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      Analysis of Sequence Variations in the ABCC6 Gene among Patients with Abdominal Aortic Aneurysm and Pseudoxanthoma Elasticum

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          Abstract

          Abdominal aortic aneurysm (AAA) is characterized by dilatation of arterial walls, which is accompanied by degradation of elastin and collagen molecules. Biochemical and environmental factors are known to be relevant for AAA development, and familial predisposition is well recognized. A connective tissue disorder that is also associated with fragmentation of elastic fibers is Pseudoxanthoma elasticum (PXE). PXE is caused by mutations in the ABCC6 gene and mainly affects dermal, ocular and all vascular tissues. To investigate whether variations in ABCC6 are found in AAA patients and to determine mutations in PXE patients, we analyzed seven selected ABCC6 exons of 133 AAA and 54 PXE patients subjected to mutational analysis. In our cohort of AAA patients, we found five ABCC6 alterations, which result in missense or silent amino acid variants. The allelic frequencies of these sequence variations were not significantly different between AAA patients and healthy controls. Therefore, we suggest that alterations in ABCC6 are not a genetic risk factor for AAA. Mutational screening of the PXE patients revealed 19 different ABCC6 variations, including two novel PXE-causing mutations. These results expand the ABCC6 mutation database in PXE.

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          Most cited references 36

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          A computational analysis of sequence features involved in recognition of short introns.

           C Burge,  Emilia Lim (2001)
          Splicing of short introns by the nuclear pre-mRNA splicing machinery is thought to proceed via an "intron definition" mechanism, in which the 5' and 3' splice sites (5'ss, 3'ss, respectively) are initially recognized and paired across the intron. Here, we describe a computational analysis of sequence features involved in recognition of short introns by using available transcript data from five eukaryotes with complete or nearly complete genomic sequences. The information content of five different transcript features was measured by using methods from information theory, and Monte Carlo simulations were used to determine the amount of information required for accurate recognition of short introns in each organism. We conclude: (i) that short introns in Drosophila melanogaster and Caenorhabditis elegans contain essentially all of the information for their recognition by the splicing machinery, and computer programs that simulate splicing specificity can predict the exact boundaries of approximately 95% of short introns in both organisms; (ii) that in yeast, the 5'ss, branch signal, and 3'ss can accurately identify intron locations but do not precisely determine the location of 3' cleavage in every intron; and (iii) that the 5'ss, branch signal, and 3'ss are not sufficient to accurately identify short introns in plant and human transcripts, but that specific subsets of candidate intronic enhancer motifs can be identified in both human and Arabidopsis that contribute dramatically to the accuracy of splicing simulators.
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            Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum.

            Pseudoxanthoma elasticum (PXE) is a heritable disorder characterized by calcification of elastic fibres in skin, arteries and retina that results in dermal lesions with associated laxity and loss of elasticity, arterial insufficiency and retinal haemorrhages leading to macular degeneration. PXE is usually found as a sporadic disorder, but examples of both autosomal recessive and autosomal dominant forms of PXE have been observed. Partial manifestations of the PXE phenotype have also been described in presumed carriers in PXE families. Linkage of both dominant and recessive forms of PXE to a 5-cM domain on chromosome 16p13.1 has been reported (refs 8,9). We have refined this locus to an 820-kb region containing 6 candidate genes. Here we report the exclusion of five of these genes and the identification of the first mutations responsible for the development of PXE in a gene encoding a protein associated with multidrug resistance (ABCC6).
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              Mutations in ABCC6 cause pseudoxanthoma elasticum.

              Pseudoxanthoma elasticum (PXE) is a heritable disorder of the connective tissue. PXE patients frequently experience visual field loss and skin lesions, and occasionally cardiovascular complications. Histopathological findings reveal calcification of the elastic fibres and abnormalities of the collagen fibrils. Most PXE patients are sporadic, but autosomal recessive and dominant inheritance are also observed. We previously localized the PXE gene to chromosome 16p13.1 (refs 8,9) and constructed a physical map. Here we describe homozygosity mapping in five PXE families and the detection of deletions or mutations in ABCC6 (formerly MRP6) associated with all genetic forms of PXE in seven patients or families.
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                Author and article information

                Journal
                JVR
                J Vasc Res
                10.1159/issn.1018-1172
                Journal of Vascular Research
                S. Karger AG
                1018-1172
                1423-0135
                2005
                October 2005
                28 September 2005
                : 42
                : 5
                : 424-432
                Affiliations
                aInstitut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik der Ruhr-Universität Bochum, Bad Oeynhausen, und bDermatologische Klinik, Krankenhaus Bethesda, Freudenberg, Deutschland; cKlinische Abteilung Angiologie, Universitätsklinik für Innere Medizin II, dKlinisches Institut für Medizinische und Chemische Labordiagnostik, und eUniversitätsklinik für Notfallmedizin, Universität Wien, Wien, Österreich
                Article
                87900 J Vasc Res 2005;42:424–432
                10.1159/000087900
                16127278
                © 2005 S. Karger AG, Basel

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                Page count
                Figures: 1, Tables: 3, References: 46, Pages: 9
                Categories
                Research Paper

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