Genetics of Pulmonary Diseases 张咸宁 Tel ： ; Office: A709, Research Building 2011/03

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 ） ● P ； ● P 。

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

COPD Chronic obstructive lung disease (COPD or emphysema) is the 4th leading cause of mortality and affects more than 16 million people in the US, a number that has increased about 40% since 1982.

Pulmonary Emphysema---- α1-AT deficiency In white populations, α1-AT deficiency affects about 1 in 5000 persons, and 2% are carriers. α1-AT deficiency is an important AR condition associated with a substantial risk of COPD and cirrhosis of the liver.

Α1-AT deficiency ● α1-AT belongs to a major family of protease inhibitors, the serine protease inhibitors or serpins. ● α1-AT’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 α1-AT alleles are associated with an increased risk of lung or liver disease, but only the Z allele (Glu342Lys) is relatively common.

α1-AT gene: 14q32.1, 5 exons, 10.2 kb. α1-AT pr.: a 52-kDa glycoprotein composed of 394 AAs and 12% carbohydrate content.

α1-AT gene The α1-AT alleles are grouped into four 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.

The most frequent deficiency allele, Pi*Z, causes plasma concentrations of α1-AT 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.

The α1-AT gene is expressed in liver cells (hepatocytes).

Both sickle cell disease and α1-AT deficiency associated with homozygosity for the Z allele are examples of inherited conformational diseases. (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 α1-AT polymers.)

Α1-AT Deficiency as an Ecogenetic Disease Ecogenetics: The interaction of genetics with the environment. Ecogenetic disorder: A disorder resulting from the interaction of a genetic predisposition to a specific disease with an environmental factor.

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.

Asthma : Basic pathobiology

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).