1. Genetics of Pulmonary Diseases
张咸宁
Tel： ;
Office: C303, Teaching Building
2016/03

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
Nussbaum RL, et al. Thompson & Thompson Genetics in Medicine, 8th ed. Elsevier，2016，pp ; pp
● Clinical Case Studies-12. Cystic fibrosis

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

7. Pulmonary Emphysema---- α1-antitrypsin (AAT) deficiency α1-抗胰蛋白酶缺乏症
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

8. α1-antitrypsin (AAT) deficiency
● AAT belongs to a major family of protease inhibitors, the serine protease inhibitors or serpins→编码基因为SERPINA1，也可写为AAT、Pi，定位于14q32.13
● AAT’s principal role is to bind and inhibit elastase弹性蛋白酶, particularly elastase released from neutrophils中性白细胞 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 Pi*Z allele (p.Glu342Lys) is relatively common

9. ATT gene: 14q32. 13, 5 exons, 12. 2 kb ATT pr
ATT gene: 14q32.13, 5 exons, 12.2 kb ATT pr.: a 52-kDa glycoprotein composed of 394 AAs and 12% carbohydrate content
B: Bgl II; S: Sst; M: Mae III; A: Ava II

10. 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

12. The most frequent deficiency allele, Pi
The most frequent deficiency allele, Pi*Z, causes plasma concentrations of AAT of about 12-15% of normal in the homozygous genotype Pi*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

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

15. 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)

16. AAT Deficiency as an Ecogenetic Disease
Ecogenetics生态遗传学: 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

19. 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

20. Asthma : Basic pathobiology

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

26. CF可能的修饰基因：TGFB1、IFRD1和IL8
Mucoviscidosis: 粘液粘稠病
CF可能的修饰基因：TGFB1、IFRD1和IL8

32. 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.: >2000 different mutations（ been found worldwide in the CFTR among patients with CF