Investigation of Autosomal and X-linked Recessive Disorders of Nails and Skin

Abstract

Skin is the largest organ of the body in surface area and weight. It consists of three layers that are epidermis, dermis and subcutaneous layer. Each layer performs proper functions. It is an organ of protection, regulation and sensation. Hair, tooth, nails and sweat glands are considered as the appendages of the skin. Mutation in any of the gene involved in the formation or development of these appendages results in the abnormalities called ectodermal dysplasias. Ichthyosis is a heterogeneous family of genetic skin disorders characterized by dry scaly skin due to abnormal differentiation of terminal keratinocytes that lead to hyperkeratosis. The severity of symptoms can vary enormo llsly, from the mildest lip to life-threatening conditions. Nail is a tough sheath covering the dorsal side of terminal phalanges. Pathogenic varations in the genes involved in nail forma tion or development can lead to congenital nail disorders. Congenital and hereditary nai l disorders include a number of conditions in which nail abnormalities are present at birth or develop during infancy. Like other inherited disorders, ichthyosis and hereditary nail disorders are common where consanguineous marriages are mostly practiced. Hence, the frequency of these disorders increases with the increase in successive intermarriages in a generation. Due to the traditional, social and etlmic customs consanguineous marriages are large ly practiced in Pakistani population therefore, such disorders are very common in them. In the present study, three Pakistani families (A, B, C) with hereditary disorders were clinically and genetically evaluated. Families (A, B) segregate hereditary ichthyosis while family C inherits hereditary nail disorder. Linkage analysis using homozygosity mapping teclmique was carried out in families (A C) to find out the genes responsible for the respective hereditary disorders. Family A was linked to the TGMl gene located on chromosome 14ql1.2 but sequencing analysis did not show pathogenic variations. Family B was first screened for STS gene deletion but results showed that the gene was present in intact form suggesting the presence of other mutations. Hence sequencing analysis of all the exons was performed but no any mutati on was found . Family C was excluded from all the known gene loci of nail disorders.