ABCMdb

PMID: 9259194

Friedman KJ, Heim RA, Knowles MR, Silverman LM
Rapid characterization of the variable length polythymidine tract in the cystic fibrosis (CFTR) gene: association of the 5T allele with selected CFTR mutations and its incidence in atypical sinopulmonary disease.
Hum Mutat. 1997;10(2):108-15., [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCC7 p.Arg117His HUMAN MUTATION 10:108115 (1997) (c) 1997 WILEY-LISS, INC. HUMU 769 RESEARCH ARTICLE Rapid Characterization of the Variable Length Polythymidine Tract in the Cystic Fibrosis (CFTR) Gene: Association of the 5T Allele With Selected CFTR Mutations and Its Incidence in Atypical Sinopulmonary Disease Kenneth J. Friedman,1,2* Ruth A. Heim,2 Michael R. Knowles,3 and Lawrence M. Silverman2 1 Curriculum in Genetics, University of North Carolina, Chapel Hill, North Carolina 27154 2 Department of Pathology, University of North Carolina, Chapel Hill, North Carolina 27154 3 Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27154 Communicated by Henry A. Erlich The CFTR intron 8 variable length polythymidine tract modulates the cystic fibrosis (CF) phenotype associated with the mutation R117H. Login to comment 3 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Gly85Glu ABCC7 p.Arg75Gln ABCC7 p.Ser945Leu ABCC7 p.Asp1152His Polythymidine alleles were identified for mutations either associated with a wide range of clinical phenotypes (R117H, R347P, G85E, D1152H, R334W, 2789+5 G>A, 3849+10kb C>T), and/or located at hypermutable CpG loci (R117H, 3849+10kb C>T, R553X, R334W, S945L and R75Q). Login to comment 4 ABCC7 p.Arg117His R117H was detected in cis with each of three alleles (5T, 7T, 9T) at the intron 8 locus. Login to comment 5 ABCC7 p.Arg117His The novel R117H-9T association was detected in a 10-month old African-American male with borderline-to-mildly elevated sweat chloride values (~50-66 mEq/L). Login to comment 9 ABCC7 p.Arg117His In summary, the 5T allele was not found in cis with CF-causing mutations besides R117H, but an elevated 5T allele frequency in variant CF patients suggests 5T may be associated with disease in some situations. Login to comment 20 ABCC7 p.Arg553Gln In the context of CF, the R553Q sequence variant in exon 11 has been demonstrated in vitro partially to ameliorate the phenotype of a ∆F508 homozygote (Teem et al., 1993). Login to comment 22 ABCC7 p.Arg117His The exon 4 missense mutation, R117H, has been reported on at least two different genetic backgrounds defined by a polymorphic tract of thymidines in intron 8 (Kiesewetter et al., 1993). Login to comment 25 ABCC7 p.Arg117His ABCC7 p.Arg117His Compound heterozygotes with the ∆F508/ R117H genotype exhibit moderate lung disease, pancreatic exocrine sufficiency, borderline-to-high sweat electrolytes, and male infertility when R117H exists in cis to a 5T allele. Login to comment 26 ABCC7 p.Arg117His In contrast, an R117H in cis to a 7T may give rise to little more than male infertility (Kiesewetter, 1993). Login to comment 28 ABCC7 p.Arg117His The complex genotypes responsible for the variability of CF expression associated with R117H may have a similar impact on the clinical heterogeneity seen with other CFTR mutations. Login to comment 29 ABCC7 p.Arg117His ABCC7 p.Arg347His The mutations R117H, R347H, ∆F508, and 384910kb C>T exist in association with more than one intron 8 allele (Dörk et al., 1994; Chillón et al., 1995), but small numbers of any particular mutation-intron 8 combination make phenotypic conclusions difficult to establish. Login to comment 37 ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Gly85Glu ABCC7 p.Arg75Gln ABCC7 p.Ser945Leu ABCC7 p.Asp1152His We report the development of a rapid, nonisotopic assay that facilitates typing of this locus and utilize it to explore the role of the polythymidine tract alleles in thepathogenesisofCF.Mutationsassociatedwithclini- calheterogeneity(R347P,G85E,D1152H,R334W,and 3849 + 10kb C>T) and/or occurring at hypermutable loci (3849 + 10kb C>T, R334W, S945L, R553X, and R75Q) were analyzed for their association with different intron 8 alleles in CF and atypical patients. Login to comment 39 ABCC7 p.Arg117His ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Gly85Glu ABCC7 p.Ser945Leu ABCC7 p.Asp1152His Mutation screening was performed for R553X (Cutting et al., 