Biosynthetic and functional defects in newly identified SLC4A11 mutants and absence of COL8A2 mutations in Fuchs endothelial corneal dystrophy.

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Late -onset Fuchs endothelial corneal dystrophy (FECD ) shows genetic heterogeneity . Identification of SLC 4 A 11 as a candidate gene for congenital hereditary endothelial dystrophy with similar corneal endothelial defects as FECD and reduced mRNA expression of SLC 4 A 11 in the endothelium of FECD cases suggested that this gene may also be involved in pathogenesis of FECD . Mutations in SLC 4 A 11 give rise to SLC 4 A 11 protein marked by retention in the endoplasmic reticulum as a result of mis-folding . We screened 45 sporadic late-onset , 4 early -onset FECD patients and an early -onset autosomal dominant FECD family . We identified three previously unreported missense mutations : c .719 G >C (p .W 240 S ), c .1519 G >A (p .V 507 I ) and c .1304 C >T (p .T 434 I ) in unrelated individuals . These SLC 4 A 11 mutants , expressed in HEK 293 cells , had defects in either their cell surface expression or functional activity (rate of osmotically driven water flux ). SLC 4 A 11 mutations contribute to 11 % (5 /45 ) of sporadic late-onset FECD in the cohort studied . COL 8 A 2 , which causes some cases of early -onset FECD , was also screened in this cohort . No mutations were identified in COL 8 A 2 , in neither the late-onset cohort nor the early -onset family , suggesting genetic heterogeneity in this FECD family .