PMID: 20717170

Rene C, Paulet D, Girodon E, Costa C, Lalau G, Leclerc J, Cabet-Bey F, Bienvenu T, Blayau M, Iron A, Mittre H, Feldmann D, Guittard C, Claustres M, Georges M
p.Ser1235Arg should no longer be considered as a cystic fibrosis mutation: results from a large collaborative study.
Eur J Hum Genet. 2011 Jan;19(1):36-42. Epub 2010 Aug 18., [PubMed]
Sentences
No. Mutations Sentence Comment
0 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:0:10
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:0:560
status: NEW
view ABCC7 p.Ser1235Arg details
ARTICLE p.Ser1235Arg should no longer be considered as a cystic fibrosis mutation: results from a large collaborative study Ce´line Rene´*,1,2,3, Damien Paulet1,2, Emmanuelle Girodon4, Catherine Costa4, Guy Lalau5, Julie Leclerc5, Faı¨za Cabet-Bey6, Thierry Bienvenu7, Martine Blayau8, Albert Iron9, Herve´ Mittre10, Delphine Feldmann11, Caroline Guittard3, Mireille Claustres1,2,3 and Marie des Georges3 Among the 1700 mutations reported in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, a missense mutation, p.Ser1235Arg, is a relatively frequent finding. Login to comment
1 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:1:106
status: NEW
view ABCC7 p.Ser1235Arg details
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. Login to comment
3 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:3:74
status: NEW
view ABCC7 p.Ser1235Arg details
An exhaustive CFTR gene analysis identified a second mutation in cis of p.Ser1235Arg in all CF patients and in 81.8% CBAVD patients. Login to comment
4 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:4:84
status: NEW
view ABCC7 p.Ser1235Arg details
Moreover, epidemiological data from 42100 individuals found a higher frequency of p.Ser1235Arg in the general population than in CF or CBAVD patients. Login to comment
5 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:5:181
status: NEW
view ABCC7 p.Ser1235Arg details
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. Login to comment
11 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:11:281
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Gly628Arg
X
ABCC7 p.Gly628Arg 20717170:11:400
status: NEW
view ABCC7 p.Gly628Arg details
However, a clear statement on the pathogenicity of a mutation is difficult to obtain, in particular for missense mutations.2,3 Moreover, the existence of at least two mutations or sequence variations on the same allele, named complex alleles, complicates genetic counseling.4-11 p.Ser1235Arg (3837T4G or c.3705T4G), initially reported by Cuppens et al.12 with a second mutation on the same allele, p.Gly628Arg, is located in a poorly conserved region in the second nucleotide binding fold (NBF2). Login to comment
12 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:12:56
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:12:167
status: NEW
view ABCC7 p.Ser1235Arg details
Earlier reports failed to establish a clear impact of p.Ser1235Arg on the phenotype severity.13-16 The aim of this study was to determine whether we should consider p.Ser1235Arg as a possible CF-associated mutation or reclassify it as a neutral polymorphism. Login to comment
13 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:13:104
status: NEW
view ABCC7 p.Ser1235Arg details
Thus, we implemented a large collaborative study to repertory the patients or individuals bearing the p.Ser1235Arg mutation from nine French laboratories and compared their phenotype, genotype and associated CFTR haplotypes. Login to comment
15 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:15:41
status: NEW
view ABCC7 p.Ser1235Arg details
Here, we gather lines of evidence that p.Ser1235Arg should be no longer considered as a CF mutation. Login to comment
16 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:16:133
status: NEW
view ABCC7 p.Ser1235Arg details
