Molecular genetics of pseudoxanthoma elasticum: type and frequency of mutations in ABCC6
| Autor: | Dorothee Foernzler, Ulf-Peter Guenther, Klaus Lindpaintner, Mark Lebwohl, Robert I. Richards, Stephanie Christen-Zäch, Sara Miksch, Kenneth H. Neldner, Carol Daugherty, Rajkumar Ramesar, Berthold Struk, Amanda L. Lumsden, Daniel Hohl |
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| Rok vydání: | 2005 |
| Předmět: |
Genetic Markers
Male medicine.medical_specialty Genotype Nonsense mutation DNA Mutational Analysis Molecular Sequence Data Biology medicine.disease_cause Compound heterozygosity Molecular genetics Genetics medicine Missense mutation Humans Amino Acid Sequence Pseudoxanthoma Elasticum Genetics (clinical) Mutation Polymorphism Genetic Models Genetic Point mutation Haplotype Pseudoxanthoma elasticum medicine.disease Molecular biology Haplotypes Female Multidrug Resistance-Associated Proteins |
| Zdroj: | Human mutation. 26(3) |
| ISSN: | 1098-1004 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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