Transcript
  • Sisteme genetice

  • Sistemul ABOIstoricAustriacul Karl Landsteiner este considerat descoperitorul sistemului AB0, el primind n 1930 Premiul Nobel pentru aceasta. Totui, cehul Jan Jansk a descris i el acelai sistem n 1907, se pare, printr-o activitate independent de cea a lui Landsteiner. Grupa AB (IV) a fost descris tot n 1907 de ctre Decastrello i Sturli.Landsteiner i Alexander S. Wiener au descoperit i cellat sistem important de antigene, Rhesus (Rh), n 1937 (rezultate publicate n 1940)

  • Sistemul ABOSistemul AB0 se bazeaz pe existena a dou aglutinogene, notate A i B, i a dou aglutinine specifice: (anti A) i respectiv (anti B). Landsteiner a observat o regul a excluziunii reciproce, concretizat n faptul c indivizii care prezint pe eritrocite un aglutinogen nu au niciodat n plasm aglutinina omoloag. Un individ poate dispune de unul, ambele sau de nici unul din aglutinogene. ntotdeauna exist aglutinine corespunztoare aglutinogenului care lipsete, iar cnd sunt prezente att A ct i B, nu vor exista aglutinine. Astfel, exist 4 grupe principale n sistemul AB0:

  • Genetica sistemuluiLocusul alelelor menionate este situat pe cromozomul 9, braul lung, banda 3, subbanda 4 (9q34). Primele eritroblaste care prezint pe membran aceste antigene apar n luna a III-a de via intrauterin.

  • Genetica sistemului1. Un substrat mucopolizaharidic de baz este modificat, sub aciunea unei gene H, prin adugarea unei molecule de L-Fucoz, rezultnd substana H, sau antigenul H, comun pentru A i B. Este important de menionat faptul c substratul mucopolizaharidic are structur comun cu cea a unui antigen specific pneumococului. De fapt gena H codific o glicoziltransferaz, neaprat necesar pentru a sinteza att A ct i B.2. Dac n genotip exist gena A, atunci aceasta determin i ea sinteza unei glicoziltransferaze, care va determina ataarea la substana H a unui rest de N-acetil-galactozamin, rezultnd astfel antigenul A.3. Dac n genotip exist gena B, ea determin sinteza unei glicoziltransferaze care ataeaz la substana H un rest de D-Galactoz, rezultnd antigenul B.4. Dac genotipul cuprinde att gena A ct i gena B, relaia dintre ele este de codominan, fenotipul rezultant prezentnd ambele aglutinogene, n cantiti aproximativ egale, adic grupa sanguin AB.

  • Genetica sistemului

  • ABO system

  • Aglutininele sistemului AB0

    Sunt anticorpi (gamaglobuline, imunoglobuline) cu structur i origine obinuite, din clasele IgM i IgG. Cea mai mare parte sunt IgM, netraversnd bariera placentar. Mai sunt numite i hemaglutinine sau izohemaglutinine.Titrul lor este aproape nul la natere, devenind detectabili la vrsta de aproximativ 6 luni. Cresc apoi n ritm constant pn la 8-10 ani, cnd ajung la titrul ce se va menine pe tot parcursul vieii adulte. Scad la btrnee, dar nu dispar.Este nc incert calea prin care un organism care nu a luat niciodat contact cu antigenele de grup AB0 ajunge s sintetizeze aceti anticorpi.

  • Frecvena alelelor i fenotipurilor AB0

    Alela cea mai frecvent la nivelul ntregii populaii umane este IA, urmat de i i de IB. Se consider c IA este cea mai veche, i provenind din aceasta printr-o deleie. Deoarece IB este a treia ca frecven, se poate spune c a aprut ultima, probabil tot din IA.La romni, frecvena fenotipurilor este:Grupa 0 34%Grupa A41%Grupa B19%Grupa AB 6%n populaia global, frecvenele sunt:[4]Grupa 0 46%Grupa A40%Grupa B10%Grupa AB 4%

  • Frecvena alelelor i fenotipurilor AB0n populaia global, frecvenele sunt:Grupa 0 46%Grupa A40%Grupa B10%Grupa AB 4%

    Subgrupe AB0S-a constatat o lips de omogenitate mai ales la grupa A n pivina afinitii pentru aglutininele specifice . S-au descris astfel mai multe subgrupe A: A1, A2, A3, A5,... Am, Aq, Ad, Ax. Subgrupa A1 este grupa A clasic.Existena acestor subgrupe se datoreaz unor alele diferite IA. Cu ct indicele subgrupei este mai mare, cu att capacitatea de sintez a antigenului A este mai mic, rmnnd i o cantitate de antigen H neconvertit n A. Rezult deci fenotipuri intermediare ntre A i 0, cu hematii de grup A ce prezint i antigen H, specific grupei 0. Subgrupele cele mai frecvente sunt A2 i A3.