MATERIALS AND METHODS Patients and individuals Data were collected from 104 subjects heterozygous or compound heterozygous for the p.Ser1235Arg mutation registered from the French CF network of Received 22 March 2010; revised 10 June 2010; accepted 29 June 2010; published online 18 August 2010 1Universite´ Montpellier1, UFR de Me´decine, Montpellier, France; 2INSERM U827, Laboratoire de Ge´ne´tique de Maladies Rares, Montpellier, France; 3CHU Montpellier, Hoˆpital Arnaud de Villeneuve, Laboratoire de Ge´ne´tique Mole´culaire, Montpellier, France; 4Service de Biochimie-Ge´ne´tique et Inserm U955 e´quipe 11, Groupe Henri Mondor-Albert Chenevier, APHP, Cre´teil, France; 5Poˆle de Biochimie et Biologie Mole´culaire, Centre de Biologie Pathologie, CHU de Lille, Lille, France; 6Service d`Endocrinologie Mole´culaire et Maladies rares, Centre de Biologie et Pathologie Est, CHU de Lyon, Bron, France; 7Laboratoire de Biochimie-Ge´ne´tique, Hoˆpital Cochin, APHP, Paris, France; 8Laboratoire de Ge´ne´tique Mole´culaire, CHU Pontchaillou, Rennes, France; 9Laboratoire de Ge´ne´tique Mole´culaire, Service de Ge´ne´tique Me´dicale, Groupe Hospitalier Pellegrin, CHU de Bordeaux, Bordeaux, France; 10Laboratoire de Biochimie B, CHU Georges Cle´menceau, Caen, France; 11Laboratoire de Biochimie et Biologie Mole´culaire, Hoˆpital d`Enfants Armand Trousseau, APHP, Paris, France *Correspondence: Dr C Rene´, INSERM U827, Laboratoire de Ge´ne´tique Mole´culaire et Chromosomique, CHU, Institut Universitaire de Recherche Clinique, 641 Avenue du Doyen Gaston Giraud, Montpellier Cedex 5, 34093, France. Login to comment
21 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:21:50
status: NEW
view ABCC7 p.Ser1235Arg details
Molecular epidemiological study To evaluate the p.Ser1235Arg frequency in the general population, we screened for 2114 samples: 929 anonymized dried-blood spot of neonates presenting positive or negative immunoreactive trypsinogen (IRT) at day 3 obtained from the center for neonatal screening in Montpellier, South of France, and 1185 genomic DNA from CF patient`s or relative`s partners from the cohort of the Southern France (Laboratory of Molecular Genetics of Montpellier) or from the cohort of the Northern France (Laboratory of Molecular Genetics of Lille). Login to comment
28 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:28:5
status: NEW
view ABCC7 p.Ser1235Arg details
If p.Ser1235Arg was found alone, a screening for large CFTR rearrangements was performed using a semiquantitative fluorescent multiplex PCR assay. Login to comment
31 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:31:49
status: NEW
view ABCC7 p.Ser1235Arg details
To determine the haplotype associated with the p.Ser1235Arg allele, six microsatellite markers (IVS1(CA), IVS8(CA), IVS8(TG)m, IVS8(T)n, IVS17b(TA) and IVS17b(CA)) and one biallelic marker (p.Met470Val or 1540A4G (c.1408A4G)) were investigated. Login to comment
33 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:33:143
status: NEW
view ABCC7 p.Ser1235Arg details
Spots of 3 mm diameter, punched from anonymized cards, were distributed in 96-well plates and DNA was extracted using methanol extraction.17 p.Ser1235Arg was screened using DHPLC technology and each abnormal pattern was confirmed by sequencing analysis. Login to comment
34 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:34:71
status: NEW
view ABCC7 p.Ser1235Arg details
Computer-assisted analysis To predict the potential pathogenicity of p.Ser1235Arg, we used PolyPhen and SIFT softwares. Login to comment
41 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:41:56
status: NEW
view ABCC7 p.Ser1235Arg details
To gain some insight into the potential effect of the p.Ser1235Arg mutation from a structural point of view, we used the experimental structures of MJ0796 (in complex with ATP, pdb identifier 1l2t) as template for modeling as previously described by Eudes et al.22 The MJ0796 structure was visualized with MBT SimpleViewer software (San Diego, CA, USA). Login to comment
45 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:45:6
status: NEW
view ABCC7 p.Ser1235Arg details
The p.Ser1235Arg mutation was inserted into the pcDNA3-CFTR vector by site-directed mutagenesis using QuickChange II site-directed mutagenesis kit (Agilent Technologies, Massy, France) according to the manufacturer`s instructions. Login to comment
46 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:46:140
status: NEW
