Mutational analysis in sodium-borate cotransporter SLC4A11 in consanguineous families from Punjab, Pakistan

Abstract

Aim To identify the molecular basis of Congenital Hereditary Endothelial Dystrophy CHED caused by mutations in SLC4A11, in the consanguineous Pakistani families. Methods A total of 7 consanguineous families affected with Congenital Hereditary Endothelial Dystrophy were diagnosed and registered with the help of ophthalmologists. Blood samples were collected from affected and unaffected members of the enrolled families. Mutational analysis was carried out by DNA sequencing using both Sanger and Whole Exome Sequencing (WES). Probands of each pedigree from the 7 families were used for WES. Results were analyzed with the help of different bioinformatics tools. Results The sequencing results demonstrated three known homozygous mutations in gene SLC4A11 in probands of 7 families. These mutations p.Glu675Ala, p.Val824Met, and p.Arg158fs include 2 missense and 1 frameshift mutation. The mutations result in amino acids that were highly conserved in SLC4A11 across different species. The mutations were segregated with the disease phenotype in the families. Conclusion This study reports 3 mutations in 7 families. One of the pathogenic mutations (p.R158fs) was identified for the first time in the Pakistani population. However, two mutations (p.Glu675Ala, p.Val824Met) were previously reported in two and one Pakistani family respectively. As these mutations segregate with the disease phenotype and bioinformatics tool also liable them as pathogenic, they are deemed as probable cause of underlying disease.

A Biallelic Truncating Variant in the TPR Domain of GEMIN5 Associated with Intellectual Disability and Cerebral Atrophy

“…DNA was extracted from whole blood samples using a modified version of the LCWU standard non-organic procedure [ 26 , 27 ]. Blood samples were thawed in warm water in preparation for RBC lysis.…”

Structural insights into the conformational changes of BTR1/SLC4A11 in complex with PIP2

“…However, lack of details of the densities precludes the further determination of their identities. In our BTR1 outward-facing state model, pathogenic mutations H724A and E675Q 15,27,28 are located at the substrate binding site and near the extra densities (Supplementary Fig. 3h).…”