Molecular Genetics of Some Common Mendelian Disorders

8/10/2019 Molecular Genetics of Some Common Mendelian Disorders

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MOLECULAR GENETICS

BY : E. SURYADI

Faculty of Medicine GMU


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Kinds of molecular genetic of

human diseaseHemoglobinopathiesFamilial hypercholesterolemia

Duchenne muscular dystrophy Huntingtons disease Cystic fibrosisFragile X syndrome

Disorders of the urea cycleCollagen and its disorders :

-Osteogenesis imperfecta (OI)-Ehlers-Danlos syndrome (EDS)


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The structure of hemoglobin A is tetramer

(2 alfa and 2 beta chains) Autosomal disorders at a molecular DNAlevel

The globin gene clusters on chromosome 16include two alfa globin genes and onchromosome 11 one beta globin gene

Various mutations in the beta globin genecause structural alteration in haemoglobin( e. g. :Hb A, Hb S, Hb C)

Haemoglobinopathies


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The DNA and protein abnormalities incodon 6 , which lead to sickle hemoglobin

and hemoglobin C

Codon 5 Codon 6 Codon 7

HbA (DNA)am.acid

CCT Pro

GAGGlu

GAG. Glu.

HbS (DNA)am.acid

CCT Pro

GTG Val

GAG. Glu.

HbC (DNA)am. Acid

CCT Pro

A AGLys

GAG. Glu.


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The point mutation that producehaemoblobin S and causes sickle cell

anemiaDNA triplet 6.CTPy. CAPyRNA codon 6 GAG .GUG..

glu -----> valinGAG AAG glu -- lysine

Change of B chain of Hb from glutamine tovalin causes change erythrocyte form fromdisc to sickle form hemolytic anemia


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THALASSAEMIA

DUE TO A REDUCED RATE OF PRODUCTION0F ONE OR MORE GLOBIN CHAINS

Imbalance in their production

Alfa globin chains may be absent or reducedcalled alfa thallasaemia (normal: 4 genes alfaglobin)

Beta globin chains may be absent or reducedcalled beta thallasaemia.

Mutation in the first intron of beta globingene.


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Five mutations that have been describedin the beginning of the first intron of the

beta globin geneExon 1 Intron 1 Phenotype

Normal .GCCAG .GTTGGTAT.. BIVS.pos1 .GCCAG . A TTGGTAT.. BoIVS.pos1 .GCCAG . TTTGGTAT.. BoIVS.pos5 .GCCAG .GTTG TTAT.. B+IVS.pos5 .GCCAG .GTTG CTAT.. B+IVS.pos6 .GCCAG .GTTGGCTA.. B+

B = normal; Bo=absent; B+=reduceNotes: the intron always begins with a GT (the splice donor) and

ends with an AG (the splice acceptor)


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Familial hypercholesterolemia

An autosomal dominant disease affecting 1 in500 individuals5% of myocardial infarction patients underthe age of 60

Characterized by elevated serum cholesterol300-600 mg/dl and low density lipoprotein(LDL) cholesterol greater than 200 mg/dlClinical signs : xanthomas, xanthelasma,atherosclerotic cardiovascular diseaseHomozygous affected have very high bloodcholesterol levels (600-1,200 mg/dl)


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Deficiency of LDL receptor

LDL receptor gene is 45 kb in length has 18exons, has been mapped to chromosome 19.

The gene encodes a 5,3 kb mRNAThe ligand binding domain is encoded by 5exons =292 aaEGF precursor homology : 8 exons =400 aaO-linked sugars : 1 exon =58 aaThe membrane spanning :16 exons =22 aa

The cytoplasmic tail : 17 exons = 50 aa


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Four various mutation in the LDL

receptor gene (functional classes)1. a failure to synthesize the receptor (13

mutation have been defined)

2. a failure to transport newly synthesizedLDL receptor from ER to the GC3. a failure or deficient in binding LDL4. the LDL receptor fails to be localized in

coated pits and result in defectiveinternalization of bound LDL or receptormislocation


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Duchenne muscular dystrophy(DMD)

First described in 1961 X linked pattern of inheritance

A milder form of X linked musculardystrophy identified by Becker in 1955(BMD)The site of the break point : Xp21 bandThe gene product dystrophinThe gene spans 2-4 million base pairsof DNA and contain 79 exons


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DMD cont The 14 kilobase mRNA transcriptencodes dystrophinDystrophin is a cytoskeletal membraneprotein and that is expressed in skeletal,cardiac, and smooth musclePatients with DMD have little or nodemonstrable dystrophin proteinPatients with BMD have reduced amountof dystrophin or produce dystrophin ofabnormal size60-70% of male DMD & BMD havedeletion in dystrophin gene.