  • Sistemul Rh

    Sistemul Rh (Rhesus sau CDE) clasific sngele uman dup prezena sau absena unor proteine specifice pe suprafaa hematiilor. Determinarea statutului Rh ine cont de cea mai frecvent dintre acestea: factorul D, sau antigenul D.Indivizii ale cror hematii prezint antigen D pe membran sunt considerai Rh+ (pozitiv), ceilali Rh- (negativ). Spre deosebire de sistemul AB0, n sistemul Rh absena antigenului nu presupune existena anticorpilor specifici; indivizii Rh- nu au n mod normal n ser anticorpi anti D.Statutul Rh se asociaz obligatoriu grupei din sistemul AB0, astfel c "grupa sanguin" este exprimat prin adugarea semnului + sau - la grupa AB0; de exemplu: A+, B+, 0+, 0- etc. Aceste informaii reprezint minimul necesar n practica medical pentru realizarea unei transfuzii.

  • Sistemul RhFactorul D este codificat de o gen (1p36.2-p34) D. Aceasta determin direct sinteza antigenului D, i are o alel recesiv d. Deci indivizii cu fenotip Rh+ pot avea genotip DD sau Dd, pe cnd cei Rh- doar dd. n aceeai zon a cromozomului mai exist i un locus pentru altfel de alele: C, c, E, e (locusul CE). Ordinea pe cromozom este C-E-D, i din acest motiv se tinde ctre nlocuirea prescurtrii CDE cu CED. Alelele C, c, E, e, D, d se transmit nlnuit. Astfel, pot exista 8 haplotipuri (haplotipul reprezint configuraia genelor pe un singur cromozom dintr-o pereche): Dce, DCe, DcE, DCE, dce, dCe, dcE, dCE. C, c, E i e nu se exprim dect cnd n genotip nu exist D.

  • Sistemul RhLa nivelul populaiei globale, frecvena fenotipurilor Rh este:Rh+84%Rh-16%La poporul romn, frecvenele sunt apropiate de media global, cu 86% Rh+, iar ca medie pentru populaia european se consider 85% Rh+. Exist abateri remarcabile de la medie n cazul unor populaii. Spre exemplu, la africani, asiatici i eschimoi, frecvena fenotipului Rh+ este peste 95%.

  • Sistemul RhFrecvena integrat a grupelor AB0/RhLa nivelul populaiei globale, frecvenele medii ale grupelor AB0 coroborate cu Rh sunt:A-6%A+ 34%B-2%B+9%AB-1%AB+3%0-7%0+38%

  • Compatibilitate

    Problema compatibilitii se pune atunci cnd se dorete realizarea unei transfuzii sanguine. Clasic, n sistemul AB0, exist noiunile de donator universal (cu referire la grupa 0, care nu are aglutinogene) i de primitor universal (cu referire la grupa AB, care nu are aglutinine). Ele nu sunt ns utile dect pentru transfuzii cu volum redus de snge, mai mic de 500 ml. n cazul transfuziei a peste 500 ml, se folosete exclusiv snge izogrup, adic de aceeai grup cu a primitorului. Aceasta pentru c, dei de exemplu grupa 0 nu are aglutinogene, are totui aglutinine. Acestea devin de ajuns de diluate n sngele primitorului pentru a nu da reacii sesizabile, dar la volume mari contactul lor cu aglutinogenele unui primitor de grup A, B sau AB poate determina aglutinarea intravascular a eritrocitelor.n afar de sistemul AB0, n cazul unei transfuzii este obligatoriu s se in seama i de grupa Rh+. Sngele Rh+ poate fi primit doar de indivizi Rh+, pe cnd cel Rh- se poate administra la Rh- i Rh+ fr nici o problem, deoarece n sistemul Rh nu exist anticorpi n absena factorului antigenic. Este de menionat c totui, teoretic, indivizii Rh- ar putea primi o dat n via snge Rh+, urmnd ca dup aceea s dezvolte anticorpi antiRh. Aceast variant este ns evitat cu mare atenie n practic, deoarece poate duce la erori ulterioare cu consecine grave.

