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Genetics of Pulmonary Diseases

Genetics of Pulmonary Diseases. 张咸宁 zhangxianning@zju.edu.cn Tel： 13105819271; 88208367 Office: C303, Teaching Building 2015/04. Learning Objectives. l. 掌握肺气肿、哮喘、囊性纤维化等肺部疾病的相关遗传学知识。 2. 了解肺部疾病的遗传学研究现状。. Required Reading. Thompson &Thompson Genetics in Medicine, 7 th Ed （双语版， 2009 ）

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Genetics of Pulmonary Diseases

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  1. Genetics of Pulmonary Diseases 张咸宁 zhangxianning@zju.edu.cn Tel：13105819271; 88208367 Office: C303, Teaching Building 2015/04

  2. Learning Objectives l.掌握肺气肿、哮喘、囊性纤维化等肺部疾病的相关遗传学知识。 2.了解肺部疾病的遗传学研究现状。

  3. Required Reading Thompson &Thompson Genetics in Medicine, 7th Ed （双语版，2009） ● pp273-274； ● pp280-284。

  4. Runge MS, et al. Principles of molecular medicine. 2nd ed. Humana Press, 2006

  5. COPD • Chronic obstructive lung disease (COPD or emphysema肺气肿)is the4th leading cause of morbidity and mortality in theUnited States and is expected to rank 3rd as the causeof death worldwide by 2020. Vestbo J, et al. Am J Respir Crit Care Med 2013;187(4):347-65.

  6. Pulmonary Emphysema----α1-antitrypsin (AAT) deficiency • AAT deficiency is a proven genetic determinant of COPD. • In white populations, AAT deficiency affects ~1/5 000, and 2% are carriers. • AAT deficiency is an important AR condition associated with a substantial risk of COPD and cirrhosis of the liver.

  7. α1-antitrypsin (AAT) deficiency ● AAT belongs to a major family of protease inhibitors, the serine protease inhibitors or serpins. ●AAT’s principal role is to bind and inhibit elastase, particularly elastase released from neutrophils in the lower respiratory tract, to maintain protease/antiprotease balance. ● A dozen or so AAT alleles are associated with an increased risk of lung or liver disease, but only the Z allele (p.Glu342Lys) is relatively common.

  8. ATTgene: 14q32.13, 5 exons, 12.2 kb.ATTpr.:a 52-kDa glycoproteincomposed of 394 AAsand 12% carbohydratecontent. B: Bgl II; S: Sst; M: Mae III; A: Ava II

  9. α1-antitrypsin (AAT) gene • The AAT alleles are grouped into 4 classes: (i) normal, (ii) deficiency, (iii) null alleles, and (iv) dysfunctional alleles. • The typical normal allele is Pi*M; the most important deficiency alleles are Pi*Z, Pi*P, and Pi*S. • About 2%-4% of the population in Central and Northern Europe are MZ heterozygotes.

  10. The most frequent deficiency allele, Pi*Z, causes plasma concentrations of AAT of about 12%-15% of normal in the homozygous genotypePi*ZZ and 64% in the heterozygote (Pi*MZ). MS heterozygotes have 86% of the MM homozygote activity. The molecular genetic diagnosis is facilitated by the presence of variant restriction enzyme sites.

  11. The AAT gene is expressed in liver cells (hepatocytes)

  12. Both sickle cell disease and AAT deficiency associated with homozygosity for the Z allele are examples of inherited conformational diseases（构象疾病）. (The liver disease associated with the Z allele is thought to result from a novel property of the mutant protein—its tendency to aggregate, trapping it within the RER of hepatocytes. The molecular basis of the Z protein aggregation is a consequence of structural changes in the Z protein that predispose to the formation of long bead-like necklaces of mutant AAT polymers.)

  13. AAT Deficiency as an Ecogenetic Disease • Ecogenetics: The study of genetically determined differences in susceptibility to the action of physical, chemical and infectious agents in the environment. • Ecogenetic disorder: A disorder resulting from the interaction of a genetic predisposition to a specific disease with an environmental factor.

  14. Asthma • Asthma is a complex disease affecting over 300 million individuals in the developed world. 90% of all asthma cases, including asthma in adults, have their origin in childhood.

  15. Asthma : Basic pathobiology

  16. Exon = expressed sequence Exome（外显子组）: The collection of protein-coding regions (exons) in the genome.

  17. Mucoviscidosis: 粘液粘稠病 Polymorphisms in other genes modify the severity of pulmonary manifestation. Examples of modifying genes are TGF1 on 19q13.1 and IFRD1

  18. 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 1900 different mutations（http://www.genet.sickkids.on.ca/app）have been found worldwide in the CFTR among patients with cystic fibrosis (CF).

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