Observation of nine previously reported and 10 non-reported SLC4A11 mutations among 20 Iranian CHED probands and identification of an MPDZ mutation as possible cause of CHED and FECD in one family

Abstract

Background/aimsSLC4A11 is the only known causative gene of congenital hereditary endothelial dystrophy (CHED). Mutation screenings have shown that most but not all patients with CHED harbour mutations in SLC4A11, suggesting that other CHED-causing genes may exist. We aimed to screen SLC4A11 in Iranian patients to learn the mutation spectrum of this gene among Iranians and to gain further knowledge on potential contribution of other genes to CHED aetiology.MethodsSLC4A11 was screened in 21 Iranian patients with CHED by sequencing. Previously unreported variations were checked in at least 200 controls, and segregation analysis within families and bioinformatics predictions on effects of variations were performed. Exome sequencing was done for the single patient without an SLC4A11 mutation and for her parents.ResultsNine previously reported and 10 unreported SLC4A11 mutations were observed among 20 patients; a mutation was not found in one patient. A mutation in MPDZ was identified as the only candidate cause of CHED in this patient. Her mother who carried the same mutation was diagnosed with Fuchs endothelial corneal dystrophy (FECD).ConclusionSLC4A11 mutations are the usual cause of CHED in Iranians. The 10 novel mutations observed contribute significantly to the approximately 85 mutations reported since discovery of the role of the gene in CHED pathogenesis more than 10 years ago. MPDZ mutations may be a cause of CHED and even FECD in a minority of patients. Proposed functions of MPDZ with respect to tight junctions and maintenance of the corneal endothelial barrier are in accordance with a role in corneal endothelial pathobiology.

Energy Shortage in Human and Mouse Models ofSLC4A11-Associated Corneal Endothelial Dystrophies

“…Approximately 94 SLC4A11 mutations have been identified in individuals with CHED. 4,6,9,[31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48] Although a large number of these mutations result in SLC4A11 protein misfolding and failure to mature to the plasma membrane, 5,6,[49][50][51] some mutations affect SLC4A11 transporter function without impacting membrane trafficking 17,52,53 or cause aberrant SLC4A11 pre-mRNA splicing and subsequent reduced SLC4A11 expression. 47 Collectively, these observations support the hypothesis that loss of SLC4A11 function is the primary pathogenetic mechanism in CHED rather than mutant SLC4A11 protein misfolding/mislocalization in the endoplasmic reticulum (ER).…”

Identification and in silico analysis of a spectrum of SLC4A11 variations in Indian familial and sporadic cases of congenital hereditary endothelial dystrophy

“…The patient did not have the SLC4A11 mutation. The mother carrying the MPDZ gene variation had a mild FECD phenotype, a phenomenon seen in patients with the SLC4A11 gene [ 38 ]. However, evidence for MPDZ in SLC4A11 negative cases is scarce and requires further studies.…”

Rescue of the Congenital Hereditary Endothelial Dystrophy Mouse Model by Adeno-Associated Virus–Mediated Slc4a11 Replacement

“…CHED is common among people in India, Saudi Arabia, and Iran. Several studies have shown that nearly 100% of the CHED patients had mutations in Slc4a11 [31][32][33] . There are several SLC4A11 mutations associated with CHED 8,31,34 .…”