ABCMdb

PMID: 15463906

Dugueperoux I, Bellis G, Lesure JF, Renouil M, Flodrops H, De Braekeleer M
Cystic fibrosis at the Reunion Island (France): spectrum of mutations and genotype-phenotype for the Y122X mutation.
J Cyst Fibros. 2004 Aug;3(3):185-8., [PubMed]

Sentences

No. Mutations Sentence Comment

5 ABCC7 p.Tyr122* Three CFTR mutations accounted for 75% of the detected CF alleles at the Reunion Island (DF508, Y122X, and 3120 + 1G ! Login to comment 7 ABCC7 p.Tyr122* ABCC7 p.Tyr122* ABCC7 p.Tyr122* The DF508/DF508, DF508/Y122X, and Y122X/Y122X genotypes accounted for 60.2% of the CF patients. Login to comment 8 ABCC7 p.Tyr122* Patients carrying at least one Y122X mutation were pancreatic insufficient, had high sweat chloride values and significantly lower anthropometric measures. Login to comment 12 ABCC7 p.Tyr122* The Y122X allele appears to be associated with a severe phenotype. Login to comment 14 ABCC7 p.Tyr122* Keywords: Cystic fibrosis; Y122X; Genotype-phenotype; Reunion Island; Rare mutations; 3120+1G!A 1. Login to comment 21 ABCC7 p.Tyr122* Because of its specificity (history and population constitution), we decided to study the spectrum of mutations identified in the island and the genotype-phenotype correlation of the most frequent mutation (Y122X) using the French Cystic Fibrosis Registry. Login to comment 32 ABCC7 p.Tyr122* ABCC7 p.Tyr122* In a second step, we extracted the available data for all 11 patients homozygous for the Y122X mutation and 17 compound heterozygotes for the Y122X and DF508 mutations, as previously described [1]. Login to comment 33 ABCC7 p.Tyr122* Because of the small size of the CF population, the patients followed at the Reunion Island (ten Y122X homozygotes and ten compound heterozygotes) were compared to all 20 Reunion Island patients homozygous for the DF508 mutation. Login to comment 45 ABCC7 p.Tyr122* Three accounted for 90.4% of the identified mutations: DF508 (53.4%), Y122X (32.2%), and 3120 + 1G ! Login to comment 49 ABCC7 p.Tyr122* ABCC7 p.Tyr122* ABCC7 p.Tyr122* Three genotypes accounted for 79.1% of the fully identified genotypes; they were DF508/DF508 (32.8%), DF508/Y122X (26.9%), and Y122X/Y122X (19.4%). Login to comment 50 ABCC7 p.Tyr122* ABCC7 p.Tyr122* ABCC7 p.Tyr122* Fifty-six patients (28 DF508/DF508, 17 Y122X/DF508, and 11 Y122X/Y122X) were included in the genotype-phenotype study (Table 2). Login to comment 53 ABCC7 p.Tyr122* Although the mean age at diagnosis (excluding those diagnosed prenatally or on familial history and those neonatally screened) was not statistically different between all three groups ( p = 0.90), patients homozygous for the Y122X tended to be diagnosed early, the median age for this group being much lower than for both other groups. Login to comment 58 ABCC7 p.Tyr122* ABCC7 p.Tyr122* Patients homozygous for the Y122X mutation or compound heterozygous for the Y122X and DF508 mutations had significantly lower anthropometric measures (height and weight) than those homozygous for the DF508 mutation. Login to comment 62 ABCC7 p.Tyr122* Aspergillus was more frequently identified in the patients carrying at least one Y122X allele, but the difference was not significant ( p = 0.08). Login to comment 63 ABCC7 p.Tyr122* One 17-year-old Y122X/DF508 male had a cardiopulmonary transplantation in 2000. Login to comment 66 ABCC7 p.Tyr122* ABCC7 p.Tyr122* ABCC7 p.Tyr122* Nasal polyposis was more frequent among CF patients carrying at least one Y122X allele compared to Table 1 Mutations and genotypes identified among CF patients born in the Reunion Island Mutations Number (%) Genotypes Number (%) DeltaF508 78 (53.42) DeltaF508/DeltaF508 22 (32.84) Y122X 47 (32.19) DeltaF508/Y122X 18 (26.87) 3120 +1G ! Login to comment 67 ABCC7 p.Gly542* ABCC7 p.Tyr122* ABCC7 p.Tyr122* A 7 (4.79) Y122X/Y122X 13 (19.40) G542X 2 (1.37) 3120 + 1G ! Login to comment 75 ABCC7 p.Ala455Glu G 1 (0.68) DeltaF508/A455E 1 (1.49) 2789 + 5G ! Login to comment 76 ABCC7 p.Ala455Glu ABCC7 p.Gly542* ABCC7 p.Asp993Tyr A 1 (0.68) DeltaF508/ D993Y 1 (1.49) 993del5 1 (0.68) DeltaF508/ G542X 1 (1.49) A455E 1 (0.68) DeltaF508/2183AA ! Login to comment 77 ABCC7 p.Gly551Asp ABCC7 p.Gly149Arg ABCC7 p.Gly85Glu ABCC7 p.Tyr122* ABCC7 p.Asp993Tyr G 1 (1.49) D993Y 1 (0.68) DeltaF508/ G551D 1 (1.49) G149R 1 (0.68) DeltaF508/1161delC 1 (1.49) G85E 1 (0.68) Y122X/3120 + 1G ! Login to comment 78 ABCC7 p.Arg1162* ABCC7 p.Tyr122* A 1 (1.49) R1162X 1 (0.68) Y122X/1717-1G ! Login to comment 79 ABCC7 p.Gly551Asp