OA1 Mutations and Deletions in X-Linked Ocular Albinism

Abstract

X-linked ocular albinism (OA1), Nettleship-Falls type, is characterized by decreased ocular pigmentation, foveal hypoplasia, nystagmus, photodysphoria, and reduced visual acuity. Affected males usually demonstrate melanin macroglobules on skin biopsy. We now report results of deletion and mutation screening of the full-length OA1 gene in 29 unrelated North American and Australian X-linked ocular albinism (OA) probands, including five with additional, nonocular phenotypic abnormalities (Schnur et al. 1994). We detected 13 intragenic gene deletions, including 3 of exon 1, 2 of exon 2, 2 of exon 4, and 6 others, which span exons 2-8. Eight new missense mutations were identified, which cluster within exons 1, 2, 3, and 6 in conserved and/or putative transmembrane domains of the protein. There was also a splice acceptor-site mutation, a nonsense mutation, a single base deletion, and a previously reported 17-bp exon 1 deletion. All patients with nonocular phenotypic abnormalities had detectable mutations. In summary, 26 (approximately 90%) of 29 probands had detectable alterations of OA1, thus confirming that OA1 is the major locus for X-linked OA.

An unconventional dileucine-based motif and a novel cytosolic motif are required for the lysosomal and melanosomal targeting of OA1

“…2A) (Schnur et al, 1998;Bassi et al, 2001). The role of these mutations in the pathogenesis of the disease remains to be established, since previous studies have shown that, in the context of the native OA1, they do not determine ER retention of the protein nor other apparent sorting defects (d 'Addio et al, 2000;.…”

Normal Tissue Depresses While Tumor Tissue Enhances Human T Cell Responses In Vivo to a Novel Self/Tumor Melanoma Antigen, OA1

“…The Nettleship Falls ocular albinism, also known as ocular albinism type I, is associated with the functional absence of functional OA1 and is characterized by reduced visual acuity, foveal hypoplasia, retinal hypopigmentation, congenital nystagmus, and photophobia (17). Nettleship Falls ocular albinism can be caused by a variety of mutations within the X chromosome-encoded OA1 gene, including frameshifts, missense, and nonsense mutations, frequent large intragenic deletions and less frequent whole gene deletions (18,19). Several males from a large cohort of OA1 gene-loss patients were selected for analysis because they were known or suspected to have large intragenic OA1 deletions.…”

Ocular Albinism Type 1: More Than Meets The Eye

“…Four of the Class III mutants (W133R, A138V, S152N, and T232K) represent mutations in patients known to have MMGs upon skin biopsy (23). This suggests that although Class III mutants traffic correctly to the endolysosomal compartment and retain the ability to cause enlargement of LE diameter, the loss of an additional function of OA1 is likely to be responsible for the presence of MMGs (and albinism) in persons bearing this class of mutations, and correlates with the lack of effect of these mutants on M6PR distribution.…”