ABCMdb

PMID: 11491164

Massie RJ, Poplawski N, Wilcken B, Goldblatt J, Byrnes C, Robertson C
Intron-8 polythymidine sequence in Australasian individuals with CF mutations R117H and R117C.
Eur Respir J. 2001 Jun;17(6):1195-200., [PubMed]

Sentences

No. Mutations Sentence Comment

3 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117Cys ABSTRACT: Compound heterozygotes for a severe cystic fibrosis transmembrane conductance regulator (CFTR) mutation and the R117H or R117C mutation (R117H/ C) have clinical presentations that vary from classic cystic fibrosis (CF) to an incidental genetic finding. Login to comment 4 ABCC7 p.Arg117His The aim of this study was to assess the influence of the intron-8 polythymidine sequence (IVS8) on the relationship between genotype and phenotype of individuals with R117H/C. Login to comment 5 ABCC7 p.Arg117His All individuals with R117H/C known to CF clinics in Australia and New Zealand were retrospectively studied by collecting information on genotype, age, pancreatic status, sweat electrolytes, sputum microbiology and pulmonary function. Login to comment 6 ABCC7 p.Arg117His ABCC7 p.Arg117Cys Forty-one individuals (39 with R117H and two with R117C), 16 on an IVS8-5T background and 25 on an IVS8-7T background were identified. Login to comment 7 ABCC7 p.Arg117His Twelve individuals presented clinically, four were siblings of known R117H/C compound heterozygotes and 25 were detected by newborn screening. Login to comment 8 ABCC7 p.Arg117His Eleven of 14 of the IVS8-5T group (78%) with sweat chloride results available had sweat Clw60 mmol?L-1 compared to 5 (20%) of the R117H/7T group (Chi-squared~10.4, p~0.001). Login to comment 11 ABCC7 p.Arg117His In conclusion, most individuals with R117H/C on a IVS8-5T background have an elevated sweat chloride and clinical cystic fibrosis, which in some cases is severe. Login to comment 12 ABCC7 p.Arg117His Most individuals with R117H/C on an IVS8-7T background do not have clinical cystic fibrosis but should be followed for the development of clinical disease. Login to comment 15 ABCC7 p.Arg117His Correspondence: R.J.H. Massie Dept of Respiratory Medicine Royal Children9s Hospital Melbourne 3052 Australia Fax: 61 393491289 Keywords: Cystic fibrosis genotype phenotype R117H Received: June 26 2000 Accepted after revision January 15 2001 The correlation between genotype and phenotype in cystic fibrosis (CF) is not always clear [1]. Login to comment 16 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117Cys In general, individuals who are compound heterozygotes for a severe cystic fibrosis transmembrane conductance regulator (CFTR) mutation and R117H or R117C (R117H/C) have milder disease. Login to comment 18 ABCC7 p.Arg117His R117H/C are class IV mutations associated with the production of a CFTR protein which has altered channel properties [3, 4]. Login to comment 19 ABCC7 p.Arg117His Chloride transport through R117H/C CFTR is reduced and this is thought to explain the milder phenotype [3, 4]. Login to comment 20 ABCC7 p.Arg117His The variable presentation amongst R117H/C compound heterozygotes may be explained, in part, by the efficiency of exon-9 splicing. Login to comment 25 ABCC7 p.Arg117His The variable presentation of individuals with R117H/C makes it difficult to be certain of the clinical outcome. Login to comment 26 ABCC7 p.Arg117His However, the widespread availability of CFTR gene mutation testing, in particular through newborn screening programmes and antenatal testing, has created the need to predict the prognosis of individuals who are compound heterozygotes for a severe CFTR mutation and R117H/C who may be asymptomatic at the time of testing. Login to comment 28 ABCC7 p.Arg117His The criteria includes the presence of two disease producing CFTR mutations of which R117H/C are only considered disease producing mutations when in cis with IVS8-5T [8]. Login to comment 29 ABCC7 p.Arg117His ABCC7 p.Arg117His Despite this, there are reports of individuals with CF-like conditions who