Molecular Genetics 8

Molecular Genetics 8 - Molecular genetics VIII Nov.6, 2008...

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Molecular genetics VIII Nov.6, 2008 Francke 8 1 11/5/08 HumBio 2A Molec.Genetics VIII 1 • Expanding Knowledge of the Metabolic and Molecular Basis of Inherited Disease –Gene-Disease relationships • How Do Defective Proteins Lead to Diseases? –Enzymes, membrane receptors, extracellular matrix proteins Molecular Genetics VIII Molecular Mechanisms of Genetic Diseases 11/5/08 HumBio 2A Molec.Genetics VIII 2 1978 1989 2001 4th 6th 8th edition 11/5/08 HumBio 2A Molec.Genetics VIII 3 OMIM Online Mendelian Inheritance in Man http://www.ncbi.nlm.nih.gov/sites/entrez?db=OMIM Catalog of human genes and genetic disorders authored and edited by Dr. Victor A. McKusick and his colleagues at Johns Hopkins and elsewhere Developed for the World Wide Web by NCBI, the National Center for Biotechnology Information.
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Molecular genetics VIII Nov.6, 2008 Francke 8 2 11/5/08 HumBio 2A Molec.Genetics VIII 4 Mutation at DNA level Disease phenotype Molecular pathology Consequences of mutation at level of mRNA Protein Cell biology Organismal biology GENE 1 DISEASE A DISEASE B DISEASE C DISEASE D Possible Mechanisms: • Different types of mutation: - Nonsense versus missense - Loss-of-function versus gain-of-function (“dominant negative”) • Mutation involves different protein domains - Substrate binding site, transmembrane or signaling domain Different diseases that are clinically defined were not previously recognized as allelic (or as being part of a larger phenotypic spectrum) Mutations in One Gene can cause Many Genetic Disorders 11/5/08 HumBio 2A Molec.Genetics VIII 6 Phenotype-genotype correlations in fibroblast growth factor receptor 3 (FGFR3) mutations Extracellular domain T r a n s m e m b r a n e Intracellular domain Distinct disorders: Achondroplasia (A) Hypochondroplasia (H) Thanarophoric dysplasia (T1,T2) Cutis gyrata (skin disease) (CA) Craniosynostosis syndrome (M) Missense mutations in different protein domains
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Molecular genetics VIII Nov.6, 2008 Francke 8 3 11/5/08 HumBio 2A Molec.Genetics VIII 7 CAUSE: G to A point mutation at nucleotide 1138 of the FGFR3 gene causes a glycine to arginine substitution at position 380 of the polypeptide chain (in 98% of cases) 5’-TAC G GG GTG-3’ Tyr Gly Val A GG Arg Achondroplasia - mutation in fibroblast growth factor receptor 3 gene EFFECT : Gly380Arg mutation results in constitutive activation of the FGF receptor CONCLUSION: FGFR3 mutations in achondroplasia are gain-of- function mutations that activate the negative growth control exerted by the FGFR3 pathway 11/5/08 HumBio 2A Molec.Genetics VIII 8 DISEASE 1 GENE A GENE B GENE C GENE D Genetic Disorders caused by Mutations in One of Many Genes Possible Mechanisms: • Genes A, B, C and D encode subunits of same heteromeric protein or protein complex • Genes A, B, C and D encode steps of the same regulatory or signal transduction pathway A clinically defined disease entity may not be homogenous but consist of slightly different sub-types 11/5/08 HumBio 2A Molec.Genetics VIII 9 Retinitis pigmentosa (RP) clinical end-stage of
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This note was uploaded on 11/08/2009 for the course HUMBIO 2A taught by Professor Boggs,c;durham,w during the Spring '08 term at Stanford.

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Molecular Genetics 8 - Molecular genetics VIII Nov.6, 2008...

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