view ABCC7 p.Ser1235Arg details
The human CFTR genomic region encompassing exon 19 with the flanking intronic sequences was amplified from a patient heterozygous for the p.Ser1235Arg using primers: FOR 5'-AATTCTGGAGCTCGAGCAGGCCTATA CAGAGCCCATT-3' and REV 5'-CTCTTAATTTGCTAGCCATTTTCAAG ATGGGAAATCTAAAACA-3' (which introduce NheI and XhoI sites in the PCR product). Login to comment
65 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:65:65
status: NEW
view ABCC7 p.Ser1235Arg details
RESULTS Genotype/phenotype description of individuals carrying p.Ser1235Arg Among 104 subjects from 91 unrelated families reported by the 9 French laboratories, 6 patients are affected with classical CF (Table 1a). Login to comment
68 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:68:56
status: NEW
view ABCC7 p.Ser1235Arg details
The (TG)13(T)5 allele was found in nine subjects with p.Ser1235Arg (Table 1a). Login to comment
69 ABCC7 p.Arg117His
X
ABCC7 p.Arg117His 20717170:69:126
status: NEW
view ABCC7 p.Arg117His details
ABCC7 p.Arg1070Trp
X
ABCC7 p.Arg1070Trp 20717170:69:146
status: NEW
view ABCC7 p.Arg1070Trp details
Of these, eight were compound heterozygous for p.Phe508del, and two for mutations associated with CF-related diseases,3,27 (p.Arg117His;T7) and p.Arg1070Trp (http://www.genet.sickkids.on.ca/cftr/). Login to comment
70 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:70:58
status: NEW
view ABCC7 p.Ser1235Arg details
Among 42 patients with monosymptomatic disease carrying p.Ser1235Arg (Table 1a), eight cases (19%) were compound heterozygotes, seven for a severe mutation and one for the intronic variant 406-6T4C (c.274-6T4C). Login to comment
71 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:71:71
status: NEW
view ABCC7 p.Ser1235Arg details
Of these, five harbored the (TG)13(T)5 allele associated in cis with p.Ser1235Arg. Login to comment
72 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:72:53
status: NEW
view ABCC7 p.Ser1235Arg details
In all, 34 individuals (81%) were heterozygous for p.Ser1235Arg: 5 with reduced sperm quality; 16 with sinopulmonary problems such as bronchiectasis, asthma, nasal polyposis and chronic obstructive pulmonary disease; and 13 with digestive symptoms (meconium ileus at birth, pancreatitis and liver disease). Login to comment
75 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:75:32
status: NEW
view ABCC7 p.Ser1235Arg details
Among them, five carried only p.Ser1235Arg and were considered simple heterozygote because extensive scanning did not reveal a second CF mutation.28 Three cases were compound heterozygous for another mutation. Login to comment
78 ABCC7 p.Val920Met
X
ABCC7 p.Val920Met 20717170:78:48
status: NEW
view ABCC7 p.Val920Met details
The second carried the rare missense mutation p.Val920Met and depressed values of digestive enzymes were observed at 17 weeks of pregnancy. Login to comment
79 ABCC7 p.Arg668Cys
X
ABCC7 p.Arg668Cys 20717170:79:71
status: NEW
view ABCC7 p.Arg668Cys details
ABCC7 p.Gly576Ala
X
ABCC7 p.Gly576Ala 20717170:79:58
status: NEW
view ABCC7 p.Gly576Ala details
In the last case, the fetus carried the complex allele (p.Gly576Ala; p.Arg668Cys), considered as a mild mutation involved in CBAVD or disseminated bronchiectasis phenotypes in adults.29-31 Although the fetus presented hyperechogenic fetal bowel, the parents were reassured regarding the risk of classical CF. Login to comment
81 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:81:95
status: NEW
view ABCC7 p.Ser1235Arg details
Among 37 individuals tested for cascade carrier screening, 14 were compound heterozygous for p.Ser1235Arg and another CFTR mutation (Table 1b), all being relatives of patients or carriers. Login to comment
84 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:84:110
status: NEW
view ABCC7 p.Ser1235Arg details
Notably, cases 4 and 5 were two fertile fathers carrying a class I mutation (severe) associated in trans of p.Ser1235Arg. Login to comment
85 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:85:17
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:85:125
status: NEW
view ABCC7 p.Ser1235Arg details
