Blood Group Genetics. Zakład Genetyki Medycznej Department of Medical Genetics Medical University of Warsaw - PDF

Blood Group Genetics Zakład Genetyki Medycznej 2013 Department of Medical Genetics Medical University of Warsaw Classical genetics Classical genetics laws: Mendel's First Law Law of Segregation Mendel's

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Blood Group Genetics Zakład Genetyki Medycznej 2013 Department of Medical Genetics Medical University of Warsaw Classical genetics Classical genetics laws: Mendel's First Law Law of Segregation Mendel's SecondLaw Law of Independent Assortment Co-dominance phenotypic expression of gene s alleles is simultaneous and independent Epistasis phenomenon in which one gene influences the phenotypic expression of another gene, while not being its allele Blood Group Systems Blood Group antigenic determinants on the surface of erythrocytes distinguished by the immune system in individuals without a particular antigen (alloantibodies) 285 antigens 33 group systems Group system consists of one or more antigens controlled at a single gene locus, or by two or more very closely linked homologous genes Collection consist of serologically, biochemically, or genetically related antigens, which do not fit the criteria required for system status(200 series) 901 Series (or public ) contains antigens with an incidence of greater than 90% and which cannot be included in a system or collectioni 700 Series (or private ) contains antigens with an incidence of less than 1% and which cannot be included in a system or collection Red blood cells group systems Nr Nazwa Symbol Gen Chromosom Nr Nazwa Symbol Gen Chromosom 001 ABO ABO ABO 9q H H FUT1 19q13.33 GYPA, GYPB, 002 MNS MNS GYPE 4q Kx XK XK Xp P1PK P1PK A4GALT 22q Gerbich GE GYPC 2q Rh RH RHD, RHCE 1p Cromer CROM CD55 1q Lutheran LU LU 19q Knops KN CR1 1q Kell KEL KEL 7q Indian IN CD44 11p Lewis LE FUT3 19p Ok OK BSG 19p Duffy FY DARC 1q Raph RAPH CD151 11p Kidd JK SLC14A1 18q John Milton Hagen JMH SEMA7A 15q Diego DI SLC4A1 17q I I GCNT2 6p Yt YT ACHE 7q Globoside GLOB B3GALT3 3q Xg XG XG, MIC2 Xp Gill GIL AQP3 9p Scianna SC ERMAP 1p Rh-associated glycoprotein RHAG RHAG 6p21-qter 014 Dombrock DO ART4 12p FORS FORS GBGT1 9q Colton CO AQP1 7p JR JR ABCG2 4q Landsteiner-Wiener LW ICAM4 19p LAN LAN ABCB6 2q Chido/Rodgers CH/RG C4A, C4B 6p21.3 T/Tn (antygeny Th, Tk, Tr, Tx) C1GALT1, C1GALT1C1 7p14-p13 CAD Sid (Sda) As of 2013 International Society of Blood Transfusion Nomenclature Antigens system specificity ABO AB Phenotype Allele MNS:1,-2, 8 system ABO*012 system allele MNS M C + ABO 0 Genotype ABO*101/103 allele 1 allele 2 ABO AA ABO group system ABO Group System Basic blood types A, B, AB, O Antigens are oligosaccharides modified by gene specific transferases Present in most cells, and in secretors in secretions and body fluids Antigens appear around 6 week of embryonic life, but their full expression occurs from 6 to 18 months after birth ABO Group System Antigen specificity conditioning: Antigen A = N-acetylgalactosamine Antigen B = D-galactose Antigen H = L-fucose ABO Group System Gene ABO 9q34.1-q exons ( bp, in total 18 kpz), longest 6 and 7 coding region: 1065 bp = 353 AA, proteins: transferase A, transferase B Alleles: A -110 alleles (9 subgroups), allele 101 is taken as reference B -46 alleles (6 subgroups) 0-62 alleles (most frequent del within exon 6) ABO Group System Transferase A vs Transferase B:: 7 SNP-6 (1) and 7 (6) exon, while two substitutions determine substrate specificity (L266M i G268A) Allele Deletion in codon 117, frameshift, STOP codon 02 G268A = lack of activity in transferases A and B ABO Group System Amorphic allele 0 is recessive to A and B Co-dominance of alleles A and B H Group System No. of antigens 1 (antigen H) Nature of antigen Carrier molecule Genes