ABCMdb

PMID: 10777364

Wang J, Bowman MC, Hsu E, Wertz K, Wong LJ
A novel mutation in the CFTR gene correlates with severe clinical phenotype in seven Hispanic patients.
J Med Genet. 2000 Mar;37(3):215-8., [PubMed]

Sentences

No. Mutations Sentence Comment

237 ABCC7 p.Trp1282* For example, the frequency of the W1282X mutation is 1.2% in the white population, but it is as high as 60% in Ashkenazi Jews.8 That of F508 is 70% in northern Europeans but it is less than 50% in Spanish and Hispanics.7 9 In order to provide accurate genetic counselling, it is necessary to determine the prevalent mutations in each ethnic group. Login to comment 240 ABCC7 p.Trp1282* The clinical diagnosis of CF has been recently reviewed.10 Although the structure and function of F508 and W1282X mutant CFTR have been studied, there is a shortage of genotype-phenotype correlation studies of rare mutations, particularly the ones that appear to be unique to Hispanic CF patients. Login to comment 241 ABCC7 p.Arg1066Cys This is partly because of the lack of an eVective method for screening the mutations in the large CFTR gene and because a significant proportion (about 40%) of Hispanic CF mutations have not been identified.9 We recently described the clinical features of a patient homozygous for R1066C and a group of Hispanic patients with the 3849+10kbC>T mutation.11 12 In an eVort to continue searching for unknown CF mutations in Hispanic patients, we have developed an eVective method, temporal temperature gradient gel electrophoresis (TTGE), to screen DNA abnormalities in CF chromosomes and have identified several novel mutations. Login to comment 290 ABCC7 p.Leu1258* The deleterious frameshift mutation, 3876delA (L1258X), was detected in six out of 29 unrelated Hispanic CF patients attending the CHLA CF clinic. Login to comment 292 ABCC7 p.Gly542* The frequency of this mutation in the Hispanic CF patients attending CHLA is similar to that of G542X, only second to F508. Login to comment 294 ABCC7 p.Trp1282* ABCC7 p.Trp1282* ABCC7 p.Trp1282* Like those with F508/ F508, F508/W1282X, and W1282X/W1282X, patients with the 3876delA/ F508 mutation had variable pulmonary function. Login to comment 320 ABCC7 p.Trp1282* ABCC7 p.Gly1244Glu ABCC7 p.Gly1349Asp ABCC7 p.Ser1255Pro ABCC7 p.Ser1255Pro ABCC7 p.Asn1303Lys ABCC7 p.Ser1255* ABCC7 p.Ser1255* Since ATP hydrolysis at NBD2 terminates a burst of activities associated with opening the channel, loss of NBD2 would confer a loss of the gating control.21 A recent study shows that the Walker A motif in NBD2 is more solvent accessible than that in NBD1, suggesting a diVerence in structure and function for the two NBDs.22 In addition to 3876delA, a few other mutations in NBD2, including G1244E, S1255P, S1255X, 3905insT, W1282X, N1303K, and G1349D, all result in a PI phenotype.5 23 It should be noted that S1255P, S1255X, 3905insT, and 3876delA are all clustered around the Walker A motif. Login to comment 339 ABCC7 p.Trp1282* Hum Genet 1997;101:365-70. 8 Shoshani T, Augarten A, Gazit E, et al. Association of a nonsense mutation (W1282X), the most common mutation in the Ashkenazi Jewish cystic fibrosis patients in Israel, with presentation of severe disease. Login to comment 343 ABCC7 p.Arg1066Cys Cystic fibrosis in a Puerto Rican female homozygous for the R1066C mutation. Login to comment 552 ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu The proportion of patients homozygous for F508 remains quite constant between the three age groups, whereas there is a decline in that of the patients carrying the 621+1G→T/ F508 genotype and an increase of those having a F508/A455E or 621+1G→T/A455E genotype. Login to comment 554 ABCC7 p.Ala455Glu The A455E mutation group contains all the patients with that mutation, independently of the second mutation composing their genotype. Login to comment 555 ABCC7 p.Ala455Glu The CF