Frequencies of p.Ser1235Arg in the general, CF and CBAVD French populations In 2114 subjects of the general population, 32 p.Ser1235Arg alleles were detected, representing an allelic frequency of 0.76% (Table 2). Login to comment
87 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:87:212
status: NEW
view ABCC7 p.Ser1235Arg details
This allele frequency was compared with those of patients collated in a French study affected with CF (8/7420 alleles) or CBAVD (7/1626 alleles), 0.11 and 0.43%, respectively.32 By w2 statistical analysis, the p.Ser1235Arg allelic frequency is significantly higher in the general population than in CF patients (0.76 vs 0.11%, Po0.001) but not statistically different from the CBAVD group (0.76 vs 0.43%, P4 0.1). Login to comment
89 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:89:141
status: NEW
view ABCC7 p.Ser1235Arg details
Among them, five with severe disease, harbored the p.Arg785X mutation, whereas another presenting a mild phenotype had the complex allele (p.Ser1235Arg;T5). Login to comment
90 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:90:11
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:90:153
status: NEW
view ABCC7 p.Ser1235Arg details
When the p.Ser1235Arg frequencies in CF, CBAVD and the general population were compared with the frequencies of p.Phe508del (Table 2), it appears that p.Ser1235Arg is as frequent as p.Phe508del (P¼0.91) in the general population (respectively, 0.76 vs 0.82%); however, its implication in classical CF is significantly different (0.11 vs 67.2% (Po0.0001) and 2.86% (Po0.0001), respectively). Login to comment
91 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:91:2
status: NEW
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p.Ser1235Arg haplotype backgrounds Haplotypic markers and familial segregation were completed in 36 cases (Table 3). Login to comment
92 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:92:124
status: NEW
view ABCC7 p.Ser1235Arg details
The analysis of haplotypes based on four intragenic CFTR markers (IVS1(CA), IVS8(CA), M470V and IVS17b(CA)) revealed that p.Ser1235Arg is always present on the same haplotype 26-17-M-13. Login to comment
94 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:94:81
status: NEW
view ABCC7 p.Ser1235Arg details
Table 1a Genotype and phenotype of CF, CBAVD and CF-like patients carrying the p.Ser1235Arg mutation Genotype Phenotype No. Login to comment
95 ABCC7 p.Gly551Asp
X
ABCC7 p.Gly551Asp 20717170:95:256
status: NEW
view ABCC7 p.Gly551Asp details
ABCC7 p.Arg117His
X
ABCC7 p.Arg117His 20717170:95:391
status: NEW
view ABCC7 p.Arg117His details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:95:32
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:95:79
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:95:118
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:95:187
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:95:232
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:95:278
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:95:322
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:95:367
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:95:417
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:95:450
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:95:473
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:95:546
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:95:580
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:95:619
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:95:678
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:95:736
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:95:783
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:95:829
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:95:875
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:95:923
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:95:960
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:95:1004
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:95:1048
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:95:1115
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:95:1169
