ABCMdb

PMID: 11788090

Strandvik B, Bjorck E, Fallstrom M, Gronowitz E, Thountzouris J, Lindblad A, Markiewicz D, Wahlstrom J, Tsui LC, Zielenski J
Spectrum of mutations in the CFTR gene of patients with classical and atypical forms of cystic fibrosis from southwestern Sweden: identification of 12 novel mutations.
Genet Test. 2001 Fall;5(3):235-42., [PubMed]

Sentences

No. Mutations Sentence Comment

5 ABCC7 p.Arg764* ABCC7 p.Arg117Cys ABCC7 p.Glu60* Eight mutations with a frequency above 1% (DF508, 394delTT, R117C, 3659delC, E60X, 1112delT, R764X, and 621 1 1G R T) accounted for 78% of CF chromosomes and have been recommended for inclusion in the CFTR mutation screening panel for molecular diagnosis of CF in this region. Login to comment 6 ABCC7 p.Arg117Cys The multiple occurrence of specific CFTR alleles less common than the predominant DF508 mutation (394delTT, R117C, 3659delC) allowed for genotype-phenotype comparisons and revealed consistent relationships between these mutations and disease severity. Login to comment 27 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Arg74Trp ABCC7 p.Arg560Thr ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln ABCC7 p.Thr338Ile ABCC7 p.Ser945Leu ABCC7 p.Arg668Cys ABCC7 p.Arg764* ABCC7 p.Arg117Cys ABCC7 p.Val603Phe ABCC7 p.Glu60* ABCC7 p.Gln1238* ABCC7 p.Ile506Leu ABCC7 p.Arg1162Gln ABCC7 p.Tyr161Asp ABCC7 p.Glu1401* ABCC7 p.Asn1088Asp ABCC7 p.Trp361Arg MUTATIONS IDENTIFIED IN 258 CHROMOSOMES IN THE CF POPULATION ATTENDING THE SOUTH-WESTERN SWEDISH CF CENTRE Location in the Frequency of Mutation gene, exon Number of mutations mutation (%) Homozygotes Heterozygotes DF508 10 161 62.4 56 49 394delTT 3 13 5.0 3 7 R117C 4 7 2.7 7 3659delC 19 5 1.9 5 E60X 3 4 1.6 4 1112delT 7 4 1.6 1 2 R764X 13 4 1.6 1 2 621 1 1G ® T 4 3 1.2 3 G551D 11 2 0.8 2 I506L 10 2 0.8 2 N1088D (R75Q) 17b 2 0.8 2 Q1238X 19 2 0.8 2 R117H (IVS8-5T) 4 2 0.8 2 V603F (IVS8-5T) 13 2 0.8 2 1716G ® A 10 2 0.8 2 R75Q 3 2 0.8 2 R533X 11 1 0.4 1 2329A ® G Promoter 1 0.4 1 297-3 C ® A 2 1 0.4 1 Y161D 4 1 0.4 1 994del9 Exon/intron 6b 1 0.4 1 1154insTC 7 1 0.4 1 W361R 7 1 0.4 1 T338I 7 1 0.4 1 1249-5A ® G Intron 7 1 0.4 1 1717-2A ® G Intron 10 1 0.4 1 R560T 11 1 0.4 1 E1401X 23 1 0.4 1 3126del4 17a 1 0.4 1 S945L 15 1 0.4 1 R668C 13 1 0.4 1 2622 1 2del6 Intron 13 1 0.4 1 R1162Q Exon 19 1 0.4 1 3849 1 10kbC ® T Intron 19 1 0.4 1 R74W Exon 3 1 0.4 1 2363C ® T Promoter 1 0.4 1 IVS8-5Ta Intron 8 1 0.4 1 Unidentified 20 7.8 Total 258 100 61 116 The new mutations are displayed in bold. Login to comment 40 ABCC7 p.Arg117Cys Two other mutations with frequencies exceeding 2% were R117C and 3659delC. Login to comment 45 ABCC7 p.Arg764* In addition, 5 patients were homozygous for other mutations; three for 394delTT, and one each for 1112delT and R764X (Table 1 and 2). Login to comment 46 ABCC7 p.Arg117Cys Among the most common non-D508 alleles, three (394del TT, R117C, and 3659delC) were detected in the context of full CFTR genotypes in 22 CF patients (Table 2). Login to comment 49 ABCC7 p.Arg117Cys In contrast, patients (n 5 7) with the R117C allele (all paired with the DF508 deletion) tended to present with a mild form of CF [pancreatic sufficiency(PS), good pulmonary status]. Login to comment 51 ABCC7 p.Ile506Leu One patient with the 3659delC allele and a mild mutation on the second chromosome (I506L), presentedwith a mild form of CF (Table 2). Login to comment 53 ABCC7 p.Arg117Cys ABCC7 p.Arg117Cys ABCC7 p.Ile506Leu CLINICAL PROFILES OF THE PATIENTS WITH MOST