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孟德尔遗传方式疾病

孟德尔遗传方式疾病. 张咸宁 zhangxianning@zju.edu.cn Tel：13105819271; 88208367 Office: C303, Teaching Building 2014/09. Major Patterns of Monogenic Inheritance. Patterns of autosomal dominant inheritance (AD) 常染色体显性 Patterns of autosomal recessive inheritance (AR) 常染色体隐性

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孟德尔遗传方式疾病

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  1. 孟德尔遗传方式疾病 张咸宁 zhangxianning@zju.edu.cn Tel：13105819271; 88208367 Office: C303, Teaching Building 2014/09

  2. Major Patterns of Monogenic Inheritance • Patterns of autosomal dominant inheritance (AD)常染色体显性 • Patterns of autosomal recessive inheritance (AR)常染色体隐性 • Patterns of X-linked recessive inheritance (XD) X-连锁显性 • Patterns of X-linked dominant inheritance (XR) X-连锁隐性 • Patterns of Y-linked inheritanceY-连锁

  3. Symbols Commonly Used in Pedigree Charts

  4. Proband（先证者）: III-5 Pedigree drawing software：Progeny, etc.

  5. AD

  6. AD

  7. AD

  8. AD

  9. Marfan综合征

  10. 强直性肌营养不良

  11. AR

  12. AR

  13. AR

  14. AR

  15. Wilson disease: Cu toxicity, AR Wilson SAK. Brain, 1912; 34:295-507

  16. CFTR Gene • 1st gene identified by positional cloning • Identified by the research group led by Dr. Lap-Chee Tsui (徐立之) at Toronto, Canada - (1989)  Identification of the cystic fibrosis gene: chromosome walking and jumping.  Science 245: 1059-1065. - (1989)  Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA.  Science 245: 1066-1073. - (1989)  Identification of the cystic fibrosis gene: genetic analysis.  Science 245: 1073-1080.

  17. XR

  18. XR

  19. XR

  20. XR

  21. DMD:Xp21.2, 79 exons, 2.4 mb

  22. DMD: Gower’s maneuver

  23. XD

  24. XD

  25. 抗维生素D佝偻病

  26. Y-linked

  27. Special features of mitochondrial genetics mtDNA is maternally inherited. Paternal inheritance of mtDNA disease has been documented in only 1 instance. Schwartz M, Vissing J. NEJM, 2002;347:576–580

  28. Mitochondrial diseases

  29. Leber hereditary optical neuropathy, LHON（Leber视神经萎缩） 患者多在18～20岁发病，男性较多见，个体细胞中突变mtDNA超过96％时发病，少于80％时男性患者症状不明显。 临床表现为双侧视神经严重萎缩引起的急性或亚急性双侧中央视力丧失，可伴有神经、心血管、骨骼肌等系统异常，如头痛、癫痫及心律失常等。

  30. Unusual Features of AD • Reduced penetrance • Variable expressivity • High frequency of new mutations

  31. Factors affecting pedigree patterns • Onset age • Pleiotropy: multiple effects of a single gene (one gene, more than one effect ) • Genetic heterogeneity • Expressivity and penetrance • Coefficient of relationship and consanguineous marriage • Sex-limited phenotypes and sex-influenced phenotypes • genomic imprinting • Anticipation • X inactivation, …

  32. Pleiotropy（多效性） • multiple effects of a single gene (one gene, more than one effect ) • E.g.: Marfan syndrome (FBN1gene)

  33. Genetic Heterogeneity（遗传异质性） The phenomenon that a disorder can be caused by different allelic or non-allelic mutations. • Locus heterogeneity • Allelic heterogeneity • Phenotypic (Clinical) heterogeneity

  34. Genetic Heterogeneity • Allelic heterogeneity:In a population, there may be a number of different mutant alleles at a single locus. In an individual, the same or similar phenotypes may be caused by different mutant alleles rather than by identical alleles at the locus. • E.g.: nearly 1400 different mutations have been found worldwide in the CFTR among patients with cystic fibrosis (CF).

  35. Genetic Heterogeneity • Locus heterogeneity:The production of identical phenotypes by mutations at two or more different loci. • Eg: Osteogenesis Imperfecta (OI) or Brittle bone disease: Cs 7 & 17.

  36. Genetic Heterogeneity • Phenotypic (Clinical) heterogeneity: The term describing the occurrence of clinically different phenotypes from mutations in the same gene. • Eg: RET gene mutation caused Hirschsprung disease or multiple endocrine neoplasia type 2A and 2Bor both.

  37. Genomic imprinting（基因组印迹） • The phenomenon of a gene or region of a chromosome showing different expression depending on the parent of origin.

  38. Anticipation（遗传早现） • The tendency for some AD diseases to manifest at an earlier age and/or to increase in severity with each succeeding generation.

  39. Trinucleotide CAG repeat sizes in Huntington disease • Normal ≤26 • Mutable 27-35 • Reduced penetrance 36-39 • Fully penetrance ≥40

  40. 49,XXXXY

  41. X inactivation (X染色体失活。lyonization) • Inactivation of genes on one X chromosome in somatic cells of female mammals, occurring early in embryonic life, at about the time of implantation.

  42. Mechanisms of Epigenetic Inheritance • Epigenetic:The term that refers to any factor • that can affect gene function without change in • the genotype. • DNA methylation • Genomic imprinting (parent-of-origin silencing) • Histone Modifications • Regulatory non-coding RNAs

  43. Homoplasmy & Heteroplasmy • Homoplasmy（纯质性）: The presence of only one type of mtDNA in the mitochondria of a single individual. • Heteroplasmy（杂质性） : The presence of more than one type of mtDNA in the mitochondria of a single individual.

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