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Arg668Cys
X
ABCC7 p.Arg668Cys 20717170:95:1061
status: NEW
view ABCC7 p.Arg668Cys details
ABCC7 p.Arg1070Trp
X
ABCC7 p.Arg1070Trp 20717170:95:346
status: NEW
view ABCC7 p.Arg1070Trp details
ABCC7 p.Val920Met
X
ABCC7 p.Val920Met 20717170:95:1128
status: NEW
view ABCC7 p.Val920Met details
of subjects Allele 1 Allele 2 p.Ser1235Arg;p.Arg785X p.Phe508del Severe CF 2 p.Ser1235Arg;p.Arg785X NAa Severe CF 1 p.Ser1235Arg;875+1G4A (c.743+1C4A) 3629delT (c.3497delT) Severe CF 1 p.Ser1235Arg;p.Arg785X p.Gly542X Severe CF 1 p.Ser1235Arg;(TG)13(T)5 p.Gly551Asp Mild CF 1 p.Ser1235Arg;(TG)13(T)5 p.Phe508del CBAVD 6 p.Ser1235Arg;(TG)13(T)5 p.Arg1070Trp CBAVD 1 p.Ser1235Arg;(TG)13(T)5 p.Arg117His; (T)7 CBAVD 1 p.Ser1235Arg p.Phe508del CBAVD 1 p.Ser1235Arg - CBAVD 1 p.Ser1235Arg;(TG)13(T)5 p.Phe508del CUAVD 1 Suspicion CF/mild phenotype: p.Ser1235Arg - Genital symptoms 5 p.Ser1235Arg - Respiratory symptoms 16 p.Ser1235Arg;(TG)13(T)5 p.Phe508del Respiratory symptoms 2 p.Ser1235Arg 406-6T4C (c.274-6T4C) Respiratory symptoms 1 p.Ser1235Arg p.Tyr1092X Respiratory symptoms 1 p.Ser1235Arg p.Glu831X Respiratory symptoms 1 p.Ser1235Arg p.Gln493X Respiratory symptoms 1 p.Ser1235Arg p.Ile507del Respiratory symptoms 1 p.Ser1235Arg - Digestive symptoms 13 p.Ser1235Arg p.Gly542X Digestive symptoms 1 p.Ser1235Arg - Hyperechogenic fetal bowel 5 p.Ser1235Arg p.Arg668Cys; p.Arg576Ala Hyperechogenic fetal bowel 1 p.Ser1235Arg p.Val920Met Hyperechogenic fetal bowel 1 p.Ser1235Arg p.Phe508del Hyperechogenic fetal bowel 1 aNA: not available; we could only test the mother and a healthy sister (the patient was deceased and the father`s DNA was not available). Login to comment
97 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:97:51
status: NEW
view ABCC7 p.Ser1235Arg details
The p.Arg785X found in CF patients in cis of the p.Ser1235Arg occurs on a single haplotype 26-17-12-7-M-35-13. Login to comment
98 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:98:22
status: NEW
view ABCC7 p.Ser1235Arg details
The complex allele (p.Ser1235Arg;(TG)13(T)5) characteristic of CBAVD was also found to be carried on a unique haplotype (26-17-13-5-M-33-13). Login to comment
104 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:104:192
status: NEW
view ABCC7 p.Ser1235Arg details
To evaluate the functional impact of the mutation on the CFTR maturation, we performed western blot analysis on whole-cell extracts from COS-7 cells transfected with either wild-type or the p.Ser1235Arg constructs (Figure 1c). Login to comment
105 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:105:89
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:105:151
status: NEW
view ABCC7 p.Ser1235Arg details
The results show the presence of the fully glycosylated CFTR protein (band C) with the p.Ser1235Arg construct, suggesting that the maturation of the p.Ser1235Arg-CFTR protein is not altered. Login to comment
106 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:106:29
status: NEW
view ABCC7 p.Ser1235Arg details
These results suggest that p.Ser1235Arg has no functional impact on the CFTR protein. Login to comment
107 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:107:27
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:107:108
status: NEW
view ABCC7 p.Ser1235Arg details
Functional impact of the p.Ser1235Arg on the splicing According to the Splicing Sequences Finder tools,34 p.Ser1235Arg does not seem to impact the splicing of CFTR transcript. Login to comment
111 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:111:74
status: NEW
view ABCC7 p.Ser1235Arg details
As shown in Figure 2b, compared with the wild type, the presence of the p.Ser1235Arg alteration does not modify the exon 19 inclusion in the mRNA. Login to comment
112 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:112:36
status: NEW
view ABCC7 p.Ser1235Arg details
Together, these data suggest that p.Ser1235Arg has no effect on the CFTR mRNA splicing. Login to comment
113 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:113:85
status: NEW
view ABCC7 p.Ser1235Arg details
DISCUSSION Since its initial description in 1993, the clinical significance of the p.Ser1235Arg mutation remains unclear. Login to comment
