The Solute Carrier Family 26 Member 9 Is a Modifier of the Rapidly Progressing Cystic Fibrosis Associated with F508del CFTR Mutations

Abstract

AbstractCystic fibrosis (CF) is an autosomal recessive disease caused by mutations to the CF transmembrane conductance regulator (CFTR). Symptoms and severity of the disease vary shown that modifier genes influence disease severity and clinical course. We previously reported epithelial sodium channel (ENaC) genes as modifiers of disease severity in long-term non-progressors sharing deltaF508 homozygous forCFTRgenotype. Here we describe the opposite, modifier genes that may be associated with rapidly progressing CF (RPCF) in a cohort of patients with the shared deltaF508 homozygous genotype. We have identified three rare missenseSLC26A9variants in four individuals (out of six) deemed to have RPCF: c.229G>A; p.G77S (present in two patients), c.1885C>T; p.P629S and c.2546G>A; p.R849Q. By analyzing publicly available single cell sequencing dataset from LungMAP, we revealed that bothSLC26A9andCFTRmRNA are highly enriched in Alveolar type 2 (AT2) cells, with a few (greater than 1%) in respiratory airway secretory (RAS) cells and ionocytes. Structural modeling suggests deleterious effects of these mutations as they are in critical protein domains which might affect the ion transportation capability of SLC26A9. The enrichment of rare and potentially deleteriousSLC26A9mutations in patients with RPCF suggestsSLC26A9is a modifier gene associated with RPCF.