Description of a symptomless cystic fibrosis L346P/M348K compound heterozygous Cypriot individual

Deltas, Constantinos; Boteva, Kalina; Georgiou, Andreas; Papageorgiou, Elena; Georgiou, Christina

doi:10.1006/mcpr.1996.0042

Cited by 10 publications

(10 citation statements)

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“…The two linked missense substitutions G576A and R668C, for example, have previously been classified as polymorphisms on normal chromosomes (Fanen et al 1992), as polymorphisms on CBAVD alleles (Osborne et al 1993;Culard et al 1994) or as separate disease-causing mutations in CBAVD (Anguiano et al 1992;Chillón et al 1995;Mercier et al 1995). The penetrance of a CBAVD allele probably depends on the severity of the other allele in trans (Deltas et al 1996). In addition, the expression of a clinical phenotype can be influenced by modifying genes, as has recently been observed in CF mice (Rozmahel et al 1996).…”

Section: Discussionmentioning

confidence: 95%

Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens

et al. 1997

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Congenital absence of the vas deferens (CAVD) is a frequent cause for obstructive azoospermia and accounts for 1%-2% of male infertility. A high incidence of mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene has recently been reported in males with CAVD. We have investigated a cohort of 106 German patients with congenital bilateral or unilateral absence of the vas deferens for mutations in the coding region, flanking intron regions and promotor sequences of the CFTR gene. Of the CAVD patients, 75% carried CFTR mutations or disease-associated CFTR variants, such as the "5T" allele, on both chromosomes. The distribution of mutation genotypes clearly differed from that observed in cystic fibrosis. None of the CAVD patients was homozygous for delta F508 and none was compound heterozygous for delta F508 and a nonsense or frameshift mutation. Instead, homozygosity was found for a few mild missense or splicing mutations, and the majority of CAVD mutations were missense substitutions. Twenty-one German CAVD patients were compound heterozygous for delta F508 and R117H, which was the most frequent CAVD genotype in our study group. Haplotype analysis indicated a common origin for R117H in our population, whereas another frequent CAVD mutation, viz. the "5T allele" was a recurrent mutation on different intragenic haplotypes and multiple ethnic backgrounds. We identified a total of 46 different mutations and variants, of which 15 mutations have not previously been reported. Thirteen novel missense mutations and one unique amino-acid insertion may be confined to the CAVD phenotype. A few splice or missense variants, such as F508C or 1716 G-->A, are proposed here as possible candidate CAVD mutations with an apparently reduced penetrance. Clinical examination of patients with CFTR mutations on both chromosomes revealed elevated sweat chloride concentrations and discrete symptoms of respiratory disease in a subset of patients. Thus, our collaborative study shows that CAVD without renal malformation is a primary genital form of cystic fibrosis in the vast majority of German patients and links the particular expression of clinical symptoms in CAVD with a distinct subset of CFTR mutation genotypes.

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Section: Discussionmentioning

confidence: 95%

Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens

et al. 1997

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“…The expression of a clinical phenotype can be influenced by modifying genes, as has been observed in CF mice (Rozmahel et al ., 1996) and very recently in humans (Zielenski et al ., 1999). In addition, the penetrance of a mutated CFTR allele can also depend to some extent on the severity of the second allele in trans (Deltas et al ., 1996).…”

Section: Atypical Forms Of Cystic Fibrosismentioning

confidence: 99%

CFTR gene mutations and male infertility

Stuhrmann

Dörk

2000

Andrologia

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Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are a relatively frequent cause of male infertility. Depending on their molecular consequences, CFTR mutations may either result in typical cystic fibrosis (CF), one of the most common autosomal recessive disorders, which is characterized by chronic lung disease, pancreatic exocrine insufficiency, an increase in the concentration of sweat electrolytes and male infertility, due to obstructive azoospermia, or in atypical (often monosymptomatic) forms of CF such as congenital absence of the vas deferens (bi- or unilateral), bilateral ejaculatory duct obstruction or bilateral obstructions within the epididymides. All males with idiopathic obstructive azoospermia bear an increased risk for CF offspring. Couples requesting microsurgical epididymal sperm aspiration and in vitro fertilization, e.g. intracytoplasmic sperm injection, should be offered genetic counselling and molecular genetic analysis of the CFTR gene, if male infertility due to obstructive azoospermia is the underlying cause.

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“…Therefore, an undetected complex allele could be the reason for the reported phenotype. In another publication, M348K was found together with the mutation L346P in a 48-year-old unaffected individual [6]. L346P in combination with F508del or 1677delTA (c.1545_1546delTA) leads to a mild or atypical phenotype.…”

Section: Introductionmentioning

confidence: 97%

“…We report on the first patient with homozygosity for the mutation M348K, with so far unknown clinical relevance. Until now, only three cases with heterozygote M348K mutation have been reported [3,5,6].…”

Section: Introductionmentioning

confidence: 99%