p.Ser1235Arg should no longer be considered as a cystic fibrosis mutation: results from a large collaborative study.
Among the 1700 mutations reported in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, a missense mutation, p.Ser1235Arg, is a relatively frequent finding. To clarify its clinical significance, we collected data from 104 subjects heterozygous for the mutation p.Ser1235Arg from the French CF network, addressed for various indications including classical CF, atypical phenotypes or carrier screening in subjects with or without a family history. Among them, 26 patients (5 having CF, 10 CBAVD (congenital bilateral absence of the vas deferens) and 11 with CF-like symptoms) and 14 healthy subjects were compound heterozygous for a second CFTR mutation. An exhaustive CFTR gene analysis identified a second mutation in cis of p.Ser1235Arg in all CF patients and in 81.8% CBAVD patients. Moreover, epidemiological data from >2100 individuals found a higher frequency of p.Ser1235Arg in the general population than in CF or CBAVD patients. These data, added to the fact that in silico analysis and functional assays suggest a benign nature of this substitution, give several lines of evidence against an association of p.Ser1235Arg with CF or CBAVD.
René
Céline
C
Université Montpellier1, UFR de Médecine, Montpellier, France. celine.rene@inserm.fr
Paulet
Damien
D
Girodon
Emmanuelle
E
Costa
Catherine
C
Lalau
Guy
G
Leclerc
Julie
J
Cabet-Bey
Faïza
F
Bienvenu
Thierry
T
Blayau
Martine
M
Iron
Albert
A
Mittre
Hervé
H
Feldmann
Delphine
D
Guittard
Caroline
C
Claustres
Mireille
M
Georges
Marie des
Md
D000595:Amino Acid Sequence; D001120:Arginine / Q000235:genetics; D003550:Cystic Fibrosis / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D052801:Male Urogenital Diseases; D008958:Models, Molecular; D017720:Molecular Epidemiology; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011247:Pregnancy; D011296:Prenatal Diagnosis; D012694:Serine / Q000235:genetics; D014564:Urogenital Abnormalities / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D014649:Vas Deferens / Q000002:abnormalities
C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D012694:Serine; D001120:Arginine