114 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:114:111
status: NEW
view ABCC7 p.Ser1235Arg details
This ignorance makes genetic Table 1b Genotype and familial history of asymptomatic individuals carrying the p.Ser1235Arg mutation Case no. Login to comment
115 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:115:52
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:115:130
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:115:185
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:115:241
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:115:326
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:115:355
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:115:420
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:115:481
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:115:562
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:115:651
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:115:760
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:115:804
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:115:848
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:115:900
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:115:960
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:115:1112
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:115:1435
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:115:1547
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Arg1070Trp
X
ABCC7 p.Arg1070Trp 20717170:115:210
status: NEW
view ABCC7 p.Arg1070Trp details
Genotype Familial information Allele 1 Allele 2 1 p.Ser1235Arg; (TG)13(T)5 p.Phe508del Brother of CUAVD (no parental project) 2 p.Ser1235Arg; (TG)13(T)5 p.Phe508del Sister of CUAVD 3 p.Ser1235Arg; (TG)13(T)5 p.Arg1070Trp Sister of CBAVD 4 p.Ser1235Arg p.Gly542X Father of CF [p.Phe508del]+ [p.Gly542X] and healthy children [p.Ser1235Arg]+[(TG)11(T)5] 5 p.Ser1235Arg p.Gln493X Father of CF [p.Phe508del]+ [p.Gln493X] 6 p.Ser1235Arg p.Phe508del Uncle of CF (no parental project) 7 p.Ser1235Arg p.Phe508del Mother of CF [p.Phe508del]+ [1717-1G4A (c.1585-1G4A)] 8 p.Ser1235Arg 2347delG (c.2215delG) Mother of CF [p.Phe508del]+ [2347delG (c.2215delG)] 9 p.Ser1235Arg (TG)11(T)5 Mother of non-CF fetus with hyperechogenic fetal bowel [p.Phe508del]+[(TG)11(T)5] 10 p.Ser1235Arg p.Phe508del Sister of CBAVD 11 p.Ser1235Arg p.Phe508del Sister of CBAVD 12 p.Ser1235Arg p.Glu831X Sister of CF-like patient 13 p.Ser1235Arg p.Phe508del First-cousin of CF-like patient 14 p.Ser1235Arg p.Phe508del A 18-month-old child with prenatal diagnostic based on familial history of CF Table 2 Comparison of the allelic frequencies of p.Ser1235Arg and p.Phe508del in the general population, CF and CBAVD patients Populations Significance (P-values) General population, this study CF patients30 (n¼7420) CBAVD patients30 (n¼1626) General population vs CF General population vs CBAVD p.Phe508del 0.82% (n¼1950) 67.2% 21.6% S (Po0.05) S (Po0.05) p.Ser1235Arg 0.76% (n¼4228) 0.11% 0.43% S (Po0.05) NS (P¼0.17) Significance (P-values) p.Phe508del vs p.Ser1235Arg NS (P¼0.91) S (Po0.05) S (Po0.05) Abbreviations: N, number of unrelated tested chromosomes; S, significant difference; NS, no significant difference. Login to comment
117 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:117:50
status: NEW
view ABCC7 p.Ser1235Arg details
Table 3 CFTR haplotypes for 36 fully haplotyped p.Ser1235Arg chromosomes from CF, CBAVD patients, ruled-out CF (including CF-like symptoms and fetal echogenic bowel) and general population IVS1(CA)-IVS8(CA)- M470V-IVS17b(CA) IVS8(TG)m- IVS8(T)n Mutation in cis IVS17b(TA) n % 26-17-M-13 12-7 p.Arg785X 35 4 11.1 875+1G4A (c.743+1C4A) 36 1 2.8 None 33 1 2.8 35 5 13.8 36 9 25 37 4 11.1 38 1 2.8 40 1 2.8 44 1 2.8 7 1 2.8 13-5 33 8 22.2 counseling very difficult, especially in the context of prenatal diagnosis. Login to comment
118 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:118:74
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:118:218
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:118:282
status: NEW
view ABCC7 p.Ser1235Arg details
