ABCMdb

PMID: 10480369

Romey MC, Guittard C, Chazalette JP, Frossard P, Dawson KP, Patton MA, Casals T, Bazarbachi T, Girodon E, Rault G, Bozon D, Seguret F, Demaille J, Claustres M
Complex allele [-102T>A+S549R(T>G)] is associated with milder forms of cystic fibrosis than allele S549R(T>G) alone.
Hum Genet. 1999 Jul-Aug;105(1-2):145-50., [PubMed]

Sentences

No. Mutations Sentence Comment

2 ABCC7 p.Ser549Arg ABCC7 p.Ser549Arg Age at diagnosis was higher, and current age was significantly higher (P = 0.0032) in the group with the complex allele, compared with the S549R/S549R group. Login to comment 23 ABCC7 p.Ser549Arg In order to better understand the discrepancy between the phenotypes presented by patients carrying mutation S549R, we have conducted a collaborative study aimed at comparing ethnic, clinical, and genetic data from patients with this mutation. Login to comment 48 ABCC7 p.Gly542* ABCC7 p.Ser945Leu Five patients were compound heterozygotes for the complex allele and another mutation, two with ∆F508 and three with, R334 W, G542X, or S945L, respectively, and one patient was homozygous for the [-102T>A+S549R(T>G)] complex allele. Login to comment 49 ABCC7 p.Ser549Arg ABCC7 p.Ser549Arg ABCC7 p.Ser549Arg ABCC7 p.Ser549Arg ABCC7 p.Ser549Arg ABCC7 p.Ser549Arg ABCC7 p.Ser549Arg ABCC7 p.Ser549Arg ABCC7 p.Ser549Arg ABCC7 p.Ser549Arg ABCC7 p.Ser549Arg ABCC7 p.Ser549Arg ABCC7 p.Ser549Arg ABCC7 p.Ser549Arg ABCC7 p.Ser549Arg ABCC7 p.Ser549Arg Almost all patients carrying the double mutant allele, who have been investigated so far, have a mild to moder- 146 Table 1 Clinical characteristics of 16 patients homozygous for the S549R(T>G) mutation (UAE United Arab Emirates, ND no data) Characteristic Patient D1 D2 D3 D4 D5 D6 D7 D8 D9 D10 D11 D12 D13 D14 D15 D16 Genotype S549R S549R S549R S549R S549R S549R S549R S549R S549R S549R S549R S549R S549R S549R S549R S549R Geographic background Oman UAE UAE UAE UAE UAE UAE UAE UAE UAE UAE UAE UAE UAE UAE UAE Ethnic background Arab Bedouin Bedouin Bedouin Bedouin Bedouin Bedouin Bedouin Bedouin Bedouin Bedouin Bedouin Bedouin Bedouin Bedouin Bedouin Gender F F M F F F F M M F M F F F M M Current age (years) - 4 9 - 12 8.5 5 3 7 2 10 5 3 2 - 2 Age at death 5 months - - 6.5 years - - - - - - - - - - 5 months - Age at diagnosis 3 months 6 months 2 years 1 year 4 months 8 months 8 months 3 months 3.5 years 3 months 3 years 1 year 3 months 3 months 1 month 1 month Sweat Cl- (mmol/l) 70 120 123 155 133 100 150 120 150 100 120 90 90 120 ND ND Height (percentile) ND 10 5 5 5 25 25 ND ND ND ND ND ND ND ND ND Weight (percentile) >3 5 5 5 5 10 25 ND ND ND ND ND ND ND ND ND Shwachman- ND 60 55 45 50 55 40 55 45 55 45 60 55 45 35 50 Kulczycki score Lung colonization Yes No Yes Yes Yes Yes Yes No No Yes Yes Yes Yes Yes Yes Yes Pseudomonas aerug. Login to comment 50 ABCC7 p.Gly542* ABCC7 p.Ser945Leu 5 months - 5 years 1 year 4 months 8 months 1.5 years - - 3 months 3 years 1 year 3 months 3 months 1 month 1 month (age of onset) Meconium ileus No No No No No No No No No No No No No No No No Pancreatic Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes insufficiency Table 2 Clinical characteristics of six patients carrying the complex allele: [-102T>A+S549R(T>G) (ND no data, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity) Characteristic Patient P1 P2 P3 P4 P5 P6 Genotype -102T>A+S549R(T>G) -102T>A+S549R(T>G) -102T>A+S549R(T>G) -102T>A+S549R(T>G) -102T>A+S549R(T>G) -102T>A+S549R(T>G) -102T>A+S549R(T>G) R334 W ∆F508 ∆F508 G542X S945L Geographic background South of France South of Spain South of France North of France