Understanding The Genetics of Diamond Blackfan Anemia PDF
Preview Understanding The Genetics of Diamond Blackfan Anemia
Understanding The Genetics of Diamond Blackfan Anemia Jason Farrar, MD [email protected] aracrhcihldilrdernesn.so.rogrg aarrppeeddiiaattrriiccss..oorrgg uuaammss..eedduu About Me • Assistant Professor of Pediatrics at University of Arkansas for Medical Sciences & Arkansas Children’s Hospital • I’ve studied DBA genetics most of my professional life but I’m a hematologist not a geneticist • This is a new talk • I’ve never given a professional presentation in flip-flops before today aracrhcihldilrdernesn.so.rogrg aarrppeeddiiaattrriiccss..oorrgg uuaammss..eedduu What Do We Mean By “Genetic Basis”? • Behavior or trait is passed to progeny by way of genes – cell to cell (somatic or germline changes) – Parent to child (germline) • How do we know DBA has a genetic basis? aracrhcihldilrdernesn.so.rogrg aarrppeeddiiaattrriiccss..oorrgg uuaammss..eedduu Families with DBA Aase & Smith, J Ped, 1969: 74(3), 471-4 Willig et al, Blood, 1999: 94(12), 4294-4306 aracrhcihldilrdernesn.so.rogrg aarrppeeddiiaattrriiccss..oorrgg uuaammss..eedduu An Autosomal Dominant Pedigree I II III IV aracrhcihldilrdernesn.so.rogrg aarrppeeddiiaattrriiccss..oorrgg uuaammss..eedduu Inheritance Patterns • Autosomal Dominant: One A a gene alteration is 50% chance sufficient to cause AA Aa A of offspring disease (*most DBA) with the A AA Aa • Autosomal Recessive: disorder Both copies (maternal and paternal) of gene must be A a altered to manifest 25% chance • X-linked Recessive: AA Aa A of offspring Disorder generally only with the seen in males (*DBA with a Aa aa a couple of specific gene disorder alterations) aracrhcihldilrdernesn.so.rogrg aarrppeeddiiaattrriiccss..oorrgg uuaammss..eedduu The Human Genome Our ‘Recipe Book’ • 46 total volumes (chromosomes) – Occur in 23 pairs • 2 copies of each volume ( 2 number 1’s etc.) • Last set = X,Y • A total of 22,000 recipes (genes) • Each recipe (gene) is composed of words (nucleotide triplets) • Each nucleotide (A,G,C,T) is a letter aracrhcihldilrdernesn.so.rogrg aarrppeeddiiaattrriiccss..oorrgg uuaammss..eedduu The Human Genome • Organized as 23 chromosome pairs – Think of a 46 volume 78899 collection of 22,000 7 6 5 6 8 recipes. 5 4 4 3 • Cytogenetic 3 2 2 (karyotypes) studies 1 1 – tell you if the right number of volumes are there, and if – from the outside – the books are intact aracrhcihldilrdernesn.so.rogrg aarrppeeddiiaattrriiccss..oorrgg uuaammss..eedduu Karyotypes Are Almost Always Normal in DBA (but this is how DBA gene discovery got started) 800 – 1000 bands ~ 25 genes / band 1 band ~ 3 – 5 Mb An initial clue in DBA Normal Karyotype Gustavsson et al, J Med Genet, 1997:34, 779-82 aracrhcihldilrdernesn.so.rogrg aarrppeeddiiaattrriiccss..oorrgg uuaammss..eedduu What Are the DBA Genes? Small Ribosomal Large Ribosomal Non-Ribosomal Subunit Subunit Protein RPS7 RPL5 GATA1* RPS10 RPL11 TSR2* RPS15A RPL15 * X-linked recessive RPS17 RPL18 Possible RPS19 RPL26 RPS20 RPS15 RPL27 RPS24 RPL19 RPL31 RPS26 RPL35 RPS27 RPL35A RPS28 RPS29 aracrhcihldilrdernesn.so.rogrg aarrppeeddiiaattrriiccss..oorrgg uuaammss..eedduu
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