mendelian disorders 张咸宁 [email protected] tel : 13105819271; 88208367 office: a705,...
TRANSCRIPT
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Mendelian Disorders
Tel : 13105819271; 88208367 Office: A705, Research Building
2012/09
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Genotype: The combination of alleles that an individual possesses.Phenotype: The physical characteristics of a cell or organism as defined by its genetic constitution.
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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 inheritance Y- 连锁
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Symbols Commonly Used in Pedigree ChartsSymbols Commonly Used in Pedigree Charts
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Proband (先证者) : III-5Pedigree drawing software : Progeny, etc.
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AD
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AD
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AD
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AD
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AR
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AR
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AR
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AR
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XR
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XR
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XR
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XR
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XD
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XD
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Y-linked
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Special features of mitochondrial geneticsmtDNA is maternally inherited.
Paternal inheritance of mtDNA disease has been documented in only 1 instance. Schwartz M, Vissing J. NEJM, 2002;347:576–580
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Unusual Features of AD
1. Reduced penetrance
2. Variable expressivity
3. High frequency of new mutations
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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.
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DMD (OMIM 310200): Xp21.2, 79 Exons, 2.4 mb
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DMD: Gower’s maneuver
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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, …
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Pleiotropy (多效性)• multiple effects of a single gene (one gene,
more than one effect )• Eg: Marfan syndrome (FBN1 gene)
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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
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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.
• Eg: nearly 1400 different mutations have been found worldwide in the CFTR among patients with cystic fibrosis (CF).
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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.
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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 2B or both.
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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.
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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.
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Trinucleotide CAG repeat sizes in Huntington disease
• Normal ≤26
• Mutable 27-35
• Reduced penetrance 36-39
• Fully penetrance ≥40
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49,XXXXY
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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.
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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
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An adult organism has an estimated 1014 cells.
Cells =2 organisms:nucleus-cytosol + mt.
Mitochondria are bacterial symbionts, ~ 2-3 X 109 YRA.
Mitochondrial genome ~ 1500 genes (mtDNA + nDNA).
Each cell has 100s of mitochondria and 1000s mtDNA.
Mutations in mtDNA can be inherited maternally or acquired as somatic mutations.
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Mitochondrial inheritance
due to a mutant gene carried on the mitochondrial genome
transmitted only through mothers because sperm contain very few mitochondria (maternal inheritance母系遗传 )
inheritance and expression variable because of heteroplasmy (differing proportions of normal and mutant DNA in oocytes and tissues)
Examples: Leber hereditary optic atrophy, several myopathies
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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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Many of the pathogenic mtDNA mutations are heteroplasmic. For expression of a disease it is
required that a certain threshold (阈值) level of mutant mtDNA should be exceeded.
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Mitochondrial diseases
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Mode of inheritance Some characteristic patterns in pedigree
AR ·Affected offspring usually born to unaffected parents
· Chance of affected offspring is 25% for children of carriers
· If both parents are affected, all children will exhibit trait
· Affects either sex
· Increased incidence with parental consanguinity
AD Affected individual has at least one affected parent
Children with one affected parent have 50% risk of being affected
Affects either sex
XR · Affects almost exclusively males
· Not transmitted from father to son
· If female inherits, father must have trait
XD All daughters of affected fathers exhibit the trait
All sons of an unaffected mother will not have trait
Y-linked · Females never exhibit trait
· Son always has same phenotype as father
Mt inheritance All children of an affected mother inherit the disorder
None of the children of an affected father inherit the disorder
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Acknowledge ( PPT 特别鸣谢!)
• UCLA David Geffen School of Medicine
• www.medsch.ucla.edu/ANGEL/
• Prof. Grody WW (Divisions of Medical Prof. Grody WW (Divisions of Medical Genetics and Molecular Pathology), et al.Genetics and Molecular Pathology), et al.