ABCMdb

PMID: 10931414

Massie RJ, Wilcken B, Van Asperen P, Dorney S, Gruca M, Wiley V, Gaskin K
Pancreatic function and extended mutation analysis in DeltaF508 heterozygous infants with an elevated immunoreactive trypsinogen but normal sweat electrolyte levels.
J Pediatr. 2000 Aug;137(2):214-20., [PubMed]

Sentences

No. Mutations Sentence Comment

10 ABCC7 p.Arg117His Results: Over a 24-month period we identified 122 ࢞F508 heterozygotes and recruited 57; 4 had borderline sweat chloride levels (40 to 60 mmol/L), 5 (8.8%, 95% CI 1.4, 16.2) had a second CF mutation (R117H), and 11 (20%, 95% CI 10, 30) had the intron 8 5T allele. Login to comment 14 ABCC7 p.Arg117His Screened infants with borderline sweat chloride levels almost certainly have CF, but long-term follow-up of the infants with the genotype ࢞F508/R117H and ࢞F508/5T is required to determine their outcome. Login to comment 26 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Ser549Asn ABCC7 p.Arg560Thr Measurement of Cl levels was done by colorimetry, and measurement of sodium levels was done by flame cytometry.16 Gene Mutation Analysis Blood was taken and DNA extract- ed17 for an extended cystic fibrosis transmembrane conductance regulator protein gene mutation analysis as described previously.18 The following mutations were included: ࢞F508, ࢞I507, R117H, G551D, A455E, G542X, N1303K, W1282X, 1717-1G࢐A, R560T, R347P, R334W, R553X, R1162X, S549N, 3849+10C࢐T, and 621+1G࢐T. Login to comment 49 ABCC7 p.Arg117His Subject Genotypes Details of the gene mutation analysis and polythymidine tract alleles are presented in Table I. Five (8.8%) infants (95% CI 1.4, 16.2) had an additional exonic mutation, R117H. Login to comment 50 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His This is significantly higher than the reported frequency of R117H in the Australian CF population (1%, P < .01)27 and the reported frequency of R117H in a community-based screen of a predominantly white population (0.6%, P < .01).28 The intron 8 polythymidine sequences of the ࢞F508/R117H infants were 9T/7T. Login to comment 53 ABCC7 p.Arg117His We divided the subjects into groups on the basis of genotype and initial sweat Cl values: initial borderline (40 to 60 mmol/L) sweat Cl levels (borderline, n = 4), subjects with a second mutation (࢞F508/R117H, n = 5), subjects with the 5T allele (࢞F508/5T, n = 11), and subjects with no other mutation and initial sweat Cl level <40 mmol/L (࢞F508/-, n = 37). Login to comment 54 ABCC7 p.Arg117His Pancreatic Stimulation Tests Fifty-one infants underwent pancreatic stimulation testing including 3 of 4 infants with an initial borderline sweat Cl level, 4 of 5 infants with the R117H mutation, 10 of 11 infants with the 5T allele, and 34 with no additional mutation and sweat Cl levels <40 mmol/L (Table II). Login to comment 56 ABCC7 p.Arg117His ABCC7 p.Arg117His Male, female Intron 8 polythymidine sequences ࢞F508/R117H 5 2, 3 9T/7T ࢞I507/- 2 1, 1 7T/7T ࢞I507/- 1 0, 1 7T/5T ࢞F508/- 10 4, 6 9T/5T ࢞F508/- 37 18, 19 9T/7T ࢞F508/- 2 1, 1 9T/9T Total 57 Table I. Results of the extended CF gene mutation analysis HCO3 - + Cl- H2O Colipase activity Genotype group (mmol/kg/h) (mL/kg/h) (%) Control group (n = 43) 1.24 (0.6-1.88) 9.02 (4.97-14.5) 94 (20-200) ࢞F508/R117H (n = 4) 0.71* (0.62-0.89) 7.0 (5.8-9.4) 53* (48-59) ࢞F508/5T (n = 10) 0.81* (0.67-0.97) 7.9 (6.5-9.0) 32* (24-49) ࢞F508/- (n = 34) 0.84* (0.68-0.96) 7.5 (5.8-8.9) 30* (21-42) Borderline (n = 3) 0.44ߤ (0.37-0.52) 6 (5.9-6.2) 33* (23-50) Cystic fibrosis 0.32 (0.22-0.45) 2.9 (1.9-5.2) 35 (8-68) (PS, n = 22) Cystic fibrosis 0.18 (0.10-0.25) 2.2 (1.0-2.9) 0 (0-0) (PI, n = 20) Results are presented as median values with interquartile ranges presented in parentheses. Login to comment 62 ABCC7 p.Arg117His In those subjects with an initial sweat Cl level <40 mmol/L, including