Human Molecular Genetics, Vol 7, 465-469, Copyright © 1998 by Oxford University Press
M Qi and PH Byers
The ATP7A gene encodes a copper-transporting ATPase. Mutations in this gene
result in two clinically distinct X-linked inherited disorders: Menkes
disease and occipital horn syndrome (OHS). We identified a single exon
skipping in the ATP7A transcript in cells from the affected proband,
affected cousins and obligate carriers in a family with OHS. Genomic
sequencing identified an A-->T transversion at the +3 position in the
splice donor site of intron 10 (gtaaagt-->gttaagt) in all affected
individuals and the obligate female carriers. This mutation results in the
constitutive skipping of exon 10 and creates an in-frame deletion of
transmembrane domains 3 and 4 (78 amino acids) in the mature transcript.
The exon 10-skipped transcript is present in low amounts as an
alternatively spliced product in normal individuals. Immunocytochemical
assay shows that these two protein products have different subcellular
distributions: the major form is concentrated in the perinuclear Golgi
system while the minor form (as the only form in this family with OHS) is
co-localized with the endoplasmic reticulum- resident BiP protein (GRP78).
These findings indicate that endoplasmic reticulum localization only of a
variant ATP7A protein is insufficient to effect normal copper transport.
ARTICLES
Constitutive skipping of alternatively spliced exon 10 in the ATP7A gene abolishes Golgi localization of the menkes protein and produces the occipital horn syndrome [published erratum appears in Hum Mol Genet 1998 Jun;7(6):1059]
Department of Pathology, University of Washington, Seattle, WA 98195- 7470, USA.
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