Single nucleotide substitution mutations and polymorphisms in ECM1 gene in lipoid proteinosis in siblings of a Pakistani family

A number of mutations in extracellular matrix protein 1 (ECM1) that is a glycoprotein and expressed in skin and other tissues are reported to cause a rare, autosomal recessive disorder called lipoid proteinosis (LP). The peculiar manifestation of LP is hoarseness of voice caused by laryngeal infiltration in infancy. Skin and mucous membrane changes clinically become apparent, and the disease typically follows a slowly progressive, yet often benign, course. About 300 cases of LP have been reported, but occurrence in siblings is rare. In this study, two siblings (18 and 24-year-old) of a Pakistani family were reported to have LP. This study presents two brothers with scaly itchy lesions on whole body, hoarse voice and macroglossia. Their deceased father had similar clinical manifestations but mother, younger brother and sister were unaffected. Blood from affected and clinically unaffected family members were collected with informed consent. The ECM1 gene containing 10 exons were amplified and sequenced. Both patients showed non-pathogenic missense and silent mutations in exon 6 and 8. In exon 6, a nucleotide C was substituted to T (C→T) at codon 2, in patient 1. This nonpathogenic missense mutation causes appearance of amino acid cysteine instead of arginine that is part of normal ECM1 protein. In patient 2, polymorphism of nucleotide C to T (C/T) was observed observed in exion 6 that may lead to the appearance of cysteine and/or arginine in the resulting gene product. In exon 8, a nucleotide G was substituted to A (G→A) at codon 53, in patient 1. This substitution leads to a silent mutation as serine is coded by both forms of codon. In patient 2, polymorphism of nucleotide G to A (G/A) was observed in exion 8 that do not cause any change in the coded amino acid. These findings represent a set of missense and silent mutations supporting an unusual function of ECM1 protein, broadening the spectrum of disease-linked mutations in rare cases of LP.Key words: Lipoid proteinosis, extracellular matrix protein 1 (ECM1), missense, silent mutation, single nucleotide polymorphism, exons 6 and 8, genodermatosis