those with R117H or the 5T allele, the median pancreatic electrolyte secretion, water flow, and colipase activity were midway between values for members of the control group and pancreatic insufficient patients with CF (Figure). Login to comment 63 ABCC7 p.Arg117His Three of the 4 R117H subjects and 4 of the 11 5T subjects who had pancreatic stimulation testing had pancreatic electrolyte secretion <0.7 mmol/kg/h (CF range). Login to comment 68 ABCC7 p.Arg117His None of the R117H infants had symptoms, nor did those with the 5T allele. Login to comment 74 ABCC7 p.Arg117His This is supported by other groups who have directly measured transepithelial Cl transport from rectal suction biopsy specimens and have demonstrated reduced Cl transport through CFTR in patients with sweat Cl levels of 30 to 60 mmol/L.32,33 We found more ࢞F508/R117H compound heterozygotes than expected. Login to comment 75 ABCC7 p.Arg117His For patients with R117H, the length of the intron 8 polythymidine sequences determined the proportion of CFTR messenger RNA transcripts containing exon 9, which is critical in determining 217 an initial sweat Cl level between 30 and 40 mmol/L, and repeat sweat Cl level was in the same range (n = 2) or lower (n = 1) at 12 months; all were well on clinical evaluation. Login to comment 80 ABCC7 p.Arg117His Boxplot comparison of pancreatic electrolyte secretion (summed HCO3 - + Cl-) for control group, infants with no additional mutation and initial sweat Cl- levels <40 mmol/L (࢞F508/-), infants with 5T allele (࢞F508/5T), infants with second mutation (࢞F508/R117H), infants with borderline initial sweat test results (Borderline), patients with PS CF (CF:PS), and pancreatic insufficient patients with CF (CF:PI). Login to comment 83 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His the clinical outcome.34 The ࢞F508/ R117H genotype may cause PS CF, usually when R117H is in cis with the 5T allele,21 and congenital absence of the vas deferens when in cis with the 7T allele.20,35 The ࢞F508/R117H subjects in this study had the 9T/7T alleles and could be expected to have ~5% CFTR activity, an amount sufficient to prevent serious respiratory and pancreatic disease.36 However, variable splicing is common,15 and patients with R117H in cis with 7T have been described with PS CF,21 recurrent pancreatitis,37 and allergic bronchopulmonary aspergillosis.38 Therefore it is possible that the R117H subjects from this study may have variants of CF and represent infants missed by screening. Login to comment 86 ABCC7 p.Arg117His ABCC7 p.Arg117His The subjects with R117H or 5T meet some of the criteria for a diagnosis of CF according to the criteria of the Cystic Fibrosis Foundation,42 namely a positive newborn screening result (elevated IRT level), mutations in each CFTR gene known to cause CF, and for some R117H subjects (n = 3) and 5T subjects (n = 4), evidence of in vivo abnormalities of ion transport. Login to comment 89 ABCC7 p.Arg117His We are unable to assess the state of the vas deferens either on clinical evaluation or ultrasonography in the male infants with R117H (n = 2) or the 5T allele (n = 5) to provide evidence of disease expression. Login to comment 96 ABCC7 p.Arg117His Reduced pancreatic function in some carriers of CFTR mutations may be the explanation for the association with chronic panceatitis,37,43,44 and there are reports of other disease manifestations in apparently true carriers, such as disseminated bronchiectasis45 and allergic bronchopulmonary aspergillosis38 and perhaps asthma.46 We conclude that the excess of apparent carriers from the IRT/࢞F508 screening program is partly explained by the presence of a second mutation (R117H) and the 5T allele in some infants and that pancreatic duct function is reduced in ࢞F508 heterozygotes with neonatal hypertrypsinogenemia. Login to comment