have R117H/C with the IVS8-7T allele [5, 9, 10] and there Eur Respir J 2001; 17: 1195-1200 Printed in UK - all rights reserved Copyright #ERS Journals Ltd 2001 European Respiratory Journal ISSN 0903-1936 is no definitive information as to strength of the relationship between R117H/C, the IVS8 polythymidine sequence and the clinical outcome. Login to comment 30 ABCC7 p.Arg117His The aim of this study was to assess the relationship between genotype and phenotype of individuals known to have the R117H/C mutation and the influence of the IVS8 polythymidine sequence. Login to comment 32 ABCC7 p.Arg117His ABCC7 p.Arg117Cys Information was requested regarding all individuals, alive or deceased, who had been seen in their clinic and who were known to have the R117H or R117C mutation. Login to comment 33 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117Cys ABCC7 p.Arg117Cys R117H and R117C have been considered to be functionally equivalent [11] and have been combined in the analysis, referring to R117H and R117C collectively as R117H/C. Login to comment 35 ABCC7 p.Arg117His Individuals were known to CF clinic directors and Clinical Genetics Services on the basis of either a clinical presentation (symptoms of CF or a sibling of a patient compound heterozygote for R117H/C) or identification through newborn screening. Login to comment 39 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Arg553* One Australian centre (South Australia) includes the mutations G551D, G452X, DI507, R553X and R117H as part of routine screening of infants with an elevated IRT [12]. Login to comment 41 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Trp1282* ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Ser549Asn ABCC7 p.Arg560Thr Infants with a positive (w60 mmol?L-1 ) or borderline (40 - 60 mmol?L-1 ) sweat chloride and in whom there is an unidentified mutation are referred for an extended mutation analysis which includes: DF508, R117H, G551D, A455E, G542X, N1303K, W1282X, 1717-1, R560T, R347P, R334W, R1162X, S549N, 621z1, 3849z10CwT, and the IVS8 polythymidine sequence. Login to comment 45 ABCC7 p.Arg117His ABCC7 p.Arg117Cys R117H was detected by ARMS (Western Australia, New South Wales, Victoria, Tasmania, New Zealand) or ASO (South Australia) and R117C was detected using a restriction enzyme digest (Western Australia, New South Wales, Victoria, Tasmania), ASO (South Australia) or ARMS (New Zealand). Login to comment 54 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117Cys Results Genotype Forty-one individuals with R117H/C (39 R117H and two R117C) being followed at one of the CF clinics in Australia and New Zealand were identified. Login to comment 56 ABCC7 p.Arg117His Thirty-four of the 39 individuals were compound heterozygotes for R117H/C and DF508. Login to comment 57 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Gly542* Two of the individuals had a second severe mutation (G542X/R117H and G551D/R117H), four had an unknown second mutation and one patient was homozygous for R117H. Login to comment 58 ABCC7 p.Arg117His Sixteen individuals had R117H on an IVS8-5T background and 25 on an IVS8-7T background. Login to comment 59 ABCC7 p.Arg117His The phase of each chromosome was unknown, preventing identification of the direct association between R117H and the IVS8 polythymidine sequence. Login to comment 60 ABCC7 p.Arg117His However, previous studies have indicated that where present, IVS8-9T occurs in cis with DF508 [5] and that R117H is the only mutation that occurs in cis with IVS8-5T [18]. Login to comment 62 ABCC7 p.Arg117His Presentation Twenty-five of the 41 (61%) individuals were discovered through newborn screening, 12 (29%) because of respiratory symptoms and four (10%) were siblings of an R117H/C compound heterozygote (three had a younger sibling with a positive newborn screening test and one had a sibling presenting clinically). Login to comment 67 ABCC7 p.Arg117His Both PI individuals had R117H/C on an IVS8-5T background. Login to comment 83 ABCC7 