ABCMdb

PMID: 1380943

Osborne L, Santis G, Schwarz M, Klinger K, Dork T, McIntosh I, Schwartz M, Nunes V, Macek M Jr, Reiss J, et al.
Incidence and expression of the N1303K mutation of the cystic fibrosis (CFTR) gene.
Hum Genet. 1992 Aug;89(6):653-8., [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCC7 p.Asn1303Lys Hum Genet (1992) 89:653-658 Incidence and expression 9 Springer-Verlag1992 of the N1303K mutation of the cystic fibrosis (CFTR) gene L. Osborne 1, G. Santis 1, M. Schwarz 2, K. Klinger 3, T. Dfrk 4, I. Mclntosh 5. , M. Schwartz 6, V. Nunes 7, M. Macek Jr. Login to comment 6 ABCC7 p.Asn1303Lys The N1303K mutation was identified in the second nucleotide binding fold of the cystic fibrosis (CF) gene last year. Login to comment 8 ABCC7 p.Asn1303Lys N1303K, identified on 216 of nearly 15000 CF chromo- * Present address: Centre for Medical Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA Correspondence to: L. Osborne somes tested, accounts for 1.5% of all CF chromosomes. Login to comment 9 ABCC7 p.Asn1303Lys The frequency of the N1303K allele varies significantly between countries and ethnic groups, being more common in Southern than in Northern Europe. Login to comment 12 ABCC7 p.Asn1303Lys N1303K is associated with four different linked marker haplotypes for the polymorphic markers XV-2c, KM.19 and pMP6d-9. Login to comment 14 ABCC7 p.Asn1303Lys We clas- sify N1303K as a "severe" mutation with respect to the pancreas, but can find no correlation between this mutation, in either the homozygous or heterozygous state, and the severity of lung disease. Login to comment 16 ABCC7 p.Asn1303Lys The discovery of the non-conservative amino acid substitution of lysine for asparagine in the putative second nucleotide binding fold (NBF) of the CFTR (N1303K) was reported earlier this year (Osborne et al. 1991). Login to comment 20 ABCC7 p.Asn1303Lys In the original study (Osborne et al. 1991), the N1303K mutation was associated with the commonest CF haplotype and accounted for 1.7% of the total number of CF chromosomes analysed, and 5.8% of the non-AF508-carrying CF chromosomes. Login to comment 21 ABCC7 p.Asn1303Lys These observations raised the possibility that the N1303K mutation could account for a significant proportion of uncharacterised CF chromosomes, particularly in Southern Europe, where the AF508 mutation is found less frequently. Login to comment 22 ABCC7 p.Asn1303Lys This prompted us to initiate a collaborative study with laboratories throughout the world in order to define the frequency of the N1303K mutation in different ethnic groups. Login to comment 23 ABCC7 p.Asn1303Lys In addition, clinical information was obtained on patients carrying the N1303K mutation in order to define the clinical phenotype associated with this mutation. Login to comment 25 ABCC7 p.Asn1303Lys In this collaborative study, we describe the frequency, haplotype association and clinical manifestations associated with the N1303K mutation. Login to comment 30 ABCC7 p.Asn1303Lys Patients were screened for the N1303K mutation using one of 3 methods: a) direct sequencing of exon 21 DNA amplified by the polymerase chain reaction (PCR), b) designed mismatch primers (Bal et al. 1992; Ng et al. 1991; Friedman et al. 1991), and c) dot blot hybridisation to normal and mutant allele-specific oligonucleotides (Osborne et al. 1991). Login to comment 35 ABCC7 p.Asn1303Lys The frequency of N1303K in Northern and in Southern Europe was then compared using chi-squared analysis. Login to comment 37 ABCC7 p.Asn1303Lys The total number of CF chromosomes carrying the N1303K allele for the two geographical areas was compared both as a proportion of the total number of CF chromosomes analysed, and as a proportion of those without the AF508 mutation. Login to comment 39 ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys Age at diagnosis, evidence of chronic sputum colonisation by P.aeruginosa and history of meconium ileus was compared between the AF508/N1303K and N1303K/NI303K genotype groups using Mann-Whitney or chi-squared analysis as appropriate. Login to comment 40 ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys The FEV1 percentage of that predicted was compared between age-matched patients with the AF508/N1303K and N1303K/N1303K genotype using the Mann-Whitney test. Login to comment 41 ABCC7 p.Gly551Asp ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys Mean age at diagnosis was compared between the AF508/N1303K, WI282X/NI303K and G551D/N1303K genotypes using chi-squared analysis. Login to comment 44 ABCC7 p.Asn1303Lys Clinical data was contributed either from the Frequency and distribution A total of 216 CF chromosomes carrying the