Etiogenesis of the European cystic fibrosis polymorphism: Heterozygote advantage against venereal syphilis?

Hollander, David H.

doi:10.1016/0306-9877(82)90102-5

Cited by 9 publications

(2 citation statements)

References 13 publications

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“…The maintenance of CF alleles within the Caucasian population was attributed to an advantage of the heterozygous state, either transmitted through the CFTR gene itself or by genes within linkage disequilibrium to CFTR, the so-called hitchhiking genes. The advantage of the carrier status has been based on a longevity advantage due to resistance to viral and bacterial pathogens (Stuart and Burdon 1974;Shier 1975;Baxter et al 1988;Hollander 1982;Cassano 1985;Meindl 1987;Rodman and Zamundio 1991;Gabriel et al 1994). On the other hand, an elevated frequency of mutant CFTR alleles has been found in several disease conditions, predominantly but not exclusively for pulmonary diseases (Warner et al 1976;Dumur et al 1990aDumur et al , 1990bPoller et al 1991;Chillon et al 1995;Pignatti et al 1995Pignatti et al , 1996Friedman et al 1997;Sharer et al 1998;Noone and Knowles 2001).…”

Section: Introductionmentioning

confidence: 99%

Genes in the vicinity of CFTR modulate the cystic fibrosis phenotype in highly concordant or discordant F508del homozygous sib pairs

et al. 2003

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Cystic fibrosis (CF) is the most common severe autosomal recessive disease among Caucasians and is caused by lesions within the cystic fibrosis transmembrane conductance regulator ( CFTR) gene. The variability of CF disease severity suggests the effect of modifying factors. Thirty-four highly concordant and highly discordant F508del homozygous sib pairs, who have been selected out of a group of 114 pairs for extreme disease phenotypes by nutritional and pulmonary status, were typed at single nucleotide polymorphisms (SNPs) and short tandem repeat polymorphisms (STRPs) in the 24-cM CFTR-spanning region between D7S525 and D7S495. Allele frequencies differed significantly at D7S495, located within a 21-cM distance 3' of CFTR, comparing concordant mildly affected, concordant severely affected and discordant sib pairs, as judged by hypothesis-free permutation analysis by Monte Carlo simulation. A rare haplotype of two SNPs within the leptin gene promotor was found exclusively among the concordant mildly affected pairs. All concordant sib pairs shared the paternal F508del chromosome between CFTR and D7S495, whilst the cohort of discordant sib pairs inherited equal proportions of recombined and non-recombined parental chromosomes. We conclude that disease manifestation in CF is modulated by loci in the partially imprinted region 3' of CFTR that determine stature, food intake and energy homeostasis, such as the Silver-Russel-Syndrome candidate gene region and LEP.

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Section: Introductionmentioning

confidence: 99%

Genes in the vicinity of CFTR modulate the cystic fibrosis phenotype in highly concordant or discordant F508del homozygous sib pairs

et al. 2003

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“…Genetic drift may perhaps be responsible for the higher incidence of Phe508del in previously isolated communities 4 but does not explain its high prevalence throughout Central and Northern Europe. Deviations from the Hardy–Weinberg equilibrium may also result from balanced selection in favour of the variant, possibly due to protection against historic pandemic infections, such as chronic diarrhea 35 , 36 , cholera 37 , 38 , thyphus 39 , tuberculosis 40 , 41 , including even syphilis 42 and bubonic plague 43 . Historically, relative protection against those pandemic infections together with unimpaired fertility may have allowed carriers of the Phe508del-variant to produce more offspring 33 .…”

Section: Discussionmentioning

confidence: 99%

Identification and selection of healthy spermatozoa in heterozygous carriers of the Phe508del-variant of the CFTR-gene in assisted reproduction

Geyter

Gallati-Kraemer

Zhang

et al. 2022

Sci Rep

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The pathogenic variant Phe508del of the CFTR-gene is the most frequent cause of cystic fibrosis (CF). Whereas male CF-patients are infertile due to bilateral agenesis of the efferent ducts, the fertility status of male heterozygous carriers is uncertain. We aimed at demonstrating the involvement of the CFTR-ion channel during sperm capacitation and to potentially select variant-free spermatozoa in heterozygous carriers of the CFTR-variant using flow cytometry (FC). Using FC and sorting, single cell polymerase chain reaction, immuno-fluorescent staining an experimental study was performed on nine fertile semen donors and three heterozygous infertile men carrying the Phe508del gene variant. Chemical inhibition of CFTR interfered with sperm capacitation. Most viable spermatozoa of heterozygous carriers of the Phe508del variant of the CFTR-gene show immune-fluorescent CFTR. Sperm capacitation in Phe508del carriers was similar to that in healthy semen donors. Distribution of the Phe508del allele in trio data of CF-affected families corresponded to the expected recessive inheritance pattern. Infertility in Phe508del heterozygous men is unlikely to be caused by the pathogenic variant although some contribution cannot be excluded. Normal sperm capacitation in carriers of pathogenic variants of the Phe508del-gene may in part explain the high prevalence of a potentially lethal recessive disorder.

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Cystic Fibrosis ΔF508 Heterozygotes, Smoking, and Reproduction: Studies of 9141 Individuals from a General Population Sample

et al. 1998

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Etiogenesis of the European cystic fibrosis polymorphism: Heterozygote advantage against venereal syphilis?

Cited by 9 publications

References 13 publications

Genes in the vicinity of CFTR modulate the cystic fibrosis phenotype in highly concordant or discordant F508del homozygous sib pairs

Genes in the vicinity of CFTR modulate the cystic fibrosis phenotype in highly concordant or discordant F508del homozygous sib pairs

Identification and selection of healthy spermatozoa in heterozygous carriers of the Phe508del-variant of the CFTR-gene in assisted reproduction

Cystic Fibrosis ΔF508 Heterozygotes, Smoking, and Reproduction: Studies of 9141 Individuals from a General Population Sample

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