Constitutive skipping of alternatively spliced exon 10 in the ATP7A gene abolishes Golgi localization of the menkes protein and produces the occipital horn syndrome.

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.