Asian Research Thesis Index

Abstract

The research work, presented in the dissertation, described characterization of eighteen families segregating various types of isolated and syndromic skin disorders. Four of the families showed clinical features of congenital ichthyosis, two junctional epidermolysis bullosa, four hair loss disorders, two isolated spoon shaped nail/koilonychias, two hypohidrotic ectodermal dysplasia (HED), one each with ectodermal dysplasia syndactyly syndrome, hypotrichosis, palmoplantar keratoderma and nail dysplasia, hypotrichosis-anonychia-post-axial polydactyly and hair-nailteeth-skin type ectodermal dysplasia. Clinical investigation of affected members in each family was carried out with the help of medical officers/dermatologists working at local government and private hospitals. Based on the clinical spectrum developed in each family, genetic characterization was performed by typing microsatellite and SNP markers. Further, disease causing variants were searched using exome and /or Sanger sequencing. In one case effect of the mutation was validated through exon trapping. Bioinformatics tools and protein modeling studies were performed where possible. In addition to associating skin phenotypes with three novel genes, seven novels and six known mutations were identified in families segregating other skin-related clinical features. Two novel missense mutations p.Asp34Glu and p.Gly439Ser were identified in the PNPLA1 and ST14 gene, respectively causing two different types of ichthyosis. In a related phenotype called junctional epidermolysis bullosa, observed in two other families, sequence analysis revealed a novel non-sense (p.Ser3298*) and a previously reported missense variant (p.Arg1303Gln) in the LAMA3 and COL17A1 gene, respectively. Four other novel variants including p.Gln230*, p.Trp485*, p.Gln417* and p.Leu81Pro were detected in the genes LIPH, CDH3, EDAR and PVRL4, respectively. The mutations in the LIPH and CDH3 produced hair loss disorders, in the EDAR results in hypohidrotic ectodermal dysplasia (HED) and in the PVRL4 results in ectodermal dysplasia cutaneous syndactyly syndrome. Previously reported sequence variants including a missense (p.Pro498Leu) in the DSP gene causing hypotrichosis-palmoplantar keratoderma-nail dysplasia, a missense (p.Asp63Val) in the LPAR6 gene causing hypotrichosis, a missense (p.Gly382Ser) in the EDAR gene causing HED, and a non-sense (p.Arg110*) in the LIPH and a missense (p.Met1Ileu) in the RSPO4 producing hypotrichosis-nail dysplasia (anonychia) -post-axial polydactyly were identified as well.

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