Sequence Analysis of Candidate Genes Involved in Causing Hereditary Hypotrichosis in Consanguineous Families

Abstract

The skin acts as a barrier between the body and its environment by providing protection as well as the specific functions of lubrication and thermoregulation. Skin appendages such as nails, teeth, sweat glands, and hairs all provide similar roles such as immunological surveillance, epidermal barrier function, pigmentation, and defensive mechanism in the skin. Human hair is an utter epitome of aesthetics, with approximately 5 billion hairs functioning as a protective coating. Genetic defects in the expression of the genes involved in hair follicle development led to inherited hair loss disorders known as hypotrichosis that can be syndromic or isolated. The non-syndromic hereditary hypotrichosis is characterized by scalp hair loss and loss of eyebrows and eyelashes. The current study investigated three consanguineous Pakistani families (A-C) at clinical and genetic levels. All three families segregated the disorder hypotrichosis in an autosomal recessive manner. Affected members in these families showed various degrees of hair abnormality phenotypes from sparse to complete hair loss. Initially, a search for the causative genes and variants was carried out using microsatellite markers to establish linkage in the families. Genotyping was performed using markers linked to nine candidate genes, including HR (8p21.3), DSG4/DSC3 (18q12.1), LPAR6 (13q14.2), and LIPH (3q27.2), C3ORF52 (3q13.2), LSS (21q22.3), KRT25 (17q21.2), DSP (6p24.3) and CDH3 (16q22.1). Analysis of the PCR-amplified products revealed that none of the families showed linkage to the tested genes. DNA of an affected member in family A was then subjected to whole exome sequencing. Filtering of the exome data led to the identification of nine sequence variants, including five homozygous and four compound heterozygous. The four homozygous variants were found polymorphic. One of the homozygous variants [c.146A>T, p.(Gln49Leu)] in the canonical transcript of the RPL21 gene on chromosome 13q appeared as a causative variant but the variant was not segregated.