Genetics of Pulmonary Diseases Tel ; Office: A709, Research Building 2011/03 Learning Objectives l. 2. Required Reading Thompson &Thompson Genetics in Medicine, 7 th Ed 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---- 1-AT deficiency In white populations, 1-AT deficiency affects about 1 in 5000 persons, and 2% are carriers. 1-AT deficiency is an important AR condition associated with a substantial risk of COPD and cirrhosis of the liver. 1-AT deficiency 1-AT belongs to a major family of protease inhibitors, the serine protease inhibitors or serpins. 1-ATs 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 1-AT alleles are associated with an increased risk of lung or liver disease, but only the Z allele (Glu342Lys) is relatively common. 1-AT gene: 14q32.1, 5 exons, 10.2 kb. 1-AT pr.: a 52-kDa glycoprotein composed of 394 AAs and 12% carbohydrate content. 1-AT gene The 1-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 1-AT of about 1215% 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 1-AT gene is expressed in liver cells (hepatocytes). Both sickle cell disease and 1-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 proteinits 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 1-AT polymers.) 1-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).