Heterogeneity of reproductive tract abnormalities in men with absence of the vas deferens: role of cystic fibrosis transmembrane conductance regulator gene mutations

Jarvi, Keith; McCallum, Stewart W.; Zielenski, Julian; Durie, Peter R.; Tullis, Elizabeth; Wilchanski, Michael; Margolis, M.; Asch, Murray; Гинзбург, Б. Г.; Martin, Sheelagh; Buckspan, Martin B.; Tsui, Lap‐Chee

doi:10.1016/s0015-0282(98)00247-7

Cited by 47 publications

(40 citation statements)

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“…Although it is possible that some men with CBAVD carry undetected mutations, we found that 90% of men with CBAVD carried a CFTR gene mutation on one or two alleles. This is consistent with previous reports (11)(12)(13)(14)(15)(16)(17), including our own (18)(19)(20). A wide variety of mutations were represented in the men with CBAVD; 37 of 120 (31%) alleles were from the 24 CF-causing mutations listed in the consensus document and 35 were identified at least once in the CF group.…”

Section: Table 4 Diagnosis Of Cystic Fibrosis By Disease-causing Mutsupporting

confidence: 92%

“…Most men with CF are infertile due to obstructive azoospermia, which in its severest form presents as congenital bilateral absence of the vas deferens (CBAVD) (7-10). CBAVD also occurs in 1 to 2% of infertile males who are otherwise healthy, the majority of whom carry CFTR gene mutations on one or both alleles (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Typically, the CFTR genotype in men with CBAVD includes at least one "mild" missense or splice variant.…”

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confidence: 99%

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Mutations in the Cystic Fibrosis Transmembrane Regulator Gene andIn VivoTransepithelial Potentials

Wilschanski

Dupuis²,

Ellis³

et al. 2006

Am J Respir Crit Care Med

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161

108

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Aim: To examine the relationship between cystic fibrosis transmembrane regulator gene mutations (CFTR) and in vivo transepithelial potentials. Methods: We prospectively evaluated 162 men including 31 healthy subjects, 21 obligate heterozygotes, 60 with congenital bilateral absence of the vas deferens (CBAVD) and 50 with CF by extensive CFTR genotyping, sweat chloride and nasal potential difference testing. Results: Six (10%) men with CBAVD carried no CFTR mutations, 18 (30%) carried one mutation, including the 5T variant, and 36 (60%) carried mutations on both alleles, for a significantly higher rate carrying one or more mutations than healthy controls (90% versus 19%, p Ͻ 0.001). There was an overlapping spectrum of ion channel measurements among the men with CBAVD, ranging from values in the control and obligate heterozygote range at one extreme, to values in the CF range at the other. All pancreatic-sufficient patients with CF and 34 of 36 patients with CBAVD with mutations on both alleles carried at least one mild mutation. However, the distribution of mild mutations in the two groups differed greatly. Genotyping, sweat chloride and nasal potential difference (alone or in combination) excluded CF in all CBAVD men with no mutations. CF was confirmed in 56% and 67% of CBAVD men carrying 1 and 2 CFTR mutations, respectively. Conclusion: Abnormalities of CFTR transepithelial function correlate with the number and severity of CFTR gene mutations.Keywords: CFTR mutations; congenital bilateral absence of the vas deferens; cystic fibrosis; nasal potential difference; sweat chlorideThe heterogeneity of cystic fibrosis (CF) disease is partially explained by more than 1,300 different mutations in the CFTR gene (1). Most classically diagnosed patients with CF carry severe loss-of-function mutations on both alleles and have evidence of pancreatic insufficiency (PI) (2). Those with nonclassic CF carry a mild CFTR gene mutation on at least one allele, and usually retain sufficient residual pancreatic function to confer pancreatic sufficiency (PS) (3-6). Patients with PS are usually diagnosed in adolescence or adulthood with less severe symptoms and variable but generally milder pulmonary disease. Most men with CF are infertile due to obstructive azoospermia, which in its severest form presents as congenital bilateral absence of the vas deferens (CBAVD) (7-10). CBAVD also occurs in 1 to 2% of infertile males who are otherwise healthy, the majority of whom carry CFTR gene mutations on one or both alleles (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Typically, the CFTR genotype in men with CBAVD includes at least one "mild" missense or splice variant. Similar combinations of CFTR gene mutations have been observed in patients with other CFTRassociated phenotypes, including idiopathic chronic pancreatitis (21-23) and chronic sinusitis (24), but the frequency of gene mutations in these patients is lower than in men with CBAVD.The relation between the number and severity of CFTR gene mutations and the degree of CFTR-mediated dysfunc...

