3 Atypical Mendelian Inheritance-第2部分-上传课件.pptVIP

* * * * * * * * * * * * * * Atypical Mendelian Inheritance-2 Department of Medical Genetics Yaping Liu (刘雅萍) ypliu@ibms.pumc.edu.cn Key Topics Pseudoautosomal inheritance Pseudodomiant inheritance X-linked dominant inheritance with male lethality Mosaicism Genetic anticipation Uniparental disomy Imprinting disorders Digenic inheritance Triallelic inheritance Mitochondrial inheritance Modifier genes p1 p2 ? p1 p2 汗液氯离子 129mmol/L； 131mmol/L 肺功能 正常 阻塞性通气功能障碍 CFTR基因突变 p.G970D纯合 p.G970D纯合 p.G970D/+ p.G970D/+ Modifier Gene 修 饰 基 因 p1 p2 Modifier Genes Phenotype genotype correlation Pleiotropy Penetrance Expressivity Multiple modifier oligogenic small quantitative effects Modifier Genes in Mendelian Disorders The Example of Cystic Fibrosis （CF） 主要参考文献：Garry R. Cutting Ann N Y Acad Sci: 2010 December; 1214:57-69 Clinical Features of Classic Nonclassic CF CF CFTR Protein Function CF is an autosomal recessive genetic disorder caused by mutations in the CFTR gene. The normal CFTR protein product is a chloride channel protein found in membranes of cells that line passageways of the lungs, liver, pancreas, intestines, reproductive tract, and skin CFTR controls chloride ion movement in and out of the cell. CFTR Protein Function CFTR mutation spectrum CF is caused by mutations in the CFTR gene which encodes a protein expressed in the apical membrane of exocrine epithelial cells. Over 1,800 mutations in CFTR F508del accounts for ~70% of CF alleles in Caucasian ~15–20 less common mutations accounts for 15% of CF alleles in Caucasians Allelic variation in CFTR accounts for only a portion of phenotypic variability Six classes of CFTR mutations Class I: Defective Synthesis Class II: Defective Protein Processing and Trafficking Class III: Defective Regulation or Gating Class IV: Defective Chloride Conductance Class V: Reduced Synthesis or Trafficking Class VI: Decreased Stability John P. Clancy1 and Manu Jain. Personalized Medicine in Cystic Fibrosis Dawning of a New Er