Identification and analysis of a novel mutation in PEPD gene in two Kashmiri siblings with prolidase enzyme deficiency

Prolidase deficiency (PD) is a rare inborn disorder of collagen metabolism characterized by chronic recurrent cutaneous ulceration. We report a novel 3 bp insertion in the 12th exon of the PEPD gene in two Kashmiri siblings with prolidase deficiency phenotype. This mutation results in addition of an extra alanine residue at the amino-acid position number 304 of prolidase peptide. The structural analysis showed that this Ala insertion is located at the helix (a.a. 300–320), which contains several important hydrogen bonds between residues essential for structural folding for the enzyme activity. In silico analysis suggests that this insertion mutation might distort or bend the helical feature to affect the hydrogen-bond network between residues of neighboring secondary structures and deform the metal-binding geometry of the enzyme. Although approximately 70 PEPD gene mutations and polymorphisms have been reported in various ethnic groups, we however report, for the first time, the identification of insertion mutation in human the PEPD gene.

► Examined Female siblings with chronic recurrent ulceration of lower extremity.
► Previously, TLC of their Urine showed increase in diimminopeptides, indicator of PD.
► All exons of PEPD gene including splice junction were amplified and sequenced.
► Novel homozygous Ala. insertion in 12th exon, 304th amino acid of prolidase peptide.
► In-silico shows, it may distort hydrogen bonding & metal binding geometry of enzyme.