Identification and in-silico analysis of SLC4A11 mutations in Indian patients with congenital hereditary endothelial dystrophy (CHED)

Abstract

Purpose : Congenital Hereditary Endothelial Dystrophy (CHED) is a rare form of corneal endothelial dystrophy. Mutations in SLC4A11, an abundant corneal solute transporter, leads to CHED. The purpose of this study is to identify SLC4A11 mutations in familial and non-familial CHED cases and in-silico analysis of the identified mutation.

Methods : The study involved 10 CHED patients (6 females and 4 males) from 2 familial and 5 sporadic cases with mean age around 11 years. Clinical diagnosis of CHED was based on the typical clinical characteristics such as a bilateral ground glass appearance of the cornea with increased corneal thickness assessed clinically and documented using high resolution optical coherence tomography. Blood samples were collected with informed consent, from each participants. Genomic DNA was isolated followed by screening for all coding exons with flanking intronic region of SLC4A11 gene using direct sequencing method. In addition, 80 controls were excluded for the presence of identified variations. Further, in-silico analysis was performed using homology-based modeling (Modeller10.1) for all identified SLC4A11 mutations.

Results : Two familial cases of CHED were identified with novel homozygous c.1514C>G (p.Ser489Trp) and compound heterozygous c.591A>C (p.Arg161Arg) + c.2456insT (p.Val805fs) mutations respectively. Among five non-familial cases, two cases were identified with novel homozygous mutations c.1487G>T (p.Ser480Ile), intronic mutation c.620-2A>G respectively and other with previously reported homozygous c.2653C>T (p.Arg869Cys) mutation. Remaining two cases could not be identified with CHED related pathogenic mutations. Homology modelling based in-silico analysis predicted change in protein stability, protein local flexibility and hydrogen bond interactions caused due to such mutations.

Conclusions : Our study shows a spectrum of SLC4A11 mutations ranging from exonic, intronic, homozygous, heterozygous and compound heterozygous in CHED patients. These mutations showed different grade of deleterious effect in in-silico analysis. In two of the non-familial cases, SLC4A11 mutation was not observed thereby indicating involvement of any other gene or genetic mechanism. Our study aided in the mutational spectrum of SLC4A11 in the pathogenesis of CHED.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.