The CFTR 3849+10kbC->T and 2789+5G->A alleles are associated with a mild CF phenotype

Abstract

Most cystic fibrosis (CF) transmembrane receptor mutations are rare. The French CF Registry offers an opportunity to study the genotype-phenotype relationship of these rare alleles.Since 1992, 39 CF patients carrying one copy of the 3849+10kbC-.T mutation and 88 the 2789+5G-.A allele have been seen at least once in a CF care centre. Among them, 16 carrying the 3849+10kbC-.T/DF508 genotype and 34 with the 2789+5G-.A/DF508 genotype were seen in 2000. Their age at diagnosis, sweat chloride concentration, anthropometric and lung function results, and clinical aspects were compared with those homozygous for the DF508 mutation matched for sex, age and CF care centre.Major differences, most of them statistically significant, in the age at diagnosis, prevalence of pancreatic insufficiency, and other clinical signs, anthropometric and lung function measures were observed between both compound heterozygote groups and their matched DF508/DF508 groups. The mean sweat chloride concentration was also lower (close to normal values) among 3849+10kbC-.T/DF508 patients, but not among 2789+5G-.A/DF508 patients.In conclusion, both mutations studied here are associated with a milder course of cystic fibrosis disease. The 3849+10kbC-.T and 2789+5G-.A alleles are splice site mutations, leading to abnormal mRNA; however, a small amount of normally spliced transcripts can also be detected. The presence of these small amounts of normal cystic fibrosis transmembrane receptor protein in these cystic fibrosis patients is likely to be responsible for the milder severity of disease and a better life expectancy.

Assessing the residual CFTR gene expression in human nasal epithelium cells bearing CFTR splicing mutations causing cystic fibrosis

“…First, concerning the genotype-phenotype relationship, different clinical features in class V patients (age at diagnosis, current age, etc.) indicated a milder phenotype compared with CF-F508del patients in agreement with previous reports 25,26 and also with c.580-1G4T patients, although in this case statistical analysis was unavailable. Nevertheless, we have also observed some severe clinical complications in class V patients probably attributable to the aging process; we should keep in mind that the c.2657 þ 5G4A CF patients analyzed in this study are in the upper range of the life expectancy among CF patients.…”

Clinical course of cystic fibrosis on adult patients carrying "mild" mutations

“…Эта самая частая "мягкая" мутация в мире при водит к возникновению скрытого сайта инициации транскрипции, в результате чего образуется матрич ная РНК с дополнительным экзоном, кодирующим 38 аминокислот. Однако некоторая часть транскрип тов мРНК продолжает соединяться правильно, что приводит к незначительному нарушению функции белка МВТР [17]. Уникальность данной мутации состоит еще и в том, что при ее наличии большин ство мужчин с МВ не являются бесплодными, в то время как при других генетических комбинациях,…”

Massive Nasal Polyposis in a Patient with Newly Diagnosed Cystic Fibrosis

“…Going to molecular analysis, our patient bears a G542X/3849+10Kb C>T genotype. In general, 3849+10Kb C>T mutation generally has a mild clinical phenotype [6,7]. The boy did not present classical symptoms of CF.…”