Clinical and Molecular Characterization of Hereditary Skin Disorders in Consanguineous Families

Abstract

The skin makes an effective barri er between orgal1l sm and their surrounding environment, preventing the entry of pathogens, ward off chemical and physical assaults and keep the water-so lutes concentration in balance tlu'ough osmoregulation. Inherited ichthyosis and palmoplantar keratoderma are group of genetic disorders, characterized by dry skin, scaling and hyperkeratosis of the skin surface. It can be in isolated conditions limi ted to th e skin or appear secondarily with invo lvement of other cutaneous or systemic abnormaliti es. The molecular basis of these manifestations has been clearly understood by identification of mutations in genes involved in skin barrier formation. The study presented in the dissertation investigated clinical and molecular characterization of tlu'ee consanguineous Pakistani families (A, B, C), segregating different types of autosomal recessive congenital skin disorders. Family A presented diffuse palmoplantar keratoderma, family B showed lamellar ichthyosis and family C having ichthyosis vul garis phenotypes. Genotyping using microsatellite markers and haplotype analysis were used to establi sh linkage in these famili es. Sanger sequencing of ABCA J 2 and FLG was performed by dideoxy chain termination method in fami ly B, C. Affected members of fami ly A were found heterozygous for different combination of parental alleles thus, excluding this family for linkage to known genes/loci. Family B was found linked to ABCA12 gene on chromosome 2q35 whereas, Family C showed linkage to FLG gene on chromosome lq21.3. Sanger sequencing was performed for anal ysis of linked genes both for family B, C. In family B, selected exons (32 and 49) of ABCAl2 gene were sequenced. Analysis of results fai led to show any pathogenic variant, suggesting the invol vement of another exon or regul atory sequences. In family C, all three exons of the FLG gene were sequenced which revealed no sequence variant, suggesting that mutation might be present 111 regulatory sequences of the gene or another unknown gene in the same region