Through genotype/phenotype analysis of patients or individuals carrying p.Ser1235Arg, analyzed by the French network and functional analysis, we present several lines of evidence that argue against an association of p.Ser1235Arg with CF or CBAVD, although a partial penetrance of p.Ser1235Arg could not be ruled out. Login to comment
119 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:119:43
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:119:181
status: NEW
view ABCC7 p.Ser1235Arg details
First, the presence of a complex allele [p.Ser1235Arg;class I mutation] in trans of a severe mutation in five patients presenting severe disease (Table 1a) strongly suggests that p.Ser1235Arg alone cannot be considered as a CF-causing mutation. Login to comment
120 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:120:120
status: NEW
view ABCC7 p.Ser1235Arg details
Moreover, among the 11 patients referred for CAVD, 9 are compound heterozygous for a mutation and the complex allele [p.Ser1235Arg;(TG)13(T)5]. Login to comment
121 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:121:52
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:121:168
status: NEW
view ABCC7 p.Ser1235Arg details
The (TG)13(T)5 allele without the contribution of p.Ser1235Arg is sufficient to result in male infertility or in mild phenotypes.24,25,35 Among the two patients with p.Ser1235Arg as single allele, one has the mutation p.Phe508del in trans whereas no other mutation was identified in the second one. Login to comment
124 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:124:38
status: NEW
view ABCC7 p.Ser1235Arg details
Three, carrying the complex allele [p.Ser1235Arg;(TG)13(T)5] are sisters or brother of CBAVD or CUAVD patients and no respiratory or digestive symptom was reported. Login to comment
126 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:126:50
status: NEW
view ABCC7 p.Ser1235Arg details
Three adult males are compound heterozygous for p.Ser1235Arg and a severe mutation; two (cases 4 and 5) are biological fathers of CF children and transmitted the severe mutation. Login to comment
129 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:129:30
status: NEW
view ABCC7 p.Ser1235Arg details
Third, the frequency of the p.Ser1235Arg in the general population (Table 2) is higher than in CF and CBAVD patients, in accordance with previous reports,14,37 and is close to the p.Phe508del frequency (0.82%). Login to comment
130 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:130:42
status: NEW
view ABCC7 p.Ser1235Arg details
In contrast, in CF or CBAVD groups, the p.Ser1235Arg frequency is significantly lower than p.Phe508del. Login to comment
133 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:133:68
status: NEW
view ABCC7 p.Ser1235Arg details
These data are confirmed by functional studies, which showed that p.Ser1235Arg does not alter the CFTR mRNA correct splicing and the protein maturation. Login to comment
134 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:134:181
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Gly628Arg
X
ABCC7 p.Gly628Arg 20717170:134:126
status: NEW
view ABCC7 p.Gly628Arg details
These data are consistent with previous functional study of this locus in combination with alleles found at p.Met470Val and p.Gly628Arg loci.13 Wei et al.13 demonstrated that the p.Ser1235Arg CFTR protein does not cause change in the chloride transport activity. Login to comment
135 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:135:27
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:135:182
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Gly628Arg
X
ABCC7 p.Gly628Arg 20717170:135:15
status: NEW
view ABCC7 p.Gly628Arg details
Besides, the p.Gly628Arg/p.Ser1235Arg mutant protein induces a significantly lower cAMP-dependent chloride transport activity than the Figure 1 Structural and processing impact of p.Ser1235Arg mutation on the CFTR protein. Login to comment
140 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:140:65
status: NEW
view ABCC7 p.Ser1235Arg details
(c) COS-7 cell lines were transfected with either wild-type or p.Ser1235Arg CFTR constructs. Login to comment
