Gene mapping and molecular analysis of some inherited skin disorders in consanguineous Pakistani families

Abstract

In recent years, an enormous progress has been made in human genetics which has resulted in the identification of genes and gene variants associated with inherited single-gene disorders (i.e. Mendelian traits) in man. Techniques have been developed for the identification, functional analysis and manipulation of normal and mutant genes. Many of these achievements are very important in medicine and they have led to an improved diagnosis as well as understanding of the basic mechanisms behind different traits. Efficient identification of novel genes and gene variants behind single gene traits benefit from consanguineous marriages and large family sizes. For these reasons, Pakistan is a suitable country for the study of Mendelian disorders. The aim of this thesis has been to identify genes and allele variants involved in the pathogenesis of some inherited disorders of the ectoderm and its appendages (skin, nails, teeth, sweat glands and hair). Generalized anhidrosis (GA) is a congenital or acquired disease characterized by heat intolerance and loss of sweating. The condition is most often recognized in systemic diseases such as ectodermal dysplasia, diabetes mellitus or polyneuropathies. Isolated congenital generalized anhidrosis (CGA) is a chronic and very rare condition with a stationary clinical picture over time. Two large consanguineous families with isolated congenital generalized anhidrosis (CGA) were investigated. Skin biopsies from affected individuals revealed altered eccrine sweat gland morphology with hypoplastic excretory ducts and disorganized structure of secretory cells. Thermoregulatory test at 45°C disclosed inability to down regulate body temperature in affected individuals when compared to controls. In family A the CGA locus was mapped to chromosomal region 12p12.1-p11.2 and a maximum two point LOD score (Zmax) of 3.42 was obtained at marker locus D12S68 (Ө=0.00). The candidate gene region was restricted to 5.8 Mb using a set of highly polymorphic markers. The flanking markers spans 23 genes and expressed sequence tags. In family B the CGA locus was mapped to chromosomal region 13q32.1 and a maximum two point LOD score (Zmax) of 5.04 was obtained at marker locus D13S1280 (Ө=0.00). The candidate gene region spans 1.5 Mb of DNA and five genes.