ABCMdb

PMID: 17251343

Shi Y, Terry SF, Terry PF, Bercovitch LG, Gerard GF
Development of a rapid, reliable genetic test for pseudoxanthoma elasticum.
J Mol Diagn. 2007 Feb;9(1):105-12., [PubMed]

Sentences

No. Mutations Sentence Comment

12 ABCC6 p.Arg1141* The ABCC6 gene (Online Mendelian Inheritance of Man no. 603234) consists of 31 exons on human chromosome 16p13.1.36 The gene encodes a protein (ABCC6/MRP6) belonging to the ATP-binding cassette membrane transporter family with 1503 amino acid residues, three transmembrane segments consisting of 17 hydrophobic helices, and two conserved nucleotide binding domains (NBD1 and NBD2).7-9 ABCC6 gene mutations have been associated with autosomal recessive and sporadic forms of PXE.5,10 -13 At present, some 150 causative mutations in this gene have been observed in different populations, with most mutations being missense, nonsense, deletion/insertion, or splice site alterations clustered toward the large carboxyl-terminal end of ABCC6/MRP6 in NBD1 and NBD2.5,10 -30 The most frequent mutations in North American, European, and South African populations are c.3421CϾT (p.R1141X) in exon 24 and Alu-mediated deletion of sequences between exon 23 and 29 (ex23_ex29del).14,16,18,19,21,23 Mutations in the ABCC6 gene that cause PXE allow development of genetic tests for accurate clinical diagnosis, differential diagnosis from PXE-like phenotypes (eg, PXE-like papillary dermal elastolysis and fibroelastolytic papulosis, periumbilical perforating PXE, PXE-like presentation of beta-thalassemia, and acquired PXE syndromes), and predictive preclinical diagnosis to allow for possible intervention and for timely genetic counseling. Login to comment 31 ABCC6 p.Arg1141* The c.3421CϾT (p.R1141X) mutation in exon 24 and the deletion between exon 23 and exon 29 (ex23_ex29del) are those most commonly found in phenotypically positive samples.14,16,18,19,21,23 This published study and unpublished research sponsored by PXE International, in collaboration with Transgenomic, Inc.; Jefferson Medical College, Philadelphia, PA; Ghent University, Ghent, Belgium; and the University of Witwatersrand, Johannesburg, South Africa, determined that mutations in exons 24 and 28 and the deletion of exons 23 to 29 account for ϳ70% of the ABCC6 gene mutations in individuals affected by PXE. Login to comment 76 ABCC6 p.Arg1141* ABCC6 p.Arg1138Gln ABCC6 p.Arg1138Trp Because of the one base position difference between mutation c.3412CϾT (p.R1138W) and c.3413GϾA (p.R1138Q) in exon 24 and the 8- and 9-base position differences between the c.3413GϾA and c.3412CϾT mutations and the c.3421CϾT (p.R1141X) mutation in exon 24, the cleavage fragments from these mutations could not be distinguished by agarose gel electrophoresis. Login to comment 82 ABCC6 p.Arg1141* ABCC6 p.Arg1138Gln ABCC6 p.Arg1138Trp ABCC6 p.Arg1164* ABCC6 p.Gly1302Arg ABCC6 p.Arg1339Cys ABCC6 p.Arg1314Gln ABCC6 p.Thr1130Met Nuclease Digestion Fragment Sizes of Common Mutations in PXE Exon 24 and 28 Amino acid change Base change Fragment lengths (bp) p.T1130M c.3389CϾT 251,257/508 p.R1138W c.3412CϾT 274,234/508 p.R1138Q c.3413GϾA 275,233/508 p.R1141X c.3421CϾT 281,227/508 p.R1164X c.3490CϾT 352,156/508 p.G1302R c.3904GϾA 116,289/405 p.R1314Q c.3941GϾA 153,252/405 p.R1339C c.4015CϾT 227,178/405 The total lengths of the amplicons are listed after the slash. Login to comment 84 ABCC6 p.Gly1302Arg ABCC6 p.Arg1339Cys Patients 5 and 16 each had a mutation corresponding to c.4015CϾT (p.R1339C) (cleavage fragments of ϳ180 and ϳ230 bp), and patients 8 and 9 had one mutation corresponding to c.3904GϾA (p.G1302R) (fragments of ϳ120 and ϳ290 bp). Login to comment 105 ABCC6 p.Leu946Ile The one patient DNA, patient 10, that lacked mutations in the regions tested was found to have the mutation c.2836CϾA (p.L946I) in exon 22 by denaturing high-performance liquid chromatography and DNA sequencing (data not shown). Login to comment 107 ABCC6 p.Arg1141* ABCC6 p.Arg1164* ABCC6 p.Arg1339Cys The two most prevalent mutations were the nonsense mutations c.3421CϾT (p.R1141X) and c.3490CϾT (p.R1164X) in exon 24. c.3421CϾT is the most common mutation found in PXE patients of European origin.14,19,20,23,29 c.3490CϾT is a common mutation in individuals of British descent.16,21 Two DNA samples carried the c.3490CϾT (p.R1339C) missense mutation in one exon 28 allele, and in both cases, IVS28 ϩ 49CϾT was also present. Login to comment 130 ABCC6 p.Arg1141* Recently, a multiphase strategy was described to screen for PXE mutations in the total coding sequence of the ABCC6 gene.25 PCR-RFLP and long-range PCR were used initially to detect the most common PXE mutations, c.3421CϾT (p.R1141X) and ex23_ex29del, respectively. Login to comment