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.
"Large intragenic deletion is a common mutation in GPR143. Bassi et al.  found a diverse prevalence of large deletions between European (<10%) and North American (>50%) patients with OA1. Interestingly we also found two large intragenic deletions in our OA1 patients. "
[Show abstract][Hide abstract] ABSTRACT: There are few genetic studies and clinical descriptions of Asian patients with X-linked ocular albinism (OA1). In the present study, the mutation analysis of G protein-coupled receptor 143 gene (GPR143) and clinical characteristics were assessed in Chinese patients with OA1.
Six families with OA1 were recruited from our pediatric and genetic eye clinic. Genomic DNA was prepared from venous leukocytes. The coding regions of GPR143 were amplified by polymerase chain reaction, and subsequently analyzed by direct sequencing. The variations detected were further evaluated in available family members as well as controls.
Mutations in GPR143 were identified in each of the six families: c.849delT (p.Val284SerfsX15); c.238_240delCTC (p.Leu80del); c.658+1G>A, c.353G>A (p.Gly118Glu); g.1103_7266del6164 (p.Gly84AlafsX65), which resulted in a deletion of exons 2 and 3; and g.25985_26546del562 (p.Gly296ValfsX26), which resulted in a deletion of exon 8. Of these six, c.353G>A is a known mutation, while the other five are novel. All affected patients had nystagmus, poor visual acuity, and foveal hypoplasia. However, hypopigmentation of the iris and fundus was very mild in these patients.
Five novel mutations and one known mutation were identified in six Chinese families with OA1. These results expand the mutation spectrum of GPR143, and demonstrate the clinical characteristics of OA1 among the Chinese.
"Interestingly, the human ortholog of the SHROOM2/APXL gene, like the OA1 gene, was originally isolated by our group from the ocular albinism type 1 critical region on the distal short arm of the X-chromosome (48). The involvement of SHROOM2/APXL in ocular albinism appears unlikely, given that most patients carry mutations within the OA1 gene (34,49), while none was identified in SHROOM2/APXL (48). It is nevertheless surprising that a gene possibly implicated in the same pathways as OA1 localizes close to the OA1 gene not only in humans (where the two genes lie 20 kb apart and are transcribed in opposite directions; MVS, unpublished observations), but also mice (50) and even frogs (47). "
[Show abstract][Hide abstract] ABSTRACT: The protein product of the ocular albinism type 1 gene, named OA1, is a pigment cell-specific G protein-coupled receptor exclusively localized to intracellular organelles, namely lysosomes and melanosomes. Loss of OA1 function leads to the formation of macromelanosomes, suggesting that this receptor is implicated in organelle biogenesis, however the mechanism involved in the pathogenesis of the disease remains obscure. We report here the identification of an unexpected abnormality in melanosome distribution both in retinal pigment epithelium (RPE) and skin melanocytes of Oa1-knock-out (KO) mice, consisting in a displacement of the organelles from the central cytoplasm towards the cell periphery. Despite their depletion from the microtubule (MT)-enriched perinuclear region, Oa1-KO melanosomes were able to aggregate at the centrosome upon disruption of the actin cytoskeleton or expression of a dominant-negative construct of myosin Va. Consistently, quantification of organelle transport in living cells revealed that Oa1-KO melanosomes displayed a severe reduction in MT-based motility; however, this defect was rescued to normal following inhibition of actin-dependent capture at the cell periphery. Together, these data point to a defective regulation of organelle transport in the absence of OA1 and imply that the cytoskeleton might represent a downstream effector of this receptor. Furthermore, our results enlighten a novel function for OA1 in pigment cells and suggest that ocular albinism type 1 might result from a different pathogenetic mechanism than previously thought, based on an organelle-autonomous signalling pathway implicated in the regulation of both membrane traffic and transport.
Human Molecular Genetics 09/2008; 17(22):3487-501. DOI:10.1093/hmg/ddn241 · 6.39 Impact Factor
"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. "
[Show abstract][Hide abstract] 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.
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