oligosaccharide glycoprotein, glycolipid FUT1 (H) α-1,2-fucosyltransferase FUT2 (Se) α-1,2-fucosyltransferase (Sec1 pseudogene located 5' of FUT2 within a 30 kb region; homologous to FUT1 and FUT2) H Group System α-1,2-fucosyltransferase Fuc (α1 2) Gal (β1) h H D-galactose N-acetylgalactosamine L-fucose N-acetylgalactosamine D-galactose H Group System 19q13.3 FUT1 and FUT2 70% homology, 35 kbp distance, LD FUT1 H (h) RBC Erythoid tissues, vascular endothelium and primary sensory neurons of PNS fucosyltransferase1 FUT2 Se (se) Exocrine secretors Epithelia, saliva fucosyltransferase2 8 exons (365 AA) 2 exons (343 AA) Allele se Trp143Ter Frequent genotypes H Group System Secretors Nonsecretors H antigen on RBC present present H antigen in saliva present absent Ig anti-h absent absent Genotype H/H or H/h Se/Se or Se/se H/H or H/h se/se H Group System Bombay blood group (h/h blood group or O h or ABH null ) 0 blood type of AB0 system in individuals with ABO gene functional alleles Classical Bombay phenotype FUT1 Tyr316Ter (hh) India 1: Taiwan 1:8 000 Caucasians numerous FUT1 non-sens mutations Europe 1: H Group System Apparent group 0. Despite the existence of A and B group genes, the blood in contact with calibration sera is not agglutinating, but other than usually found in the plasma of blood group 0 anti-a and anti-b, in Bombay phenotype there are also anti-h. Rare genotypes H Group System Bombay para-bombay H antigen on RBC absent absent H antigen in saliva absent present Ig anti-h present present Genotype h/h se/se h/h Se/Se or Se/se Rh Group System Rh Group System Membrane proteins (12-transmembrane domains), 35 aa difference between antigen D and C/c or E/e RhD 30 epitopes Epitopes Rh C/c (S103P) and RhE/e (P226A) located in 2 and 4 loop, respectively; the rest not relevant Protein function: Maintenance of RBC membrane integrity NH4+ transport Rh Group System 1p36-p34, 97% homology 10 exons, ok. 75 kbp (416 AA) Rhesus box: 9 kbp, flanking RHD, high homology Rhd (dd, Rh-): RHD deletion (Caucasian population) RHDψpseudogene (African population) D/d: del RHD(~ 15% of population) C/c:four nonsynonymous SNPs, while (S103P) determines specificity, 109 bp difference in intron 2 E/e: SNP (676G C) A226P. Rh antigens are inherited as haplotypes consisting of 3 alleles Rh Group System Rh and RHAG Group Systems Rh null phenotype Rh deficiency syndrome Type amorph, regular, mod Missense mutations, splicing sites, deletion within exon RhAG proteins in RBC membrane are necessary for proper location of Rh system antigens Glikoproteina związana z Rh wykazuje 35% homologięw sekwencji aminokwasów z białkami układu Rh 6p12.3, 10 exons No polymorphisms It is not Rh antigen (separate RHAG group system) Increased osmosensitivity, shortened RBC life hemolytic anemia Spherocytes, stomatocytes Transfuzje obecność przeciwciał Rh Group System Rare Rh phenotypes D antigen 30 epitopes Weak D: all epitopes are present, but in smaller amount 1% of Caucasian population, a change of one aa causes problems with D integration into the membrane. Transfusiology: no anti-d; as a donor Rh+, as a recipient Rh Partial D: lack of some epitopes, but normal expression of present ones RHD and RHCE hybryde, difficult indentification, risk of hemolytic disease after blood transfusion Lewis Group System No. of antigens 4 Nature of antigen Carrier molecule Genes Chr. 19 oligosaccharide glycoprotein, glycolipid FUT3 α-1,3-1,4-fucosyltransferase FUT6 (FUT2 (Se) α-1,2-fucosyltransferase) Notes lack of expression in erythroid tissues, antigens adsorbed on RBC FUT3 (Le/ ) FUT3 (le/le) FUT2 (Se/ ) Le (a-b+) Le(a-b-) del FUT2 (se/se) Le (a+b-) Le(a-b-) FUT2 (385A T) Le (a+b+) Le(a-b-)* FUT3 encodes transferase attaching fructose to N-acetylgalactosamine with glycosidic bond in configuration 1,4 (Le a, Le b ) or 1,3 (Le x, Le y ) Expression: exocrine epithelial cells, mostly of endodermal origin, digestive track (pancreas, colon). Variable level of Le antigens depends on age, physiological and pathological state. Kell and XK Group Systems KEL Kell and XK Group Systems 7q33, 19 exons, 21kbp high polymorphism KEL 732 aa, 5 glycosylation sites, one transmembrane domain Most frequent antigens of Kell system: k T193M K* *lack of glycosylation aa191 Kp a R281W Kp b Js b L597P Js a Kell and XK Group Systems McLeod syndrome (XR) Kel protein is linked by a single disulfide bond to a RBC integral membrane proteinxk (Xp21.1) Features: Onset between years of age Neuropathy, cardiomyopathy, myopathy, hemolytic anemia, dementia, epileptic seizures Acanthocytes (abnormal erythrocytes) MNS MNS 4q28.2-q13.1, 97% homology GYPA: 7 exons, 60 kbp, MNS1(M) and MNS2(N) Ser1Leu, Gly5Gln GYPB: 5 exons, 58 kbp MNS3 (S) and MNS4(s) Met29Thr Duffy Duffy FY, 1q22-q23, exon 155 bp, exon 1038 bp Fy (a+), Fy (b+) 2 main alleles FYAiFYB(G125A) encode antigens Fy a and Fy b (Gly42Asp) Fy(a-b-): FYB ES : -33T C FYB within GATAbox (antigen present in different tissues!); subsaharian region (and USA) around 70% of population FYAO or FYBO: nonsense mutation in exon (no antigen in different tissues); vary rare Fy x [Fy(b+ x )]: FYB WK 265C T (Arg897Cys) linked with 298G A (Ala100Thr); Cau and Afr ca.2% Diego In Poland 6 HDFN cases have been reported Kidd Hemolytic disease of the newborn (HDN) Most common in RHD and Kell (less frequent in AB0) In contrast to Ig anti-rhd, Ig anti-kell apart from hemolysis cause also suppression of erythropoiesis Modifying factors: Simultaneous incompatibility in AB0 and Rh systems Isotype of produced IgG Dose of antigen Hemolytic disease of the newborn (HDN) Immunization producing anti-d (IgM, IgG - pass through the placenta) HDFN Symptoms: -hemolytic anemia -extramedullary hematopoiesis -multiorgan damage -respiratory distress -hemolytic jaundice Prophylaxis: Mother (Rh-) IgG anti-d Blood group genotyping Genotyping : D, C, c, E (Rh) and K (Kell) Advantages: HDFN prevention Limiting prenatal anti-d profilaxis only to RhDwomen pregnant with RhD+ child, around 60 % Techniques: PCR, sequencing, real-time PCR Material for genotyping Invasive Chorionic villus sampling (CVS) Amniocentesis Percutaneous Umbilical Cord Blood Sampling (PUBS) Non-invasive (from mother's blood) fetal cells fetal free DNA Flaws: risk of miscarriage risk of mother's immunization risk of harming the foetus Flaws: low concentration false positive results Real-time PCR Non-invasive genotyping Prevention from false results: three PCR repeats two independent DNA extractions Used controls: positive: of DNA extraction (ALB, GAPDH, CCR5 beta-globina, DNA of corn) of fetal DNA presence (SRY, STR, indel, metrassf1a, metsox14, mettbx3 PCR negatywne Aim of testing: immunoprophylaxis vs risk estimation, costs Determining RHD zygosity Linkage analysis Amplification of polymorphic loci linked with RHD deletion qpcr quantitative PCR, real-time PCR, reference gene Rhesus box based amplification Genotyping and serologic testing of blood types 0 1 vs A 1 delg vs A 1 6 SNPs including G802A, 0 3 vs A 1 insg vs A 1 insg vs A 1 C322T 0 6 vs A 1 G542A Genotyping and serologic testing of blood types Indications: - testing the foetus - individuals after transfusions - blood donors for alloimmunized recipients - donors' screening to identify rare blood types -determining frequencies of blood groups polymorphisms in population -determining paternal heterozygosity in foetuses with the risk of HDFN - genotyping patients with autoimmune hemolytic anemia Literatura obowiązkowa Genetyka medyczna Podręcznik dla studentów medycyny Gerard Drewa, Tomasz Ferenc (red.) Wydawnictwo Elsevier Urban & Partner Rozdział 13. Grupy krwi
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