Diverse prevalence of large deletions within the OA1 gene in ocular albinism type 1 patients from Europe and North America.

Telethon Institute of Genetics and Medicine, Milan, Italy.
Human Genetics (Impact Factor: 4.52). 02/2001; 108(1):51-4. DOI: 10.1007/s004390000440
Source: PubMed

ABSTRACT Ocular albinism type 1 (OA1) is an X-linked disorder mainly characterized by congenital nystagmus and photodysphoria, moderate to severe reduction of visual acuity, hypopigmentation of the retina, and the presence of macromelanosomes in the skin and eyes. We have previously isolated the gene for OA1 and characterized its protein product as melanosomal membrane glycoprotein displaying structural and functional features of G protein-coupled receptors. We and others have identified mutations of various types within the OA1 gene in patients with this disorder, including deletions and splice site, frameshift, nonsense, and missense mutations. However, different prevalences of large intragenic deletions have been reported, ranging from 10% to 50% in independent studies. To determine whether these differences might be related to the geographic origin of the OA1 families tested, we performed a further extensive mutation analysis study leading to the identification of pathogenic mutations in 30 unrelated OA1 patients mainly from Europe and North America. These results, together with our earlier mutation reports on OA1, allow us to resolve the apparent discrepancies between previous studies and point to a substantial difference in the frequency of large intragenic deletions in European (<10%) compared with North American (>50%) OA1 families. These observations and our overall refinement of point mutation distribution within the OA1 gene have important implications for the molecular diagnosis of OA1 and for the establishment of any mutation detection program for this disorder.

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    • "Additionally other types of " loss of function " mutations have been identified. Surprisingly, in approximately 30% of cases, no mutations were found (Schiaffino et al., 1995; Rosenberg and Schwartz, 1998; Bassi et al., 2001). Schnur et al. (1998) identified detectable alterations in OA1, including single bases mutations, in almost 90% of another set of patients analysed. "
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    ABSTRACT: As the most common form of ocular albinism, ocular albinism type I (OA1) is an X-linked disorder that has an estimated prevalence of about 1:50,000. We searched for mutations through the human genome sequence draft by direct sequencing on eighteen patients with OA1, both within the coding region and in a thousand base pairs upstream of its start site. Here, we have identified eight new mutations located in the coding region of the gene. Two independent mutations, both located in the most carboxyterminal protein regions, were further characterized by immunofluorescence confocal microscopy, thus showing an impairment in their subcellular distribution into the lysosomal compartment of Cos-7A cells. The mutations found can result in protein misfolding, thus underlining the importance of the structure-function relationships of the protein as a major pathogenic mechanism in ocular albinism. Seven individuals out of eighteen (38.9%) with a clinical diagnosis of ocular albinism showed mutations, thus underlining the discrepancies between the clinical phenotype features and their genotype correlations. We postulate that mutations that have not yet been identified are potentially located in non-coding conserved regions or regulatory sequences of the OA1 gene.
    Gene 12/2007; 402(1-2):20-7. DOI:10.1016/j.gene.2007.07.020 · 2.08 Impact Factor
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    • "Four different missense mutations were identified within i3 distally to the double-leucine in patients with ocular albinism, including G229V, T232K, E235K and I244V (Fig. 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 showed 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;Shen et al., 2001). "
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    ABSTRACT: The protein product of the gene responsible for ocular albinism type 1, named OA1, is a pigment-cell-specific membrane glycoprotein, displaying features of G-protein-coupled receptors, yet exclusively localized to late endosomes, lysosomes and melanosomes. To dissect the signals responsible for the intracellular localization of OA1, we generated chimeric proteins consisting of the cytosolic domains of OA1 fused to the lumenal and transmembrane domains of LAMP1; in addition, we generated missense and deletion mutants of full-length OA1. Using this approach, we identified two separate sorting signals that are both necessary and sufficient for intracellular retention, as well as lysosomal and melanosomal localization, in melanocytic and non-melanocytic cells. These sorting signals are an unconventional dileucine motif within the third cytosolic loop and a novel motif, characterized by a tryptophan-glutamic acid doublet, within the C-terminal tail. Both motifs must be mutated to promote the plasma membrane localization of OA1, suggesting that they can independently drive its intracellular targeting. In addition, both motifs act similarly as lysosomal sorting signals in non-melanocytic cells, but appear to carry different specificities in melanocytic cells. Our findings indicate that OA1 contains multiple unconventional signals responsible for its lysosomal and melanosomal localization, and reveal a remarkable and unforeseen complexity in the regulation of polytopic protein sorting to specialized secretory organelles.
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