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The rare Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutations, c.1826A > G (H609R) and c.3067_3072delATAGTG (I1023_V1024del), are associated with severe lung disease. Despite the existence of four CFTR targeted therapies, none have been approved for individuals with these mutations because the associated molecular defects were not known. In this study we examined the consequences of these mutations on protein processing and channel function in HEK293 cells. We found that, similar to F508del, H609R and I1023_V1024del-CFTR exhibited reduced protein processing and altered channel function. Because the I1023_V1024del mutation can be linked with the mutation, I148T, we also examined the protein conferred by transfection of a plasmid bearing both mutations. Interestingly, together with I148T, there was no further reduction in channel function exhibited by I1023-V1024del. Both H609R and I1023_V1024del failed to exhibit significant correction of their functional expression with lumacaftor and ivacaftor. In contrast, the triple modulator combination found in TRIKAFTATM, i.e., tezacaftor, elexacaftor and ivacaftor rescued trafficking and function of both of these mutants. These in-vitro findings suggest that patients harbouring H609R or I1023_V1024del, alone or with I148T, may benefit clinically from treatment with TRIKAFTATM. [ABSTRACT FROM AUTHOR]

Abstract: Mutation epidemiology in each ethnic group is important for cystic fibrosis diagnosis and genetic counselling. To date, little has been reported on the prevalence of cystic fibrosis in the Ecuadorian population where the mutation distribution appears to differ from that of Europe. We present a series of four Ecuadorian patients homozygous for the H609R mutation in the CFTR gene. This is the first report of detection of this mutation in the Ecuadorian population. Taking advantage of the homozygous status of the patients, an evaluation of the most important clinical parameters is presented. From the diagnostic point of view, the information provided by our study is of relevance in designing an appropriate strategy for genetic testing of patients in Ecuador and in European countries where immigration from Ecuador is common. [Copyright &y& Elsevier]