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      ABCC6 and Pseudoxanthoma Elasticum: The Face of a Rare Disease from Genetics to Advocacy

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          Abstract

          Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder characterized by the mineralization of connective tissues in the body. Primary manifestation of PXE occurs in the tissues of the skin, eyes, and cardiovascular system. PXE is primarily caused by mutations in the ABCC6 gene. The ABCC6 gene encodes the trans-membrane protein ABCC6, which is highly expressed in the kidneys and liver. PXE has high phenotypic variability, which may possibly be affected by several modifier genes. Disease advocacy organizations have had a pivotal role in bringing rare disease research to the forefront and in helping to sustain research funding for rare genetic diseases in order to help find a treatment for these diseases, pseudoxanthoma elasticum included. Because of these initiatives, individuals affected by these conditions benefit by being scientifically informed about their condition, having an effective support mechanism, and also by contributing to scientific research efforts and banking of biological samples. This rapid progress would not have been possible without the aid of disease advocacy organizations such as PXE International.

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          Most cited references 32

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          An integrated semiconductor device enabling non-optical genome sequencing.

          The seminal importance of DNA sequencing to the life sciences, biotechnology and medicine has driven the search for more scalable and lower-cost solutions. Here we describe a DNA sequencing technology in which scalable, low-cost semiconductor manufacturing techniques are used to make an integrated circuit able to directly perform non-optical DNA sequencing of genomes. Sequence data are obtained by directly sensing the ions produced by template-directed DNA polymerase synthesis using all-natural nucleotides on this massively parallel semiconductor-sensing device or ion chip. The ion chip contains ion-sensitive, field-effect transistor-based sensors in perfect register with 1.2 million wells, which provide confinement and allow parallel, simultaneous detection of independent sequencing reactions. Use of the most widely used technology for constructing integrated circuits, the complementary metal-oxide semiconductor (CMOS) process, allows for low-cost, large-scale production and scaling of the device to higher densities and larger array sizes. We show the performance of the system by sequencing three bacterial genomes, its robustness and scalability by producing ion chips with up to 10 times as many sensors and sequencing a human genome.
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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
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                11 July 2017
                July 2017
                : 18
                : 7
                Affiliations
                [1 ]Department of Biology, Trinity Washington University, College Of Arts and Sciences, 125 Michigan Avenue NE, Washington, DC 20017, USA; GarciaS@ 123456students.trinitydc.edu (S.G.); JaldinM@ 123456students.trinitydc.edu (M.J.); EtoundiC@ 123456students.trinitydc.edu (C.E.); CooperD@ 123456students.trinitydc.edu (D.C.); RolandA@ 123456students.trinitydc.edu (A.R.); DixonP@ 123456students.trinitydc.edu (P.D.); ReyesS@ 123456students.trinitydc.edu (S.R.); TuranS@ 123456trinitydc.edu (S.T.)
                [2 ]PXE International, 4301 Connecticut Avenue NW, Suite 404, Washington, DC 20008, USA; sterry@ 123456pxe.org
                [3 ]Laboratory of Translational Genomics, The Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute, National Institutes of Health, Gaithersburg, MD 20885, USA
                Author notes
                [* ]Correspondence: MoitraK@ 123456trinitydc.edu (K.M.); Deanm@ 123456mail.nih.gov (M.D.); Tel.: +1-202-884-9225 (K.M.); +1-240-760-6484 (M.D.); Fax: +1-202-884-9229 (K.M.); +1-301-402-3134 (M.D.)
                Article
                ijms-18-01488
                10.3390/ijms18071488
                5535978
                28696355
                © 2017 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

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