N1303K mutation, representing 1.5% of a total of 14708 CF chromosomes screened so far, have been identified (Table 1). Login to comment 46 ABCC7 p.Asn1303Lys Frequency (in %) of the N1303K mutation in different populations. Login to comment 47 ABCC7 p.Asn1303Lys N/A data not available Country of origin 655 Number of CF Number of % CF % non-AF508 chromosomes N1303K chromosomes chromosomes tested chromosomes withN1303K withN1303K Albania 42 0 0 0 Australiaa 458 0 0 0 Austria 42 1 2.3 Belgium 200 6 3 10.2 Brazil (S.Eur) 174 5 2.9 5 Bulgaria 150 6 4 9.4 Canadaa 958 8 0.8 2.8 French-Canadian 236 2 0.8 2 Czechoslovakiab 456 14 3.1 9.8 Denmark 586 5 0.9 5 Egypt Jewish N/A 2 France North 692 4 0.6 2.0 Southa 1456 28 2.0 4.9 Germany 1378 16 1.2 4.3 Greece 179 6 3.4 13.3 Israel Arab 40 2 5 Ash. Jew 94 4 4.2 Italy South 625 32 5.1 9.4 Italy N/A 2 Poland 200 3 1.5 5.2 Spain 728 15 2.0 South Africa 14 0 0 0 Sweden 290 0 0 0 Switzerland 402 4 1 3 Turkey 46 3 6.3 UK N. Ireland 262 1 0.4 0.9 Scotland 513 2 0.4 1.3 England 2400 17 0.7 2.6 Asian 16 0 0 0 USA Cauc. Login to comment 49 ABCC7 p.Asn1303Lys Where the N1303K mutation was found, its frequency ranged from 0.4% in Northern Ireland and Scotland to over 4% in Southern Italy, Bulgaria, Turkey and Israel (in both Arab and Ashkenazi Jewish populations). Login to comment 50 ABCC7 p.Asn1303Lys There was a significant geographical variation in the frequency of the N1303K allele, in relation both to the AF508 allele (P < 0.001) and to all other alleles (P < 0.001). Login to comment 51 ABCC7 p.Asn1303Lys The N1303K mutation was significantly more common in Southern European populations (Albania, Bulgaria, Greece, Italy, Spain, Turkey, Yugoslavia) than in Northern European populations (Austria, Belgium, Czechoslovakia, Denmark, France, Germany, Poland, Sweden, Switzerland, United Kingdom). Login to comment 52 ABCC7 p.Asn1303Lys This difference was significant when the N1303K allele was taken as a proportion of all CF alleles (P < 0.001) and when taken as a proportion of non-AF508 CF alleles (P < 0.001). Login to comment 53 ABCC7 p.Asn1303Lys One Israeli Arab, one Belgian, one Spanish, one Egyptian Jewish, one Turkish, one Swiss and four Italian patients are N1303K homozygotes (Table 2). Login to comment 54 ABCC7 p.Asn1303Lys In 79 CF patients, the mutation has been found in the heterozygous form with the AF508 mutation, whereas 27 other CF patients carried one of 11 other rarer mutations on the non-N1303K carrying chromosome. Login to comment 56 ABCC7 p.Asn1303Lys Haplotype analysis N1303K is associated with 4 different linked marker haplotypes for the polymorphic markers XV-2c, KM. 19 and pMP6d-9. Login to comment 57 ABCC7 p.Asn1303Lys In 53 out of the 58 patients (91%) for whom haplotype data was available, N1303K occurred on the XV-2c/1, KM.1912 and pMP6d-9/2 haplotype background. Login to comment 63 ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Gly542* Fifteen patients were born with meconium ileus, 10 with the AF508/N1303K genotype; 4 of the remaining 5 were G542X/N1303K patients for whom data was available, and 2 patients were N1303K/unknown. Login to comment 64 ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys The mean age at diagnosis and mean current age was not significantly different in CF patients with the AF508/ N1303K, N1303K/N1303K, W1282X/N1303K and unknown/N1303K genotypes (Table 2). Login to comment 65 ABCC7 p.Gly551Asp ABCC7 p.Asn1303Lys Data was available on only 3 of a total of 6 CF patients with the G551D/ N1303K genotype. Login to comment 67 ABCC7 p.Asn1303Lys ABCC7 p.Gly542* All the G542X/N1303K patients were diagnosed at birth. Login to comment 70 ABCC7 p.Asn1303Lys Patients with the AF508/N1303K and N1303KJN1303K genotypes were compared for a number of variables. Login to comment 75 ABCC7 p.Gly551Asp ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Arg560Thr N/A data not available Genotype Number Meana (range) age Male/ Pancreatic status Meconium Sputum female ileusb colonisation ofof patients Current At diagnosis PS PI P.aeruginosa Yes No Mean (range) of FEVj percentage of that predicted AF508 79 10 0.7 • 0.6 16 / 20 0 55 10/58 20 8 N1303K (0.5-36) (0-2.5) N1303K 10 7 1 • 1 3/3 0 6 1/6 3 1 N1303K (3-12) (0.1-1.5) G551D 6 19 9.7 • 2.2 1/ 2 0 4 0/4 3 1 N1303K (17-22) (8-12) G542X 8 7 0 • 0 2/3 0 4 4/5 0 2 N1303K (0.1-12) 621+lG---~T 1 22 18 1/0 0 1 0/1 1 0 N1303K W1282X 4 13.5 0.7 • 0.6 3 / 1 0 4 0/4 0 1 N1303K (5-23) (0.25-1.7) R560T 1 5 41 1 / 0 0 1 0/1 0 1 N1303K R553X 1 N/A N/A N/A 0 1 0/1 N/A N/A N1303K R334W 1 19 N/A 1/0 0 1 0/1 N/A N/A N1303K R1162X 1 N/A N/A N/A N/A N/A N/A N/A N/A N1303K 1717-1G---~A 2 7 N/A 0/1 N/A N/A N/A N/A N/A N1303K 