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Type: Journal article
Title: Molecular genetics of pseudoxanthoma elasticum: Type and frequency of mutations in ABCC6
Author: Miksch, S.
Lumsden, A.
Guenther, U.
Foernzler, D.
Christen-Zach, S.
Daugherty, C.
Ramesar, R.
Lebwohl, M.
Hohl, D.
Neldner, K.
Lindpaintner, K.
Richards, R.
Struk, B.
Citation: Human Mutation, 2005; 26(3):235-248
Publisher: Wiley-Liss
Issue Date: 2005
ISSN: 1059-7794
Organisation: Centre for the Molecular Genetics of Development
Statement of
Sara Miksch, Amanda Lumsden, Ulf P. Guenther, Dorothee Foernzler, Stéphanie Christen-Zäch, Carol Daugherty, Raj Kumar S. Ramesar, Mark Lebwohl, Daniel Hohl, Kenneth H. Neldner, Klaus Lindpaintner, Robert I. Richards and Berthold Struk
Abstract: Pseudoxanthoma elasticum (PXE) is a systemic heritable disorder that affects the elastic tissue in the skin, eye, and cardiovascular system. Mutations in the ABCC6 gene cause PXE. We performed a mutation screen in ABCC6 using haplotype analysis in conjunction with direct sequencing to achieve a mutation detection rate of 97%. This screen consisted of 170 PXE chromosomes in 81 families, and detected 59 distinct mutations (32 missense, eight nonsense, and six likely splice-site point mutations; one small insertion; and seven small and five large deletions). Forty-three of these mutations are novel variants, which increases the total number of PXE mutations to 121. While most mutations are rare, three nonsense mutations, a splice donor site mutation, and the large deletion comprising exons 23-29 (c.2996_4208del) were identified as relatively frequent PXE mutations at 26%, 5%, 3.5%, 3%, and 11%, respectively. Chromosomal haplotyping with two proximal and two distal polymorphic markers flanking ABCC6 demonstrated that most chromosomes that carry these relatively frequent PXE mutations have related haplotypes specific for these mutations, which suggests that these chromosomes originate from single founder mutations. The types of mutations found support loss-of-function as the molecular mechanism for the PXE phenotype. In 76 of the 81 families, the affected individuals were either homozygous for the same mutation or compound heterozygous for two mutations. In the remaining five families with one uncovered mutation, affected showed allelic compound heterozygosity for the cosegregating PXE haplotype. This demonstrates pseudo-dominance as the relevant inheritance mechanism, since disease transmission to the next generation always requires one mutant allelic variant from each parent. In contrast to other previous clinical and molecular claims, our results show evidence only for recessive PXE. This has profound consequences for the genetic counseling of families with PXE.
Keywords: PXE; membrane transporter proteins; ABC cassette proteins; ABCC6; founder mutations; haplotype analysis
Description: The definitive version may be found at
Rights: © 2005 Wiley-Liss, Inc.
RMID: 0020050950
DOI: 10.1002/humu.20206
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Appears in Collections:Molecular and Biomedical Science publications
Centre for the Molecular Genetics of Development publications

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