patients carrying the 621+1G→T mutation, but not A455E, were included in a unique group. Login to comment 556 ABCC7 p.Ala455Glu Patients homozygous or compound heterozygous for the F508 mutation, without the 621+1G→T or the A455E mutation, were grouped together. Login to comment 557 ABCC7 p.Ala455Glu We observed an increase of A455E and a depletion of 621+1G→T at older age groups, whereas the frequency of the F508 mutation stayed constant (table 1B). Login to comment 559 ABCC7 p.Ala455Glu The Kaplan-Meier survival analysis could not be performed considering the three mutations because there were no dead patients in the A455E group. Login to comment 564 ABCC7 p.Ala455Glu The F508 and 621+1G→T alleles are known to be severe mutations conferring pancreatic insuYciency when they are combined with another severe mutation.4 8 9 The A455E allele is a mild mutation associated with pancreatic suYciency and exerts a dominant eVect on the severe mutations. Login to comment 565 ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu Compound heterozygotes for the A455E mutation have a milder pulmonary disease, no meconium ileus, and no late complications, such as diabetes and liver cirrhosis.2 Therefore, since pulmonary insuYciency is the major cause of mortality in cystic fibrosis, it is not unexpected that no CF patients carrying the A455E mutation have died unlike the 13% of those with two severe mutations. Login to comment 570 ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Asn1303Lys ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr ABCC7 p.Gly85Glu ABCC7 p.Arg1158* ABCC7 p.Tyr1092* ABCC7 p.Tyr1092* ABCC7 p.Arg117Cys ABCC7 p.Ser489* ABCC7 p.Gln890* SYLVAIN R RIVARD* CHRISTIAN ALLARD† JEAN-PIERRE LEBLANC† MARCEL MILOT† GERVAIS AUBIN† FERNAND SIMARD† CLAUDE FÉREC‡ MARC DE BRAEKELEER†§¶ *Département des Sciences Fondamentales, Université du Québec à Chicoutimi, Canada Table 1 Distribution of cystic fibrosis patients diagnosed before the age of 5 by age groups in Saguenay-Lac-Saint-Jean, (A) by genotype, (B) by mutation 0-10 years 10.1-20 years Over 20 years All ages No % No % No % No % (A) Genotype F508/ F508 15 (1) 40.5 21 (2) 36.2 18 (3) 42.9 54 (6) 39.4 F508/621+1G→T 12 (1) 32.4 16 (1) 27.6 10 (1*) 23.8 38 (3*) 27.7 F508/A455E 1 2.7 6 10.3 5 11.9 12 8.8 F508/I148T 1 2.7 1 1.7 2 1.5 F508/Y1092X 3 (1) 5.2 1 2.4 4 (1) 2.9 F508/Q890X 1 2.4 1 0.7 F508/R1158X 1 2.4 1 0.7 621+1G→T/621+1G→T 2 (1) 5.4 4 6.9 1 2.4 7 (1) 5.1 621+1G→T/A455E 1 2.7 4 6.9 3 7.1 8 5.8 621+1G→T/711+1G→T 2 (1) 5.4 2 (1) 3.4 4 (2) 2.9 621+1G→T/Y1092X 1 2.7 1 0.7 621+1G→T/S489X 1 2.7 1 0.7 621+1G→T/G85E 1 (1) 1.7 1 (1) 2.4 2 (2) 1.5 A455E/R117C 1 2.7 1 0.7 N1303K/I148T 1 2.4 1 0.7 Total 37 58 42 137 Death (4) 10.8 (6) 10.3 (5*) 11.9 (15*) 10.9 (B) Mutation F508 16 (1) 43.2 25 (3) 43.1 21 (3) 51.2 62 (7) 45.6 621+1G→T 18 (3) 48.6 23 (3) 39.7 12 (2*) 29.3 53 (8*) 39.0 A455E 3 8.1 10 17.2 8 19.5 21 15.4 Total 37 58 41 136 Death (4) 10.8 (6) 10.3 (5*) (12.2) (15*) (11.0) ( ): Number of deaths. Login to comment 573 ABCC7 p.Ala455Glu 1 0.8 0.6 0.4 0.2 0 50 Age (y) A455E mutation ∆F508 mutation 621 + 1G T mutation Cumulativesurvival 0 40302010 Letters †Clinique de Fibrose Kystique, Complexe Hospitalier de la Sagamie, Chicoutimi, Canada ‡Établissement de Transfusion Sanguine de Bretagne Occidentale (ETSBO), Brest, France §Institut National d`Etudes Démographiques, Paris, France ¶Laboratoire d`Anthropologie et de Démographie Génétiques, Faculté des Sciences de l`Homme, Université Victor Segalen Bordeaux 2, 3ter Place de la Victoire, F-33076 Bordeaux Cedex, France 1 Boat TF, Welsh MJ, Beaudet AL. Cystic fibrosis. Login to comment 576 ABCC7 p.Ala455Glu New York: McGraw-Hill, 1989:2649-80. 2 De Braekeleer M, Allard C, Leblanc JP, Simard F, Aubin G. Genotype-phenotype correlation in cystic fibrosis patients compound heterozygous for the A455E mutation. Login to comment