3659delC 1 21 74 0/1 0 1 0/1 1 0 N1303K 1078delT 1 N/A N/A N/A N/A N/A N/A N/A N/A N1303K Other 90 12 4.3 • 5.6 9/9 5 19 2/17 4 10 N1303K (2-24) (0.1-15) 63 (32-101) 65 (46-84) 80 (66-93) N/A 55 70 N/A N/A N/A N/A N/A 26 N/A 66 a Mean +_SD b Shown as a fraction of the patients for whom data was available the percentage of FEV1 between age-matched N1303K homozygotes and AF508/N1303K heterozygotes (65% vs 75%, P> 0.1). Login to comment 76 ABCC7 p.Asn1303Lys Discussion Nearly 15000 CF chromosomes have now been screened for the N1303K mutation, including those from most countries where CF is prevalent. Login to comment 77 ABCC7 p.Asn1303Lys A total of 216 N1303K- carrying chromosomes has now been identified, making this mutation one of the 5 most common mutations worldwide (CF Genetic Analysis Consortium, unpublished). Login to comment 79 ABCC7 p.Trp1282* For example, the W1282X mutation has been found in approximately 55% of CF chromosomes of Ashkenazi Jewish origin, but in only 1.6% of CF chromosomes from the general CF population (Shoshani et al. 1991). Login to comment 80 ABCC7 p.Asn1303Lys In this study, we show that the frequency of the N1303K mutation varies significantlybetween countries and that this variation is independent of the AF508 allele, and of all other CF alleles as a whole. Login to comment 81 ABCC7 p.Asn1303Lys We also show that the N1303K allele is more common in Southern than in Northern Europe. Login to comment 82 ABCC7 p.Asn1303Lys However, the N1303K mutation should not be regarded as a major mutation in Southern Europe, as it only accounts for 8% of non-AF508-carrying CF chromosomes in this population. Login to comment 83 ABCC7 p.Asn1303Lys Despite its lower frequency in Northern Europe, we suggest that screening for the N1303K mutation should be included in carrier detection programmes. Login to comment 84 ABCC7 p.Asn1303Lys In most cases where the haplotype was known, N1303K was associated with the 1,2,2 haplotype at the linked markers XV-2c, KM. 19 and pMP6d-9 respectively, and was only found in association with other haplotypes in Italian, Spanish and Bulgarian chromosomes. Login to comment 86 ABCC7 p.Asn1303Lys In this study, we have tried to assess the clinical characteristics of CF patients carrying one or two copies of the N1303K mutation. Login to comment 93 ABCC7 p.Asn1303Lys These results therefore place N1303K in the so-called "severe" mutation group (Kerem E et al. 1990) with respect to pancreatic status, since this mutation does not override the effect on the pancreas of other "severe" mutations such as AF508. Login to comment 94 ABCC7 p.Asn1303Lys ABCC7 p.Gly542* Of the 15 patients who presented with meconium ileus, 4 were found to have the G542X/N1303K genotype. Login to comment 96 ABCC7 p.Asn1303Lys ABCC7 p.Gly542* Because none of the other genotypes reported in this study showed any association with meconium ileus, it seems likely that this observation relates to the G542X, and not the N1303K, allele. Login to comment 98 ABCC7 p.Asn1303Lys The severity of pulmonary disease associated with the N1303K mutation, in both the homozygous and heterozygous state, was highly variable. Login to comment 99 ABCC7 p.Asn1303Lys For example, in patients with the AF508/N1303K genotype, pulmonary function varied from being within the normal range in a Danish patient aged 20 years, to being severely abnormal in a 15-year-old English patient. Login to comment 100 ABCC7 p.Asn1303Lys More importantly, variation was also observed between patients homozygous for the N1303K mutation. Login to comment 101 ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys However, as a group, patients with the AF508/N1303K genotype were clinically indistinguishable from patients with the N1303K/ N1303K genotype; this suggests that the N1303K and AF508 mutations are associated with similar clinical expression. Login to comment 102 ABCC7 p.Asn1303Lys The N1303K mutation is one of only 4 mutations so far identified in the putative second NBF of the CFTR gene, whereas the AF508 mutation is one of many mutations within the first NBF. Login to comment 103 ABCC7 p.Asn1303Lys That the phenotypic impact of these mutations is similar is supported by in vitro studies showing that neither the AF508 nor the N1303K mutant CFTR is fully glycosylated, and that both mutant CFTRs are associated with the same defect in chloride permeability (Gregory et al. 1991). Login to comment 106 ABCC7 p.Asn1303Lys The results presented here show that the rarer N1303K genotypes is also associated with a highly variable pulmonary phenotype, and suggest that the CF genotype is unlikely to be predictive of the severity of lung disease in CF. Login to comment