RGD Reference Report - A novel Q378X mutation exists in the transmembrane transporter protein ABCC6 and its pseudogene: implications for mutation analysis in pseudoxanthoma elasticum. - Rat Genome Database

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A novel Q378X mutation exists in the transmembrane transporter protein ABCC6 and its pseudogene: implications for mutation analysis in pseudoxanthoma elasticum.

Authors: Cai, L  Lumsden, A  Guenther, UP  Neldner, SA  Zach, S  Knoblauch, H  Ramesar, R  Hohl, D  Callen, DF  Neldner, KH  Lindpaintner, K  Richards, RI  Struk, B 
Citation: Cai L, etal., J Mol Med (Berl). 2001 Sep;79(9):536-46.
RGD ID: 11038785
Pubmed: PMID:11692167   (View Abstract at PubMed)
DOI: DOI:10.1007/s001090100275   (Journal Full-text)

Pseudoxanthoma elasticum (PXE) is an inherited disorder of the elastic tissue with characteristic progressive calcification of elastic fibers in skin, eye, and the cardiovascular system. Recently mutations in the ABCC6 gene, encoding a transmembrane transporter protein, were identified as cause of the disease. Surprisingly, sequence and RFLP analysis for exon 9 with primers corresponding to flanking intronic sequence in diseased and haplotype negative members from all of our families and in a control population revealed either a homozygous or heterozygous state for the Q378X (1132C-->T) nonsense mutation in all individuals. With the publication of the genomic structure of the PXE locus we had identified the starting point of a large genomic segmental duplication within the locus in the cytogenetic interval defined by the Cy19 and Cy185 somatic cell hybrid breakpoints on chromosome 16p13.1. By means of somatic cell hybrid mapping we located this starting point telomeric to exon 10 of ABCC6. The duplication, however, does not include exon 10, but exons 1-9. These findings suggest that one or several copies of an ABCC6 pseudogene (psiABCC6) lie within this large segmental duplication. At least one copy contains exons 1-9 and maps to the chromosomal interval defined by the Cy163 and Cy11 breakpoints. Either this copy and/or an additional copy of psiABCC6 within Cy19-Cy183 carries the Q378X mutation that masks the correct identification of this nonsense mutation as being causative in pseudoxanthoma elasticum. Long-range PCR of exon 9 starting from sequence outside the genomic replication circumvents interference from the psiABCC6 DNA sequences and demonstrates that the Q378X mutation in the ABCC6 gene is associated with PXE in some families. These findings lead us to propose that gene conversion mechanisms from psiABCC6 to ABCC6 play a functional role in mutations causing PXE.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
pseudoxanthoma elasticum  IAGP 11038785DNA:nonsense mutation:exon:p.Q378X (1132C>T) (human)RGD 
pseudoxanthoma elasticum  ISOABCC6 (Homo sapiens)11038785; 11038785DNA:nonsense mutation:exon:p.Q378X (1132C>T) (human)RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Calcinosis cutis  IAGP 11038785DNA:nonsense mutation:exon:p.Q378X (1132C>T) RGD 
Objects Annotated

Genes (Rattus norvegicus)
Abcc6  (ATP binding cassette subfamily C member 6)

Genes (Mus musculus)
Abcc6  (ATP-binding cassette, sub-family C member 6)

Genes (Homo sapiens)
ABCC6  (ATP binding cassette subfamily C member 6)


Additional Information