1990), R334W (Gasparini et al., 1991), G85E (Zielenski et al., 1991a), S945L (Claustres et al., 1993), 3849 + 10kb C>T (Highsmith et al., 1994), R117H and R347P (Dean et al., 1990), 2789+5G>A (Highsmith et al., 1997), D1152H (Highsmith, per. Login to comment 41 ABCC7 p.Arg75Gln ), and R75Q (Zielenski et al., 1991a). Login to comment 43 ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Gly85Glu ABCC7 p.Ser945Leu For R553X, G85E, S945L, 3849 + 10KB C>T, and R334W, the digested samples were electrophoresed at 100 V for 2 hr in 4% agarose gels (3:1 Nusieve: SeaKem, FMC Bioproducts, Rockland, ME). Login to comment 44 ABCC7 p.Arg117His ABCC7 p.Arg347Pro ABCC7 p.Arg75Gln ABCC7 p.Asp1152His R117H, R347P, D1152H, and R75Q required electrophoresis at 230 V for 5 hr in a 10% polyacrylamide gel. Login to comment 55 ABCC7 p.Arg117His None of these 73 patients bear two detected CF mutations or were heterozygous for R117H. Login to comment 74 ABCC7 p.Arg117His Among the 14 R117H alleles we have studied, eight were associated with the 5T allele and five were on a 7T background. Login to comment 75 ABCC7 p.Arg117His In each case, the phenotype observed was concordant with the observation (Kiesewetter et al., 1993) that the shorter polythymidine tract (5T) at this locus exacerbates the symptoms secondary to R117H. Login to comment 76 ABCC7 p.Arg117His We also detected one R117H allele in cis to 9T, which has not been reported previously. Login to comment 78 ABCC7 p.Arg117His His genotype was ∆F508/R117H and 9T,9T. Login to comment 90 ABCC7 p.Arg117His None have two identified CFTR mutations, nor are any heterozygous for R117H. Login to comment 94 ABCC7 p.Arg117His ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Gly85Glu ABCC7 p.Ser945Leu ABCC7 p.Asp1152His Association of Selected CFTR Mutations with Intron 8 Polythymidine Alleles Chromosomes In cis with In cis with In cis with Mutation Site CpG locus 5T 7T 9T R75Qa EXON 3 Y 0 8 0 G85E EXON 3 N 0 5 0 R117H EXON 4 Y 8 5 1 R334W EXON 7 Y 0 4 0 R347P EXON 7 N 0 7 0 R553X EXON 11 Y 0 7 0 2789+5 G>A INTRON 14B N 0 5 0 S945L EXON 15 Y 0 3 0 D1152H EXON 18 N 0 7 0 3849+10kb C>T INTRON 19 Y 0 15 2 a Sequence variant. Login to comment 102 ABCC7 p.Trp1282* The fourth man, who presented with azoospermia and chronic lung and sinus disease, was heterozygous for W1282X and was 5T,7T. Login to comment 130 ABCC7 p.Arg117His We detected one R117H allele in association with a 9T in a patient who sweated heavily, had a low serum sodium level, and had borderline to mildly elevated sweat chloride values. Login to comment 131 ABCC7 p.Arg117His ABCC7 p.Arg117His This R117H-9T pairing has not been previously reported, although a similar clinical situation has been described in a man with a∆F508/R117H genotype in the absence of any pulmonary disease (Smith et al., 1995). Login to comment 132 ABCC7 p.Arg117His ABCC7 p.Arg117His Although we determined this individual to be a 5T,9T heterozygote, the intriguing possibility remains that R117H on a 9T background may at times be associated with a clinical scenario distinct from that commonly seen when R117H is associated with either 5T or 7T. Login to comment 133 ABCC7 p.Thr338Ile An additional report of isolated hypotonic dehydration in association with another CFTR mutation, T338I (Leoni et al., 1995), is further evidence that specific CFTR mutations may give rise to this phenotype. Login to comment 140 ABCC7 p.Arg117His In this study, the marked variability in phenotype associated with mutations other than R117H cannot be attributed to the 5T allele. Login to comment 144 ABCC7 p.Trp1282* Although the CF mutations W1282X and 3849 + 10kb C>T are prevalent in Ashkenazi Jews (Abeliovich et al., 1992; Shoshani et al., 1992), the frequency of 5T in this population has been reported to be 6% (Kerem et al., 1995), comparable to its frequency elsewhere. Login to comment 145 ABCC7 p.Arg117His The role of the 5T allele in eliciting pulmonary symptoms when not co-inherited with R117H has been difficult to define. Login to comment 157 ABCC7 p.Arg117His Thus far, only R117H has been shown to owe its phenotypic heterogeneity to the presence of the 5T and 7T alleles. Login to comment 158 ABCC7 p.Arg117His The R117H-9T association we have reported here may represent an extension of this correlation. Login to comment