Missense mutation in SLC4A11 in two Pakistani families affected with congenital hereditary endothelial dystrophy (CHED2).

BACKGROUND: Autosomal recessive congenital hereditary endothelial dystrophy (CHED2) is a recessively inherited eye disorder that is more common in consanguineous populations.
METHODS: Two families affected with CHED2 were recruited from the Punjab province of Pakistan to identify the underlying genetic defect. Blood samples from both the families, designated as CH01 and CH02, were collected. Genomic DNA was isolated. Initially, linkage analysis using microsatellite markers was carried out to confirm the linkage to the SLC4A11 gene, previously reported to be implicated in the pathology of the disease. Later on, sequencing was carried out to find the pathogenic mutation in the enrolled families. Identified variation was further confirmed by typing 50 ethnically matched normal control samples.
RESULTS: The results of linkage analysis indicated the putative linkage to SLAC4A11 gene, located at the CHED2 locus on chromosome 20p13-p12 in both families. Mutational analysis revealed an unidentified homozygous mutation c.2024A>C (p.E675A) in the affected members of both the families. Haplotype analysis of both the families showed that the affected members carry the same haplotype, thereby indicating a possibility of a common ancestral mutation. Use of bioinformatic tools including PolyPhen and SIFT suggested that a single amino acid change of E to A at position 675 affected the function of the protein.
CONCLUSION: This study reports a newly identified mutation (c.2024A>C) in the SLC4A11 gene segregating with the diseased haplotype in two consanguineous Pakistani families.