Male >female


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Huntingtons disease (HD)

An autosomal dominant conditionWith onset of involuntary movement,dementia, personality disorderCommonly occur between the ages 35-55Life expectancy averages 15 years from onset

of symptomsLocalized the gene on p arm of chromosome 4


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Huntingtons

HD has now been identified as anexpansion of a CAG trinucleotide repeat

Normal gene have between 9 and 34repeat

97,5%have fewer than 28 repeats

HD have repeats of over 55 trinucleotidewith age at onset under 30 years,although some early onset cases haveshown 35 and 50 repeats.


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Fragile X syndromeFirst described in 1969

Around 1 in 2000 individuals with manymore gene carriers

As an X linked trait

Male and female can be affected

Chromosomal analysis : a fragile site nearthe end of the long arm of X chr. at Xq27


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Fragile..

Gene has been identified and namedFMR-!Causing : involves amplification of aCGG trinucleotide repeat within this

gene.Repeat number in normal gene variesfrom 6-50PREMUTATION: CGG repeats rangingbetween 50-200 repeatsFULL MUTATION: CGG repeat more200- several thousand repeat


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CYSTIC FIBROSIS

Autosomal recessive disorderIn northern Europeans about 1 in 20

of the population is a carrier A disease incidence of 1 in 2000 liveborn infants

Localized the gene on chromosome7q31


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Cystic Fibrosis Continue

Affecting exocrine gland function, whichresults in chronic lung disease andmalabsorption

Change in the cystic fibrosis trans-membrane conductance regular gene( CFTR )The mRNA transcript is 6,5 kb in sizeand encodes a poly peptide of 1480amino acid that functions as a chloridechannel.


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More cases occur a 3 base pair

deletion in exon 10 of gene -- the

loss of phenylalanine residue at

position 508.

This mutation is called F 508


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Clinical phenotypes

Mental retardation (varying degree)Macro-orchidism in maleTypical faces with prominent foreheadLarge jaw and large ears

Joint laxity in some casesFrequent behavioral problems

Di d f h l


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Disorder of the urea cycle,Ornithine Transcarbamylase

Deficiency An autosomal dominant, sex limited

trait or X-linked inheritance, the shortarm of the X chromosome.Onset before 2 years old or infant

Becomes symptomatic after beginningprotein feedingMental and physical retardation


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OTC Deficiency

CLINICAL FINDING :

vomitingaltered temperature regulationwith profuse sweatingabnormal muscle tone

seizures coma and death elevation of blood ammonia


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Collagen and its disorder

At least 12 different type of collagen inhuman bodyThe collagen genes are distributedthroughout the human genome andare represented on several differentchromosome .These genes are large and contain asmany as 50 exonTwo inherited disorder :

osteogenesis imperfecta (OI) and

Ehlers- Danlos Syndrome (EDS)


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Type 1 Osteogenesis Imperfecta

Is the most commonIt is inherited in an autosomal dominant

Affected individuals : frequent fractures,

have a blue color to their sclera,conductive deafnessInactivation of one allele of the alfa 1gene

Only half of the normal amount of alfa 1protein produced - fragility of bonesExcess of alfa 2 protein chain---degraded


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Type II OsteogenesisImperfecta

Death occur in first few weeks or monthsof lifeCongenital fracturecollagen deficiencylacking the protein scaffoldingMutant alfa 1 gene-> abnormal collagenNew mutation AD or rarely AR


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Ehlers-Danlos Syndrome (EDS)

Type I Gravis :autosomal dominant

hyperextensible skin, hypermobile jointsType II Mitis :similar type I but milder

Type III Familial hypermobility :marked hypermobility of joint, autosomaldominant


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Type IV arterial:

thin translucent skin, marketbruising arterial and intestinalrupture, abnormal type III

collagen, ADOne allele of the alfa 1 (III) genehas been inactivated 50%

reduction of collagen type IIIType V X-linked:Similar type II, X-linked recessive


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Type VI Ocular:ocular fragility , soft, velvety skin,autosomal recessive

A deficiency of the enzyme lysylhydroxylaseWithout that hydroxylationstabilization and cross linking of thetriple helix are reduced and collagenfibers lack strength


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Trinucleotide repeat expansions

A new unstable mutationThree major genetic disorder:- fragile X syndrome,- myotonic dystrophy and

- Huntingtons disease And also been found in:- X linked spinobulbar neuropathy,- dominantly inherited spinocerebral ataxia

type 1The number of repeats of the trinucleotidesequence is variable, larger expansioncausing more severe disease


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ConclusionSome kinds of causes in the molecular genetic

of human disease are:1 - mutation of point in exon2 - mutation of point in intron3 - mutation on one or more gene which

regulate the variance of protein function4 - mutation of gene an enzyme5 - mutation on one gene which it involve in

the protein structural forming6- trinucleotide repeat expansions

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Molecular Genetics of Some Common Mendelian Disorders