Identification of Pathogenic DNA Sequence variants Underlying Clouston Syndrome

Abstract

Hidrotic ectodermal dysplasia type 2 also known as Clouston syndrome is a rare genetic disease of skin having both autosomal recessive and dominant pattern of inheritance. The clinical manifestation of the Clouston syndrome includes normal teeth, sweat glands, and palmoplantar keratoderma (PPK), nail dystrophy (micronychia or anonychia) and hair loss. The disease is caused due to the mutations in GJB6 gene located on chromosome 13q12 pericentromeric region encoding for Connexin 30 (Cx30) also known as Beta 6 Gap junction proteins. GJB6 express in different organ of the body such as esophagus, bone marrow, brain, and skin. Connexin proteins make up the hemichannel influence, selectivity of the gap junction. This gap junction connects cells by transmitting nutrients, ions, and signaling chemicals that coordinate cell activity. The GJB6 mutation results in a gap junction defect and is linked to Hidrotic ED. Four transmembrane segments, two extracellular loops, a cytoplasmic loop created by the two inner transmembrane segments, and the N- and C-termini, which are all in the cytoplasm, are all present in each connexin protein. Connexin 30 (Cx30), is encoded by the human GJB6 gene and has 261 amino acids. Five mutations, G11R, V37E, D50N, A88V, and N14S, have so far been identified in individuals with Clouston syndrome; they are all associated with nonsynonymous mutations. Moreover, the Clouston syndrome is also associated with mutations in the genes GJA1 (V41L) and GJB2 (R127H). This study was aimed to properly diagnose an autosomal recessive pattern of HED2 (Clouston syndrome). Illumina HiSeq 400 (Illumine San Diego, CA, USA) sequencing technology was performed for the screening of mutations in our selected family of HED2. Already reported missense mutation (c.209C>T in GJB6 gene) was identified in the proband and will further be validated by Sanger sequencing. In silico analysis shows that this variant is the likely cause of HED2. However, protein expression studies should be carried out to further explore the effect of this mutation accordance to their functional and structural role in disease pathogenicity