ABCMdb

PMID: 8528204

Savov A, Angelicheva D, Balassopoulou A, Jordanova A, Noussia-Arvanitakis S, Kalaydjieva L
Double mutant alleles: are they rare?
Hum Mol Genet. 1995 Jul;4(7):1169-71., [PubMed]

Sentences

No. Mutations Sentence Comment

23 ABCC7 p.Arg3Trp A C-»T transition at nucleotide position 136 generates a termination codon at amino acid position 2 (Q2X) and an A->G transition at position 139 results in the substitution of tryptophan for arginine at amino acid position 3 (R3W). Login to comment 28 ABCC7 p.Gly85Glu ABCC7 p.Leu88* ABCC7 p.Leu88* ABCC7 p.Leu88* (A) SSCP analysis of the 309 bp PCR product of exon 3 of the CFTR gene (primers 3i-5 and 3i-3); 12% 37.5:1 acrylamide:bisacrylamide gel run at 4°C, 1600 V for 24 h. Lanes 1, 2, 8, 9, 10, normal controls; lane 3, G85E/N heterozygote; lanes 4, 5, 7, L88X/N heterozygotes; lane 6, L88X/ L88X homozygote. Login to comment 30 ABCC7 p.Gly1069Arg ABCC7 p.Gly1069Arg ABCC7 p.Gly1069Arg SSCP analysis performed on 14% 37.5:1 acrylamide:bisacrylamide gel at 18°C, 1600 V for 24 h. Lanes 3, 4, 9, normal controls, lanes 1, 2, 6, 7, 8, 10, G1069R/N heterozygotes; lane 5, G1069R/G1069R homozygote. Login to comment 31 ABCC7 p.Gly1069Arg ABCC7 p.Gly1069Arg ABCC7 p.Leu88* G1069R and L88X A G->A transition at nucleotide position 3337 (exon 17b) which results in the substitution of arginine for glycine at amino acid position 1069 in the second transmembrane domain of the protein (TM10), in combination with a T-»G transversion at position 395 generating a termination signal at codon 88 was originally identified in the maternal CF allele of a patient from western Bulgaria (7). Login to comment 33 ABCC7 p.Gly1069Arg ABCC7 p.Leu88* Both patients are compound heterozygotes for the G1069R + L88X allele and AF508 and have a classical CF phenotype with pancreatic insufficiency and severe pulmonary involvement. Login to comment 35 ABCC7 p.Gly1069Arg The G1069R mutation has been detected in two CF patients from neighbouring Greece. Login to comment 36 ABCC7 p.Gly1069Arg One of the patients was found to be homozygous for G1069R. Login to comment 37 ABCC7 p.Gly1069Arg ABCC7 p.Leu88* Subsequent SSCP analysis and direct sequencing of exon 3 of the CFTR gene revealed that this patient was in fact a homozygote for the double mutant G1069R + L88X allele (Fig. Login to comment 39 ABCC7 p.Gly1069Arg The second Greek patient was found to carry G1069R alone, with AF5O8 on the other CF allele. Login to comment 41 ABCC7 p.Gly1069Arg ABCC7 p.Gly1069Arg ABCC7 p.Leu88* Severe cystic fibrosis with pancreatic insufficiency is present in the G1069R + L88X homozygote and, more important, in the patient who carries G1069R alone. Login to comment 42 ABCC7 p.Gly1069Arg ABCC7 p.Leu88* Polymorphic analysis of RFLPs flanking the CFTR gene and of intragenic microsatellite repeats demonstrated that all double mutant G1069R + L88X alleles share a common haplotype 1-2-16-30 (for KM. 19-XV.2c-IVS8CA-IVS 17bTA) (8-11). Login to comment 43 ABCC7 p.Gly1069Arg The allele which carried G1069R alone belonged to a different haplotype, namely 1-1-17-31 (for KM.19-XV.2c- IVS8CA-IVS17bTA). Login to comment 44 ABCC7 p.Gly542* ABCC7 p.Ser912Leu ABCC7 p.Gly1244Val S912L and G1244V A C->T transition at nucleotide position 2867 in exon 15 and a G->T transversion at position 3863 in exon 20 of the CFTR gene were found in a patient who also carries G542X. Login to comment 45 ABCC7 p.Ser912Leu ABCC7 p.Gly1244Val The first missense mutation results in the substitution of leucine for serine (S912L) in the transmembrane region of the CFTR protein (TM8), whereas the second leads to the replacement of glycine by valine (G1244V) in the second nucleotide binding domain. Login to comment 50 ABCC7 p.Arg553Gln ABCC7 p.Phe508Cys An additional nucleotide substitution, R553Q, has been shown to result in lower sweat electrolyte values in a patient homozygous for AF5O8 (4) and a combination of a neutral amino acid polymorphism (F508C) with another missense mutation (SI25IN) has been found to result in cystic fibrosis (5). Login to comment 51 ABCC7 p.Gly1069Arg ABCC7 p.Leu88* Two of the double mutant alleles identified in this study carry one nonsense and one missense mutation (Q2X+R3W and L88X + G1069R). Login to comment 53 ABCC7 p.Gly1069Arg Yet the nature of the amino acid substitution in both R3W and G1069R is serious enough for these mutations to be considered good candidates for disease-causing defects. Login to comment 54 ABCC7 p.Gly1069Arg ABCC7 p.Leu88* In the case of G1069R this is supported by the clinical findings in the Greek patient with this mutation (and without L88X) who has a severe CF phenotype. Login to comment 55 ABCC7 p.Ser912Leu ABCC7 p.Gly1244Val The other double mutant CF allele detected in this study carries two missense mutations (S912L + G1244V) whose independent contribution to the clinical phenotype is difficult to evaluate. Login to comment 56 ABCC7 p.Gly1244Glu ABCC7 p.Gly1244Glu Another mutation (G1244E), has been found to result from a different substitution at the same nucleotide position, namely G->A at nt 3863 in codon 1244 where glycine is replaced by glutamic acid. Login to comment 57 ABCC7 p.Gly1244Glu G1244E was initially described in an Italian patient with a mild CF phenotype (12) and has been detected in two pancreatic sufficient patients in our study. Login to comment 58 ABCC7 p.Gly1244Val The substitution of valine for glycine in G1244V may in itself result in conformational changes in an important protein domain which are more pronounced than those caused by the substitution of glutamic acid. Login to comment 59 ABCC7 p.Ser912Leu ABCC7 p.Ser912Leu ABCC7 p.Gly1244Val ABCC7 p.Gly1244Val It is also possible that G1244V alone would result in mild CF and that S912L is the main defect in the double mutant S912L + G1244V allele. Login to comment 65 ABCC7 p.Gly1069Arg ABCC7 p.Gly1069Arg ABCC7 p.Leu88* In the case of G1069R + L88X, a patient from the same geographic area has been found to carry G1069R alone, but on a chromosomal background which was different from that of the double mutant allele. Login to comment 66 ABCC7 p.Gly1069Arg ABCC7 p.Gly1069Arg ABCC7 p.Leu88* The different polymorphic characteristics of the two alleles may suggest that the origin of G1069R is independent of that of G1069R + L88X. Login to comment 67 ABCC7 p.Ser912Leu ABCC7 p.Gly1244Val Neither S912L nor G1244V have been found to occur in isolation in any of our patients. Login to comment