Abstract
Single mutations in the ATP-binding cassette transporter (ABCC6) gene (OMIM 603234) are known to cause the rare autosomal recessive disease pseudoxanthoma elasticum (PXE). Recently, we have found that copy number variations (CNVs) in pseudogenes of the ABCC6 gene are quite common. The aim of this study was to investigate the frequency and possible contribution of CNV in ABCC6 and its pseudogenes in PXE. Genomic DNA from 212 PXE individuals were examined for copy number by pyrosequencing and quantitative polymerase chain reaction (PCR) and compared with healthy individuals. The frequency of PXE individuals with any CNV was higher than in healthy individuals. The majority of variation comprised known and possibly new deletions in the ABCC6 gene and duplications of the ABCC6P1 and ABCC6P2 genes. ABCC6 deletions and ABCC6P2 duplications were not observed in 142 healthy individuals. In conclusion, by pyrosequencing and quantitative PCR, we were able to detect known and possibly new deletions in the ABCC6 gene that may have caused the PXE phenotype. Pyrosequencing may be used in PXE patients who have obtained incomplete genotype from conventional techniques. The frequency of ABCC6P2 pseudogene duplication was more common in PXE patients than healthy individuals and may affect the PXE phenotype.
Highlights
The ATP-binding cassette transporter ABCC6 belongs to a large family of membrane proteins (ABC transporters) that are highly conserved and present in all organisms from bacteria to man (Higgins 1992)
Single mutations in ABCC6 are known to cause the rare, autosomal recessive disease pseudoxanthoma elasticum (PXE, OMIM 264800), a metabolic disorder characterized by ectopic mineralization of soft connective tissues (Li et al 2009; Plomp et al 2010; Uitto et al 2010)
Five patients were excluded from further analysis because of inconclusive copy number results. Both deletions and duplications were found for ABCC6, ABCC6P1, and ABCC6P2 in the PXE patients
Summary
The ATP-binding cassette transporter ABCC6 belongs to a large family of membrane proteins (ABC transporters) that are highly conserved and present in all organisms from bacteria to man (Higgins 1992). Pseudogenes are generally defined as nonfunctional, meaning that they cannot produce a functional protein (Mighell et al 2000; Balakirev and Ayala 2003). We could show that a significant fraction of the ABC-transporter pseudogenes are transcribed. Single mutations in ABCC6 are known to cause the rare (prevalence between 1:25,000 and 1:100,000), autosomal recessive disease pseudoxanthoma elasticum (PXE, OMIM 264800), a metabolic disorder characterized by ectopic mineralization of soft connective tissues (Li et al 2009; Plomp et al 2010; Uitto et al 2010). Patients with PXE typically present with pathological findings in the a 2015 The Authors.
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