate atrophy of the choroid(the thin coating of the eye) and retina face a pro-gressive loss of vision, with total blindness usuallyoccurring between the ages of 40 and 60. The dis-ease is an inborn error of metabolism.

The gene whose mutation causes gyrate atrophyis found on chromosome 10, and encodes anenzyme called ornithine ketoacid aminotransferase(OAT). Different inherited mutations in OAT causedifferences in the severity of symptoms of the dis-ease. OAT converts the amino acid ornithine fromthe urea cycle ultimately into glutamate. In gyrateatrophy, where OAT function is affected, there is anincrease in plasma levels of ornithine.

It is already known that reduction of the aminoacid arginine in the diet has a salutary effect on mostpatients. Current lines of research into the diseaseinclude: (1) investigating how variant mutations ofthe alleles (versions of the gene inherited) interact in

order to cause the differing symptoms of the diseaseand (2) work on mouse models of the disease is fur-thering our understanding, which is hoped will leadto a true cure.

Important Links



WebsitesEye News Online [www.eye-news.com/vol3_6.dir/review/16rev3_5l.htm] containing information on gyrate atrophyThe National Eye Institute [www.nei.nih.gov/] research and information


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Retinoblastoma

Retinoblastoma occurs in early childhood and affectsabout 1 child in 20,000. The tumor develops from theimmature retina - the part of the eye responsible fordetecting light and color. There are both hereditaryand non-hereditary forms of retinoblastoma. IN thehereditary form, multiple tumors are found in botheyes, while in the non-hereditary form only one eyeis effected and by only one tumor.

In the hereditary form, a gene called Rb is lostfrom chromosome 13. Since the absence of Rbseemed to be linked to retinoblastoma, it has beensuggested that the role of Rb in normal cells is tosuppress tumor formation. Rb is found in all cells ofthe body, where under normal conditions it acts as abrake on the cell division cycle by preventing certainregulatory proteins from triggering DNA replication. IfRb is missing, a cell can replicate itself over andover in an uncontrolled manner, resulting in tumorformation.

Untreated, retinoblastoma is almost uniformlyfatal, but with early diagnosis and modern methodsof treatment the survival rate is over 90%. Since the

Rb gene is found in all cell types, studying themolecular mechanism of tumor suppression by Rbwill give insight into the progression of many types ofcancer, not just retinoblastoma.

Important Links



WebsitesThe National Eye Institute, NIH [www.nei.nih.gov/] research and patient information

Genes and Disease Female-Specific Diseases

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Female-Specific Diseases

Biomedical research has demonstrated biological differences between females and males invirtually every organ and system of the body. Research has also revealed the genetic andmolecular basis of a number of gender-based differences in health and disease, some of which arerelated to genotype XX in the female and XY in the male.

These findings suggest that there are multiple differences in the basic cellular biochemistry ofmales and females that can affect an individual's health. Many of these differences do not arisefrom differences in the hormonal regime to which males and females are exposed, but are a directresult of the genetic differences between the two sexes.

Further studies on the relative roles of the sex chromosome genes is li

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Genes and Disease