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Section: Table 4 Diagnosis Of Cystic Fibrosis By Disease-causing Mutsupporting

confidence: 92%

mentioning

confidence: 99%

Mutations in the Cystic Fibrosis Transmembrane Regulator Gene andIn VivoTransepithelial Potentials

Wilschanski

Dupuis²,

Ellis³

et al. 2006

Am J Respir Crit Care Med

Self Cite

161

108

View full text Add to dashboard Cite

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“…Many reports from different countries have identified that the disorder is associated with mutations in the CFTR gene, and the development of new technologies allowing the scanning and the rapid sequencing of the coding sequence of the gene shows that CBAVD patients are carrying in about 80% of cases two mutated alleles in the CFTR gene (Jarvi et al 1998;Claustres et al 2000). But it is also widely accepted that CF and CBAVD have complete separate clinical and prognostic characteristics and CBAVD is now considered as the paradigm of CFTR-RD.…”

Section: Cftr Mutations Associated With Cbavdmentioning

confidence: 99%

Assessing the Disease-Liability of Mutations in CFTR

Férec

Cutting

2012

Cold Spring Harbor Perspectives in Medicine

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“…Homozygous CBAVD individuals show one severe and one mild pathogenic mutation or two mild mutations, but never two severe mutations. 6 -10 In addition to classic CFTR mutations, up to 40% of CBAVD patients show the 5T allele, that is, five thymidines within intron 8, 7,8,11,12 which results in a reduction of the splicing efficiency of the CFTR gene. 13 This polymorphism is usually found with a 5 -10% prevalence in the general population.…”

Section: Introductionmentioning

confidence: 99%

Screening of mutations in the CFTR gene in 1195 couples entering assisted reproduction technique programs

et al. 2005

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Genetic testing of the cystic fibrosis transmembrane conductance ( CFTR) gene is currently performed in couples undergoing assisted reproduction techniques ( ART), because of the high prevalence of healthy carriers in the population and the pathogenic relationship with congenital bilateral absence of vas deferens ( CBAVD). However, discordant data have been reported concerning the usefulness of this genetic test in couples with no family history of cystic fibrosis ( CF). In this study, we report the results of CFTR molecular screening in 1195 couples entering ART. Genetic testing was initially carried out in a single partner of each couple. CFTR mutations were detected in 55 subjects ( 4.6%), a percentage that overlaps with the one reported in the general population. However, significantly higher frequencies of were found in CBAVD individuals ( 37.5%) and in males with nonobstructive azoospermia ( 6.6%). The 5T allele was found in 78 patients ( 6.5%). This figure was again significantly different in males with nonobstructive-azoospermia ( 9.9%) and in those with CBAVD ( 100%). All together, 139 subjects ( 11.6%) had either a CFTR mutation or the 5T allele. Subsequent molecular analysis of their partners disclosed a CFTR mutation or 5T allele in nine cases ( 6.5%). However, none of these couples had CFTR alterations in both members, a CFTR mutation being invariably present in one partner and the 5T allele in the other. In order to improve genetic counselling of these couples, the TG-M470V-5T association was analyzed, and a statistically significant relationship between 12TG-V470 and CBAVD was detected

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Heterogeneity of reproductive tract abnormalities in men with absence of the vas deferens: role of cystic fibrosis transmembrane conductance regulator gene mutations

Cited by 47 publications

References 18 publications

Mutations in the Cystic Fibrosis Transmembrane Regulator Gene andIn VivoTransepithelial Potentials

Mutations in the Cystic Fibrosis Transmembrane Regulator Gene andIn VivoTransepithelial Potentials

Assessing the Disease-Liability of Mutations in CFTR

Screening of mutations in the CFTR gene in 1195 couples entering assisted reproduction technique programs

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