  • Incompatibility for Rh system

  • Alte sisteme

    Exist numeroase alte sisteme antigenice pe elementele figurate ale sngelui. Singurele lipsite de antigene membranare specifice sunt plachetele. Numrul fenotipurilor posibile, lund n calcul toate aceste sisteme, este de ordinul miliardelor. De altfel, celulele care ajung n organism cu ocazia unei transfuzii, sunt pn la urm distruse de sistemul imunitar n cel mult 7-10 zile, fiind practic imposibil obinerea unei identiti complete ntre fenotipuile donatorului i ale primitorului.

  • Alte sistemeExist numeroase alte sisteme antigenice pe elementele figurate ale sngelui. Singurele lipsite de antigene membranare specifice sunt plachetele. Numrul fenotipurilor posibile, lund n calcul toate aceste sisteme, este de ordinul miliardelor. Celulele care ajung n organism cu ocazia unei transfuzii, sunt pn la urm distruse de sistemul imunitar n cel mult 7-10 zile, fiind practic imposibil obinerea unei identiti complete ntre fenotipuile donatorului i ale primitorului.Sistemele mai bine cunoscute sunt prezentate n tabelul urmtor:

  • Alte sisteme

  • Alte sisteme

  • Hemoglobin genesSchematic representation of the globin gene loci. The lower panel shows the alpha globin locus that resides on chromosome 16. Each of the four alpha globin genes contribute to the synthesis of the alpha globin protein. The upper panel shows the beta globin locus. The two gamma globin genes are active during fetal growth and produce hemoglobin F. The "adult" gene, beta, takes over after birth.

  • Hb A1The two chromosomes #11 have one beta globin gene each (for a total of two genes). The two chromsomes #16 have two alpha globin genes each (for a total of four genes). Hemoglobin protein has two alpha subunits and two beta subunits. Each alpha globin gene produces only about half the quantity of protein of a single beta globin gene. This keeps the production of protein subunits equal. Thalassemia occurs when a globin gene fails, and the production of globin protein subunits is thrown out of balance.

  • Hemoglobin genes

  • Tipuri de hemoglobine umane normaleIn the embryo:Gower 1 (22) Gower 2 (22) (PDB 1A9W) Hemoglobin Portland (22) In the fetus:Hemoglobin F (22) (PDB 1FDH) In adults:Hemoglobin A (22) (PDB 1BZ0) - The most common with a normal amount over 95% Hemoglobin A2 (22) - chain synthesis begins late in the third trimester and in adults, it has a normal range of 1.5-3.5% Hemoglobin F (22) - In adults Hemoglobin F is restricted to a limited population of red cells called F-cells. However, the level of Hb F can be elevated in persons with sickle-cell disease and beta-thalassemia.

    Alte tipuri de (hemo)globinMioglobina:Este identificat n muchi, ntlnindu-se la toate vertebratele, unde coloreaz muchii n rou sau cenuiu nchis.Este foarte aemntoare cu hemoglobina, ns difer de aceasta prin faptul ca nu prezint uniti tetramerice.De regul stocheaz oxigenul pentru a fi transportat mai departe.

  • HemoglobinaThe hemoglobin molecule is an assembly of four globular protein subunits. Each subunit is composed of a protein chain tightly associated with a non-protein heme group. Each protein chain arranges into a set of alpha-helix structural segments connected together in a globin fold arrangement, so called because this arrangement is the same folding motif used in other heme/globin proteins such as myoglobin.This folding pattern contains a pocket that strongly binds the heme group.

  • Structura Hb:Structura Hb:-Hb e o cromoproteina porfirica ce contine Fe si e constituita din:4 molecule de hem (cu 1 atom de Fe2+ ce leaga O2, CO2);4 catene polipeptidice (globine).-hemul reprezinta partea fiziologic activa (fixeaza si elibereaza O2,CO2)=fero-protoporfirina IX: atomul de Fe se afla n centrul inelului porfirinic;fierul heminic = Fe2+-globina e un tetramer din 4 lanturi polipeptidice, 2 cte 2 identice.Fiecare lant polipeptidic are atasata o grupare hem la ext. moleculei.Exista 6 tipuri de lanturi polipeptidice n structura globinei.

  • Gruparea HemA heme group consists of an iron (Fe) ion (charged atom) held in a heterocyclic ring, known as a porphyrin.This porphyrin ring consists of four pyrrole molecules cyclically linked together (by methene bridges) with the iron ion bound in the center.The iron ion, which is the site of oxygen binding, coordinates with the four nitrogens in the center of the ring, which all lie in one plane. The iron is bound strongly to the globular protein via the imidazole ring of the F8 histidine residue below the porphyrin ring. A sixth position can reversibly bind oxygen by a coordinate covalent bond, completing the octahedral group of six ligands. Oxygen binds in an "end-on bent" geometry where one oxygen atom binds Fe and the other protrudes at an angle. When oxygen is not bound, a very weakly bonded water molecule fills the site, forming a distorted octahedron.