North of France South of France Ethnic background Jews of Algeria ND Jews ND North of Africa Jews Gender F F F F M M Current age (years) 34 38 6 31 23 18 Age at diagnosis 6 years 35 years 3.5 years 2 months 4 months 9 years Age of first clinical symptoms 5 years ND 3 years 2 months 4 months 5 years First clinical symptoms Episodic bronchitis Dyspnea Pulmonary disease Pulmonary disease Cough Pulmonary disease Sweat Cl- (mmol/l) ND < 60 122 66 72 85 Height (percentile) 60 50 ND 60 26 30 Weight (percentile) 60 50 ND 40 12 < 25 Shwachman-Kulczycki score 85 ND 85 ND 60 85 FEV1 (% predicted) 30 19.3 89 60 59 89 FVC (% predicted) 50 38.7 96 100 76 115 Lung colonization Yes No Yes Yes Yes Yes Pseudomonas aerug. Login to comment 64 ABCC7 p.Arg334Trp ABCC7 p.Gly542* ABCC7 p.Ser945Leu As opposed to 100% of S549R(T>G)/S549R(T>G) patients, 50% of patients carrying the (-102T>A) sequence alter- 148 Table 3 Comparison of clinical features between CF patients carrying the complex allele [-102T>A+ S549R(T>G) and those carrying S549R(T>G) only Feature Patients with [-102T>A+ S549R(T>G)] Patients with S549R(T>G) P value (n = 6) (n = 16) Mean ± SD Median (5th-95th Mean ± SD Median (5th-95th (no. studied) percentile) (no. studied) percentile) Current age (years) 25 ± 11.8 (6) 27 (6-38) 5 ± 3.35 (13) 5 (2-12) 0.0032 Age at diagnosis (years) 9.0 ± 13.2 (6) 4.75 (0.16-35) 0.88 ± 1.0 (16) 0.41 (0.08-3.5) NS Sweat Cl- (mmol/l) 79.0 ± 27.13 (5) 72 (50-120) 117.2 ± 25.1 (14) 120 (70-155) 0.028 Shwachman-Kulczycki score 78.8 ± 12.5 (4) 85 (60-85) 50.0 ± 7.3 (15) 50 (35-60) 0.004 Age at onset of lung colonization 11.5 ± 6.7 (5) 11 (3.5-22) 1.0 ± 1.43 (13) 0.41 (0.08-5) 0.0022 Lung colonization 5/6 (83) 13/16 (81) NS (no. positive/no. studied) (%) Pancreatic insufficiency 3/6 (50) 16/16 (100) 0.013 (no. positive/no. studied) (%) Table 4 CFTR haplotypes for seven [-102T>A+ S549R(T>G)] chromosomes (parentheses indicate unknown phase) P1 [-102T>A+S549R(T>G)] 1 2 1 23 7 1 34 13 1 1 [-102T>A+S549R(T>G)] 1 2 1 23 7 1 34 13 1 1 P2 [-102T>A+S549R(T>G)] (1) (2) (1) 23 7 (1) 34 13 1 1 R334W (2) (1) (2) 17 7 (2) 46 13 1 1 P3 [-102T>A+S549R(T>G)] 1 2 1 23 7 1 34 13 1 1 ∆F508 1 2 1 23 9 1 31 13 1 1 P4 [-102T>A+S549R(T>G)] 1 2 1 23 7 1 34 13 1 1 ∆F508 1 2 1 23 9 1 32 13 1 1 P5 [-102T>A+S549R(T>G)] 1 2 1 23 7 1 34 13 1 1 G542X 1 2 1 22 9 1 33 13 1 1 P6 [-102T>A+S549R(T>G)] 1 2 1 23 1 34 13 1 1 S945L 2 1 2 16 7 2 29 13 1 1 Patient Genotype XV-2c KM-9 J44 IVS8CA IVS8(T)n M470V IVS17BTA IVS17BC 3601-65C/A J3.11 ation were pancreatic insufficient (P = 0.013). Login to comment 67 ABCC7 p.Ser549Arg Discussion Mutation S549R is a serine to arginine change resulting from a T to G substitution at nucleotide 1779, a site included in a six-amino acid region defined as "C consensus", which appears to be a unique feature of the ABC transporter superfamily (reviewed by Ko and Pedersen 1997). Login to comment 70 ABCC7 p.Ser549Arg S549R was originally considered as a "severe" mutation with respect to PI. Login to comment 79 ABCC7 p.Arg553Gln ABCC7 p.Arg553Gln For instance, the missense mutation R553Q, when carried on a ∆ F508 allele, has been shown to be associated with almost normal sweat electrolyte values in a patient with severe CF (Dörk et al. 1991), suggesting that R553Q may partially suppress the ∆F508 chloride transport defect in sweat glands of this patient. Login to comment 80 ABCC7 p.Arg553Gln It was later demonstrated in a yeast expression system that the abnormal folding produced by ∆F508 can be partially corrected by the additional, "revertant" mutation R553Q (Teem et al. 1993). Login to comment