COMMON CFTR MUTATIONS (DF508 NOT INCLUDED) Patient clinical data Cl2 AD/yr (mmol/liter) Mutation/ median Lung median genotype n (range) PI/PS involvement MI (range) Other 394delTT 10 1.5 (0.1-12.2) 13/0a 10/10 1/10 109 (90-140)0 394delTT/DF508 7 1.5 (0.1-12.2) 7/0a 1/70 110 (90-140)0 4 with liver disease of whom 1 died (B. cepacia syndrome) 394delTT/394delTT 3 1.5 (0.8-4.2) 3/0a 0/3 102 (100-118) R117C 7 5.5 (2.5-18) 0/7a 1/7 0/7 85 (71-100) R117C/DF508 7 5.5 (2.5-18) 0/7a - 85 (71-100) 3659delC 5 0.8 (0.3-29) 4/1a 5/5 0/5 106 (80-116)0 3659delC/DF508 4 0.6 (0.3-8.0) 4/0a 0/4 107 (100-116) 2 double lung transplanted (34, 28 years), of whom 1 had diabetes mellitus 3659delC/I506L 1 29 0/1* 0/1 80000000. Login to comment 55 ABCC7 p.Ile507Leu aThe second mutation (I507L) is mild; therefore, the patient is PS. Login to comment 75 ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln ABCC7 p.Val603Phe ABCC7 p.Val603Phe ABCC7 p.Glu60* ABCC7 p.Ile506Leu ABCC7 p.Ile506Leu ABCC7 p.Arg1162Gln ABCC7 p.Tyr161Asp ABCC7 p.Glu1401* ABCC7 p.Asn1088Asp ABCC7 p.Asn1088Asp CLINICAL DATA FOR THE CF PATIENTS CARRYING NEW MUTATIONS Age PI Lung Sweat (years) at or disease Cl Mutations diagnosis PSb (severity) (mmol/liter) Additional symptoms Frameshift 1112delT/1112delT 4 PI 111 110 1112delT/DF508 0.3 PI 111 112 1112delT/DF508 0.2a PI 111 110 3126del4/E60X 2 PI 11 130 994del9/DF508 0.08 PI 2 120 Meconium ileus RNA splice 297-3C ® A/DF508 0.3 PI 1 120 2622 1 2del6/DF508 0.25 PI 111 100 Nonsense E1401X/unknown 6 PS 2 52 Poor growth, fat malabsorption, abnormal electrophysiological response in the intestinal mucosal biopsy Missense V603F, IVS8-5T/DF508 2 PI 1 101 N1088D, R75Q/DF508 4a PS 2 78 N1088D, R75Q/DF508 2 PS 2 75 Y161D/DF508 0.4 PI 1 83 Malabsorption I506L/DF508 42.5 PS 111 103 I506L/3659delC 30 PS 111 80 R1162Q/unknown nvc PS 1 6 Frequent pneumonias V603F, IVS8-5T/unknown nvc PS (1) 24 Sinusitis, severe recurrent hypoglycemia, nasal polyps, abdominal pain Promoter? Login to comment 84 ABCC7 p.Glu60* The allele was found in 1 patient with the E60X mutation on the other chromosome. Login to comment 86 ABCC7 p.Glu1401* E1401X. Login to comment 91 ABCC7 p.Glu1401* He had a typical for CF electrophysiological response in the intestinalmucosal biopsy (Hallberg et al., 2000).Because the second mutation is unknown, the phenotypic status of the E1401X cannot be established. Login to comment 94 ABCC7 p.Tyr161Asp Missense mutations: Y161D. Login to comment 99 ABCC7 p.Val603Phe V603F. Login to comment 100 ABCC7 p.Val603Phe This missense mutation in exon 13 (R-domain) was caused by a transversion of G to T at the position 1939 of the CFTR gene and, in consequence,the change of valine to phenylalanine at amino acid position 603. Login to comment 101 ABCC7 p.Val603Phe This allele was found in a female patient with the DF508 as the second allele, and the RNA splice site IVS8-5T variantco-segregatingwith the V603F mutation. Login to comment 106 ABCC7 p.Ile506Leu I506L. Login to comment 107 ABCC7 p.Ile506Leu A missense mutation within NBD1 (exon 10) was caused by a transversion A to C at nucleotide position 1648 leading to the conservative amino acid change of isoleucine to leucine at position 506. Login to comment 108 ABCC7 p.Ile506Leu ABCC7 p.Ile506Leu The mutation was found in 2 unrelated patients; 1 with the I506L/DF508 genotype (sweat Cl2/103 mmol/liter, PS, and severe lung disease), and the other with the I506L/3659delC genotype (sweat Cl2 80 mmol/liter, PS, and severe lung disease). Login