  • Hemoglobina adulta A1In adult humans, the most common hemoglobin type is a tetramer (which contains 4 subunit proteins) called hemoglobin A, consisting of two and two subunits non-covalently bound, each made of 141 and 146 amino acid residues, respectively. This is denoted as 22. The subunits are structurally similar and about the same size. Each subunit has a molecular weight of about 17,000daltons, for a total molecular weight of the tetramer of about 68,000daltons (64,458 g/mol).[25] Thus, 1 g/dL = 0.01551mmol/L. Hemoglobin A is the most intensively studied of the hemoglobin molecules.

  • Hemoglobine umane patologiceVariant forms that cause disease:

    Hemoglobin H (4) - A variant form of hemoglobin, formed by a tetramer of chains, which may be present in variants of thalassemia. Hemoglobin Barts (4) - A variant form of hemoglobin, formed by a tetramer of chains, which may be present in variants of thalassemia. Hemoglobin S (2S2) - A variant form of hemoglobin found in people with sickle cell disease. There is a variation in the -chain gene, causing a change in the properties of hemoglobin, which results in sickling of red blood cells. Hemoglobin C (2C2) - Another variant due to a variation in the -chain gene. This variant causes a mild chronic hemolytic anemia. Hemoglobin E (2E2) - Another variant due to a variation in the -chain gene. This variant causes a mild chronic hemolytic anemia. Hemoglobin AS - A heterozygous form causing Sickle cell trait with one adult gene and one sickle cell disease gene Hemoglobin SC disease - Another heterozygous form with one sickle gene and another encoding Hemoglobin C.

  • Hb SThis diagram shows the part of the beta globin chain that is altered in Hb S beta gene. The arrows show the position that is cut by the restriction enzyme Mst II or Sau 1 and the length of the resulting portions.

  • Siclemia

  • Siclemia

  • Hemoglobina LeporeThe linked -- group provides the data that we need on unequal crossover. Some people afflicted with certain thalassemias (a kind of inherited blood disease) have a hemoglobin subunit that is part and part (Lepore hemoglobin) or one that is part and part (Kenya hemoglobin). The origin of these rare hemoglobin subunits can be explained by the unequal crossover models. Deletion chromosomes determine both Lepore and Kenya hemoglobins, causing their bearers to have the blood diseases. The origins of the reciprocal crossover products called anti-Lepore and anti-Kenya.

  • GENELE DE TIP ALFA-141 AA

  • ThalassemiaInheritance of hemoglobin genes from parents with thalassemia trait. As illustrated, the couple has one chance in four that a child will inherit two thalassemia genes. The child would have a severe form of thalassemia (thalassemia major or thalassemia intermedia). The severity varies, often significantly. The nature of the particular thalassemia genes greatly influences the clinical course of the disorder.

  • Anemia Cooley-beta talasemiaCraniu cu aspect de hair on end, datorita hiperplaziei maduvei osoase.

  • Alpha TalassemiaPeople of Asian ancestry often have two alpha globin genes deleted on the same chromosome #16. The parents each have the mild thalassemia that results with two functioning alpha globin genes. The offspring that inherits the double deletion from one parent and the single from the other will have Hemoglobin H disease (Scenario 1). The offspring who inherits no alpha genes from the parents dies in utero (Scenario 2; hydrops fetalis).

  • Alpha TalassemiaPeople of African ancestry usually have only one alpha globin gene deleted per chromosome. The parents each have the mild thalassemia that results with two functioning alpha globin genes. The offspring can, at most, inherit the relatively mild condition of the parents.

  • Deficitul de G6PDHGlucose-6-phosphate dehydrogenase deficiency is an X-linked recessive hereditary disease(long arm of the X chromosome, on band Xq28. The G6PD gene spans some 18.5 kilobases) characterised by abnormally low levels of glucose-6-phosphate dehydrogenase (abbreviated G6PD or G6PDH), a metabolic enzyme involved in the pentose phosphate pathway, especially important in red blood cell metabolism. G6PD deficiency is the most common human enzyme defect.Individuals with the disease may exhibit nonimmune hemolytic anemia in response to a number of causes, most commonly infection or exposure to certain medications or chemicals. G6PD deficiency is closely linked to favism, a disorder characterized by a hemolytic reaction to consumption of broad beans, with a name derived from the Italian name of the broad bean (fava). The name favism is sometimes used to refer to the enzyme deficiency as a whole, although this is misleading as not all people with G6PD deficiency will manifest a physically observable reaction to consumption of broad beans