ABCMdb

PMID: 10913334

Germain DP, Perdu J, Remones V, Jeunemaitre X
Homozygosity for the R1268Q mutation in MRP6, the pseudoxanthoma elasticum gene, is not disease-causing.
Biochem Biophys Res Commun. 2000 Aug 2;274(2):297-301., 2000-08-02 [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCC6 p.Arg1268Gln Homozygosity for the R1268Q Mutation in MRP6, the Pseudoxanthoma Elasticum Gene, Is Not Disease-Causing Dominique P. Germain,1 Je´roˆme Perdu, Ve´ronique Remones, and Xavier Jeunemaitre De´partement de Ge´ne´tique, Hoˆpital Europe´en Georges Pompidou, Universite´ Paris VI, Paris, France Received June 13, 2000 Pseudoxanthoma elasticum (PXE) is an inherited systemic disorder of connective tissue, characterized by progressive calcification of the elastic fibers in the eye, the skin, and the cardiovascular system, resulting in decreased vision, skin lesions, and life-threatening vascular disease, with highly variable phenotypic expression. Login to comment 4 ABCC6 p.Arg1141* ABCC6 p.Arg1268Gln In one large PXE pedigree for which we had identified a nonsense mutation (R1141X), we came across a G to A transition at position 3803 of the MRP6 cDNA sequence (R1268Q). Login to comment 6 ABCC6 p.Arg1268Gln We investigated the R1268Q mutation, and found the Q1268 allele at a relatively high frequency (0.19) in a Caucasian control population (n ‫؍‬ 62 subjects). Login to comment 8 ABCC6 p.Arg1268Gln These data indicate that the R1268Q variant in the MRP6 gene does not cause PXE per se. Login to comment 18 ABCC6 p.Arg1141* ABCC6 p.Arg1268Gln During our molecular analysis of the MRP6 gene in PXE patients, we came across a G to A transition at position 3803 of the cDNA sequence, altering the codon (CGG) for arginine to the codon (CAG) for glutamine (R1268Q) in a pedigree in which we had previously identified a nonsense mutation (R1141X). Login to comment 19 ABCC6 p.Arg1268Gln In the present study, the R1268Q mutation was investigated in relatives of our PXE patients and in a control population, to determine if this amino-acid change was a disease-causing mutation or a neutral polymorphism. Login to comment 39 ABCC6 p.Arg1268Gln Mutation R1268Q predicted the creation of a novel restriction site for BstX I. Login to comment 42 ABCC6 p.Arg1268Gln Mutation R1268Q also predicted the loss of a Msp I restriction site. Login to comment 49 ABCC6 p.Arg1141* During our mutational analysis, we found a heterozygous C to T transition at cDNA position 3421 of the MRP6 gene, predicting termination of translation at codon 1141 (R1141X) (Fig. 2). Login to comment 51 ABCC6 p.Arg1268Gln This nucleotide substitution alters the codon (CGG) for arginine to the codon (CAG) for glutamine (R1268Q). Login to comment 52 ABCC6 p.Arg1268Gln Restriction digests using BstX I, performed to examine family relatives, showed that both affected patients (II-3 and II-5) and their asymptomatic mother (I-2) were heteroallelic for R1268Q at the genomic level, the father (I-1) being a wild type homozygote. Login to comment 53 ABCC6 p.Arg1268Gln However, the proband`s asymptomatic husband (individual II-6 in Fig. 1) was found to be homozygote for R1268Q, ruling out a causative role for homozygosity for this mutation in the clinical phenotype observed in PXE patients. Login to comment 54 ABCC6 p.Arg1268Gln Mutation R1268Q also predicted the loss of a Msp I restriction site. Login to comment 57 ABCC6 p.Arg1268Gln The R1268Q mutation was identified in 24 of the 124 tested alleles, and its overall frequency was 0.19 (Fig. 3). Login to comment 60 ABCC6 p.Arg1268Gln Our results indicate that the R1268Q mutation in the MRP6 gene is a neutral polymorphism, which does not cause pseudoxanthoma elasticum when present at the homozygous state. Login to comment 66 ABCC6 p.Arg1268Gln During our mutational scanning of the MRP6 gene, in two sisters affected with pseudoxanthoma elasticum, a G to A transition, was detected at position 3803 of the MRP6 cDNA sequence, predicting a R1268Q missense mutation at the protein level. Login to comment 75 ABCC6 p.Arg1141* Detection of the R1141X nonsense mutation by direct sequencing of the MRP6 gene in the proband. Login to comment 98 ABCC6 p.Arg1268Gln We have therefore investigated the R1268Q substitution to determine its frequency, and have found its frequency to be high in a Caucasian control population. Login to comment 100 ABCC6 p.Arg1268Gln It is interesting to note that the authors also detected the R1268Q mutation in their patients population, although always in the context of compound heterozygosity. Login to comment 101 ABCC6 p.Arg1268Gln Whether the R1268Q mutation may lead to the clinical phenotype observed in patients with PXE, when found in association with another, potentially more severe, mutation in the MRP6 gene remains to be elucidated. Login to comment 103 ABCC6 p.Arg1268Gln In conclusion, while screening the MRP6 gene in patients affected with PXE, we have identified, beside disease-causing mutations, a 3803G Ͼ A transition (R1268Q) which was shown to be a harmless polymorphism when present at the homozygous state. Login to comment