to comment 110 ABCC7 p.Arg1162Gln R1162Q. Login to comment 112 ABCC7 p.Arg1162Gln It leads to a change of arginine to glutamine at amino acid position 1162. Login to comment 115 ABCC7 p.Arg1162Leu ABCC7 p.Arg1162Gln Although the second mutation in this patient is unknown, the R1162Q allele is expected to be very mild, because another mutation in this codon,R1162L was previously classified as a normal variant (Fanen et al., 1992). Login to comment 116 ABCC7 p.Asn1088Asp N1088D. Login to comment 119 ABCC7 p.Asn1088Asp ABCC7 p.Asn1088Asp The N1088D was found in two siblings (genotype N1088D/DF508) with PS, and mild or no lung disease. Login to comment 120 ABCC7 p.Arg75Gln ABCC7 p.Asn1088Asp There was a third CFTR variant, R75Q, found in these patients and associated with the N1088D allele. Login to comment 138 ABCC7 p.Arg117Cys As with the southern region of Sweden (Lund), the second most common mutation (3659delC) in the eastern part of the country (Uppsala 13.3%, Stockholm 10.5%), was much less represented in our patients (1.9%) and it was surpassed by another mutation, R117C (2.7%) (Table 4). Login to comment 145 ABCC7 p.Arg117Cys The relatively high frequency of the 394delTT (3 homozygotes) R117C and 3659delC alleles made it possible to draw genotype-phenotype correlations for patients carrying these mutations (Table 2). Login to comment 151 ABCC7 p.Ile506Leu One patient with I506L and 3659delC was diagnosed at a later age and presented with PS, but severe lung disease. Login to comment 152 ABCC7 p.Arg117Cys In the group carrying the mild R117C allele all patients were PS and diagnosed at older ages. Login to comment 158 ABCC7 p.Glu1401* Interestingly,one of these mutations (E1401X) is associated with a very mild CF presentation (age at diagnosis, 6 years; borderline sweat chloride levels of 52 mmol/liter, PS, and no lung symptoms). Login to comment 163 ABCC7 p.Arg117His dR117C or R117H. Login to comment 166 ABCC7 p.Arg117Cys The "Nm" column represents the number of different CFTR mutant alleles identified among CF chromosomes not carrying most common mutations (DF508, 394delTT, 3659delC, and R117C). Login to comment 168 ABCC7 p.Arg117Cys Patient chromosomes DF508 394delTT 3659delC R117C Othere by the nonsensemutation may produce a relativelyunstable but fully functional CFTR channel that may partially account for the milder presentation (Haardt et al., 1999). Login to comment 171 ABCC7 p.Val603Phe ABCC7 p.Tyr161Asp Two of them (V603F and Y161D) are associated with PI, moderate-to-severe lung disease, and elevated sweat chloride levels. Login to comment 172 ABCC7 p.Ile506Leu ABCC7 p.Arg1162Gln ABCC7 p.Asn1088Asp The remaining missense variants (I506L, N1088D, and R1162Q) can be classified as mild alleles because they are associated with a milder CF phenotypein genotypes with a severe second allele. Login to comment 180 ABCC7 p.Arg117Cys Near-complete screening of a local CF population provides important information for establishing the most optimal strategies for routine screeningof CF patients in this population.Our results indicate that an adjustment should be made to the panel of most common mutations used in the screening of the southwestern Swedish CF population:the addition of the R117C mutation (2.7% of CF chromosomes; Table 1). Login to comment 182 ABCC7 p.Arg117His The phenotypic effect of this mutation, like that of the more common R117H allele, may depend on the length of the T-tract variant in intron 8 (Massie et al., 1999). Login to comment