144 ABCC7 p.Gly628Arg
X
ABCC7 p.Gly628Arg 20717170:144:2
status: NEW
view ABCC7 p.Gly628Arg details
p.Gly628Arg mutant protein, showing the major importance of genetic background, particularly for missense mutations. Login to comment
145 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:145:59
status: NEW
view ABCC7 p.Ser1235Arg details
In a second step, we determined the haplotypes linked to p.Ser1235Arg and found the same haplotype in 72.4% of cases. Only the IVS17b(TA) marker presents a large variability, although three haplotypes, deriving one from the other by addition or deletion of one dinucleotide (35, 36 or 37 repeats), represent 455% of the alleles. Login to comment
146 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:146:130
status: NEW
view ABCC7 p.Ser1235Arg details
Besides, IVS1(CA) 26, a rare allele in the European populations (4.2 vs 80% for alleles 22, 23 and 24),38 is strictly linked to p.Ser1235Arg. Login to comment
147 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:147:76
status: NEW
view ABCC7 p.Ser1235Arg details
In CBAVD patients, the haplotype 26-17-13-5-M-33-13 was found in 85.7% of p.Ser1235Arg alleles. Login to comment
148 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:148:111
status: NEW
view ABCC7 p.Ser1235Arg details
These data suggest the further change of the (TG)12(T)7 to (TG)13(T)5 on a chromosome bearing the alteration p.Ser1235Arg on a background IVS17b(TA)33. Login to comment
149 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:149:36
status: NEW
view ABCC7 p.Ser1235Arg details
ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:149:288
status: NEW
view ABCC7 p.Ser1235Arg details
Together, these data suggest that p.Ser1235Arg could derive from a founding event and haplotypes differing by a single microsatellite could depend on slippage phenomena, as already proposed.39 In conclusion, there are now strong lines of evidence against a severe deleterious effect of p.Ser1235Arg and its association with classical CF or CBAVD disease. Login to comment
151 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:151:81
status: NEW
view ABCC7 p.Ser1235Arg details
These data highlight the importance of searching for a complex allele whenever p.Ser1235Arg is identified. Login to comment
152 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:152:95
status: NEW
view ABCC7 p.Ser1235Arg details
The absence of clinical effects in healthy individuals who are compound heterozygous for the p.Ser1235Arg and another severe mutation is helpful to provide adequate genetic counseling to the families with regard to its transmission in offspring. Login to comment
169 ABCC7 p.Ile148Thr
X
ABCC7 p.Ile148Thr 20717170:169:44
status: NEW
view ABCC7 p.Ile148Thr details
8 Rohlfs EM, Zhou Z, Sugarman EA et al: The I148T CFTR allele occurs on multiple haplotypes: a complex allele is associated with cystic fibrosis. Login to comment
175 ABCC7 p.Asp1270Asn
X
ABCC7 p.Asp1270Asn 20717170:175:111
status: NEW
view ABCC7 p.Asp1270Asn details
ABCC7 p.Arg74Trp
X
ABCC7 p.Arg74Trp 20717170:175:100
status: NEW
view ABCC7 p.Arg74Trp details
ABCC7 p.Ile148Thr
X
ABCC7 p.Ile148Thr 20717170:175:91
status: NEW
view ABCC7 p.Ile148Thr details
11 Claustres M, Altieri JP, Guittard C, Templin C, Chevalier-Porst F, Des Georges M: Are p.I148T, p.R74W and p.D1270N cystic fibrosis causing mutations? Login to comment
181 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:181:113
status: NEW
view ABCC7 p.Ser1235Arg details
14 Monaghan KG, Feldman GL, Barbarotto GM, Manji S, Desai TK, Snow K: Frequency and clinical significance of the S1235R mutation in the cystic fibrosis transmembrane conductance regulator gene: results from a collaborative study. Login to comment
212 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:212:75
status: NEW
view ABCC7 p.Ser1235Arg details
(b) RT-PCR analysis of mRNA of cell expressing wild-type42 or p.Ser1235Arg(S1235R) constructs. Login to comment
213 ABCC7 p.Ser1235Arg
X
ABCC7 p.Ser1235Arg 20717170:213:64
status: NEW
view ABCC7 p.Ser1235Arg details
BeaS2B cells were transfected with either empty, wild-type or p.Ser1235Arg pSPL3 vector. Login to comment