p.Arg117His Discussion This study provides evidence that the variable presentation of individuals with the R117H/C mutation is associated with differences in the IVS8. Login to comment 84 ABCC7 p.Arg117His ABCC7 p.Arg117His Most individuals with R117H/C and the IVS8-5T allele fulfil clinical and sweat test criteria for the diagnosis of CF while most individuals with R117H/C and the IVS8-7T allele do not [8]. Login to comment 87 ABCC7 p.Arg117His In general, individuals who are compound heterozygotes for a severe mutation and R117H/C on an IVS8-5T background have pancreatic sufficient CF which is mild compared to individuals with two severe mutations [2]. Login to comment 94 ABCC7 p.Arg117His Symptoms of established suppurative lung disease were present in some of the older IVS8-7T individuals, raising the possibility that significant lung disease may develop in more of the IVS8-7T group with time. This study is similar to that of KIESEWETTER et al. [5] who studied 38 pancreatic sufficient CF individuals with the DF508/R117H genotype, of whom 31 had the IVS8-5T allele and seven the IVS8-7T allele. Login to comment 95 ABCC7 p.Arg117His ABCC7 p.Arg117His A further nine DF508/R117H individuals were studied, eight males had CAVD only and one female who was asymptomatic, and in each case the R117H was associated with the IVS8-7T allele. Login to comment 96 ABCC7 p.Arg117His The difference between IVS8-5T and IVS8-7T distribution amongst symptomatic individuals with the DF508/R117H genotype was significant (Chi-squared~15.2, pv0.001). Login to comment 97 ABCC7 p.Arg117His This study recognized the need for IVS8 polythymidine analysis to explain the variability amongst individuals with the R117H mutation. Login to comment 98 ABCC7 p.Arg117His Other studies have found individuals with R117H on a IVS8-7T background to have pulmonary disease. Login to comment 99 ABCC7 p.Arg117His DEAN et al. [9] reported a 56-yr-old female with R117H/IVS8-7T who had chronic bronchitis from the age of 10 yrs, complicated by allergic bronchopulmonary aspergillosis (ABPA). Login to comment 101 ABCC7 p.Arg117His Similarly, one patient in a series of sweat test negative ABPA individuals had R117H a IVS8-7T background and could be considered to have a mild form of CF [10]. Login to comment 102 ABCC7 p.Arg117His The variability of clinical presentation of individuals with the R117H/C mutations is largely, but not entirely explained by the IVS8 polythymidine sequence. Login to comment 106 ABCC7 p.Arg117His The importance of understanding the role of the IVS8 polythymidine sequence amongst individuals with the R117H mutation was highlighted in a recent report by CHMIEL et al. [20]. Login to comment 107 ABCC7 p.Arg117His In this report an infant was diagnosed with CF on the basis of the detection of DF508 and R117H in cord blood but without IVS8 polythymidine sequencing being performed until much later. Login to comment 109 ABCC7 p.Arg117His The R117H was found to be on an IVS8-7T background and the diagnosis of CF was changed, but not without considerable emotional cost to the family. Login to comment 112 ABCC7 p.Arg117His If R117H/C is detected then it is imperative that intron-8 polythymidine sequence analysis be performed to offer some guidance as to the likely phenotype. Login to comment 113 ABCC7 p.Arg117His Most individuals with a severe cystic fibrosis mutation and R117H/C on the intron-8 polythymidine sequence-5T background will have an elevated sweat chlorine and clinical features of cystic fibrosis, which in some cases are severe and associated with an early death. Login to comment 114 ABCC7 p.Arg117His Most individuals with R117H/C on the intron-8 polythymidine sequence-7T background do not have clinical features of cystic fibrosis although over half have elevated or borderline sweat chloride. Login to comment 115 ABCC7 p.Arg117His Individuals with R117H/C on the intron-8 polythymidine sequence-7T background should be followed for the potential to develop clinical disease. Login to comment