ABCC7 p.Gly149Arg A 1 (1.49) G551D 1 (0.68) G149R/993del5 1 (1.49) TOTAL 146 TOTAL 67 Frequencies given in this table are based on the 146 CF chromosomes with an identified CFTR mutation (detection rate of 83%). Login to comment 83 ABCC7 p.Tyr122* The spectrum of CFTR mutations in natives of the Reunion Island is dominated by three mutations: DF508 present on 44.3%, Y122X on 26.7% and 3120 + 1G ! Login to comment 85 ABCC7 p.Tyr122* The Cystic Fibrosis database maintained at the Sickkids Hospital in Toronto (Canada) reports that the world-wide frequency of the DF508 mutation is close to 66% and that the Y122X and 3120 + 1G ! Login to comment 86 ABCC7 p.Tyr122* ABCC7 p.Tyr122* ABCC7 p.Tyr122* ABCC7 p.Tyr122* ABCC7 p.Tyr122* A alleles are Table 2 Characteristics of patients homozygous for the Y122X mutation, compound heterozygous for the Y122X and DF508 mutations compared to homozygous for the DF508 mutation (*no significant difference at p = 0.05) DeltaF508/DeltaF508 Y122X/DeltaF508 Y122X/Y122X p values Sex (males/females) 20/8 = 28 8/9 = 17 7/4 = 11 Age at 01/01/2001 (years) Mean age F SD 12.4 F 5.7 12.4 F 6.1 12.4 F 3.8 * Median age 11.5 13.0 12.0 Range 3-24 1-23 7-19 Age at diagnosis (months)a Mean age 31.36 F 44.53 32.50 F 51.2 24.67 F 56.02 * Median age 7.0 8.0 2.0 Range 0-160 1-159 0-139 Sweat chloride concentration (mEq/l) Mean value F SD 106.8 F 33.7 119.9 F 26.7 107.9 F 36.7 * Median value F SD 119.0 114.0 99.5 Range 25-179 110-166 68-175 Status at diagnosis Family history 3 1 1 * Prenatal diagnosis 0 0 2 0.022 Neonatal screening 3 4 3 * Meconium ileus 6 (21.4%) 4 (23.5%) 3 (27.3%) * Dehydration 0 1 0 * Gastrointestinal symptoms 19 (73.1%) 8 (53.3%) 5 (45.4%) * Respiratory symptoms 11 (39.2%) 9 (52.9%) 3 (27.3%) * Nasal polyposis 1 0 0 * Physical status Height (Z score F SD) À 0.572 F 1.095 À 1.007 F 1.025 À 2.164 F 1.474 0.002 Weight (Z score F SD) À 1.180 F 1.092 À 1.621 F1.207 À 2.291 F1.451 0.047 BMI F SD (kg/m2) 16.80 F 2.45 16.11 F1.93 16.23 F 2.79 * Pulmonary status (% of predicted value) FEV1 F SD 73.25 F 25.47 62.74 F 22.74 80.71 F 27.06 * FVC F SD 80.21 F 21.87 66.47 F 16.46 80.21 F19.37 * Throat cultures (nr of patients) Haemophilus influenzae 14 (50.0%) 3 (17.6%) 2 (18.1%) 0.042 Staphylococcus aureus 19 (67.9%) 9 (52.9%) 10 (90.9%) * Pseudomonas aeruginosa 14 (50.0%) 8 (47.0%) 7 (63.6%) * Stenotrophomonas maltophilia 2 0 0 * Burkholderia cepacia 4 1 1 * Aspergillus 6 (21.4%) 8 (47.1%) 6 (54.5%) 0.080 Candida 2 2 1 * Clinical events (number of patients) Cirrhosis 3 (10.7%) 3 (17.6%) 1 (9.1%) * Mellitus diabetes 3 (10.7%) 1 (5.9%) 1 (9.1%) * Gallstones 1 0 1 * Nasal polyposis 4 (14.2%) 6 (36.3%) 4 (36.4%) * a Excluding patients diagnosed prenatally or on familial history and those neonatally screened. Login to comment 89 ABCC7 p.Tyr122* The Y122X mutation was first described by Chevalier-Porst et al. [2] in 1992 in a white native patient of the Reunion Island. Login to comment 90 ABCC7 p.Tyr122* The Y122X mutation was first described by Chevalier-Porst et al. [2] in 1992 in a white native patient of the Reunion Island. Login to comment 91 ABCC7 p.Tyr122* The Cystic Fibrosis Genetic Analysis Consortium counted 14 CF chromosomes carrying the Y122X allele, all coming from France, without specification [3]. Login to comment 92 ABCC7 p.Tyr122* The Cystic Fibrosis Genetic Analysis Consortium counted 14 CF chromosomes carrying the Y122X allele, all coming from France, without specification [3]. Login to comment 103 ABCC7 p.Tyr122* It is presumed that the Y122X mutation was present among the first French settlers, its high frequency being probably the result of a founder effect and isolation from the mainland, followed by genetic drift. Login to comment 104 ABCC7 p.Tyr122* It is presumed that the Y122X mutation was present among the first French settlers, its high frequency being probably the result of a founder effect and isolation from the mainland, followed by genetic drift. Login to comment 106 ABCC7 p.Tyr122* This is the first genotype-phenotype correlation study on the Y122X mutation using a cohort approach. Login to comment 107 ABCC7 p.Tyr122* ABCC7 p.Tyr122* Our results showed that patients carrying the Y122X allele, either in an homozygous or compound heterozygous status, have a severe CF phenotype. Login to comment 108 ABCC7 p.Tyr122* Our results showed that patients carrying the Y122X allele, either in an homozygous or compound heterozygous status, have a severe CF phenotype. Login to comment