Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied the linkage of X-linked Nettleship-Falls ocular albinism (OA1) to Xp22.1-Xp22.3 RFLPs at 12 loci in five families, including one in which OA1 cosegregates with a deletion of steroid sulfatase (STS). We found evidence for tight linkage of OA1 to the Xp22.3 loci DXS143, STS, and DXS452. DXS452, a newly described polymorphism detected by the probe E25B1.8, is part of the sequence family "DXS278" (pCRI-S232), but represents a single genetic locus. Every female in this study was heterozygous for the DXS452 RFLP. Thus, this marker will be extremely useful for family studies and genetic counseling. Analysis of individual recombinations suggests that OA1 maps between DXS143 and DXS85. Multipoint linkage analysis was consistent with this localization but was not statistically significant. These data suggest that OA1 lies proximal to the deletion in a previously described family with OA1 and STS deletion, but maps within the Xp22.3-Xp22.2 region.
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PMID:Linkage analysis in X-linked ocular albinism. 167 24

pCRI-S232 (DXS278) is a 7-kb genomic sequence that hybridizes to multiple polymorphic X-linked restriction fragments on standard Southern analysis. Physical mapping of pCRI-S232 by pulsed-field gel electrophoresis (PFGE) suggests that a sequence in S232 is repeated in multiple X-chromosomal regions in normal individuals. Steroid sulfatase (STS) and DXS237 each hybridize to two of six X-linked SfiI fragments detected by S232. Two independent familial STS deletions, one of which is associated with a phenotype of ichthyosis plus ocular albinism (XI/OA1) and the other with nystagmus plus Rud syndrome, lack some but not all of the normal S232 PFGE fragments. We isolated a DNA fragment, E25B1.8, from a cosmid that contains S232. E25B1.8 detects a subset of the S232 polymorphic fragments on standard Southern blots plus new constant fragments; some, but not all, of the E25B1.8-hybridizing fragments are deleted in the XI/OA1 and Rud syndrome/nystagmus males. The simpler, but highly informative, polymorphism detected by E25B1.8 (DXS452) also eliminates an "intralocus" recombination seen with S232. We conclude that (1) males with STS deletions and complex phenotypes are partially deleted for DXS278, (2) DXS237 and part of DXS278 lie within 800 kb of STS, and (3) a repeat sequence within or around pCRI-S232 is probably located in multiple X-chromosomal locations spanning at least 2-3 Mb.
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PMID:Partial deletions of a sequence family ("DXS278") and its physical linkage to steroid sulfatase as detected by pulsed-field gel electrophoresis. 197 48

Nettleship-Falls ocular albinism is an X-linked disorder characterized by variable degrees of impaired visual acuity, nystagmus, and macular hypoplasia in affected males and variable fundus pigmentation but normal acuities in females. Because of extreme variability in clinical manifestation, examination of family members may be necessary to confirm the diagnosis and is essential for genetic counseling purposes. This study reports the pedigree analysis and clinical findings in a large kindred from rural Virginia with 31 males reported to be affected among the 287 individuals in the pedigree. Clinical findings were quite variable, even within sibships, and some cases had been previously misdiagnosed, even in the presence of this remarkable family history. Linkage analysis in this family did not show the expected linkage with the Xg blood group. Examination of skin biopsies clearly indicated the cutaneous abnormality of giant pigment melanosomes (GPM) in both affected males and carrier females. Our use of light microscopy for detection of characteristic GPM may be easily employed as a carrier detection test, and therefore, provide the basis for accurate genetic counseling in families with ocular albinism.
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PMID:Genetic studies of ocular albinism in a large Virginia kindred. 670 91

Although genotype-phenotype correlations in male patients with various types of nullisomy for Xp22.3 have assigned a locus for X-linked mental retardation (MRX) to an approximately 3-Mb region between DXS31 and STS, the precise location has not been determined. In this paper, we describe a 14 7/12 year old Japanese boy with mental retardation and an interstitial deletion at Xp22.3 involving STS, KAL1, and OA1, and compare the deletion map with that of previously reported three familial male patients with low-normal intelligence and a similar interstitial deletion at Xp22.3. The results suggest that the MRX gene is further localized to the roughly 1.5-Mb region between DXS1060 and DXS1139.
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PMID:Mental retardation in a boy with an interstitial deletion at Xp22.3 involving STS, KAL1, and OA1: implication for the MRX locus. 1034 Jun 59

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.
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PMID:OA1 mutations and deletions in X-linked ocular albinism. 952 34

We have identified a novel gene, transducin (beta)-like 1 (TBL1), in the Xp22.3 genomic region, that shows high homology with members of the WD-40-repeat protein family. The gene contains 18 exons spanning approximately 150 kb of the genomic region adjacent to the ocular albinism gene (OA1) on the telomeric side. However, unlike OA1, TBL1 is transcribed from telomere to centromere. Northern analysis indicates that TBL1 is ubiquitously expressed, with two transcripts of approximately 2.1 kb and 6.0 kb. The open reading frame encodes a 526-amino acid protein, which shows the presence of six beta-transducin repeats (WD-40 motif) in the C-terminal domain. The homology with known beta-subunits of G proteins and other WD-40-repeat containing proteins is restricted to the WD-40 motif. Genomic analysis revealed that the gene is either partly or entirely deleted in patients carrying Xp22.3 terminal deletions. The complexity of the contiguous gene-syndrome phenotype shared by these patients depends on the number of known disease genes involved in the deletions. Interestingly, one patient carrying a microinterstitial deletion involving the 3' portion of both TBL1 and OA1 shows the OA1 phenotype associated with X-linked late-onset sensorineural deafness. We postulate an involvement of TBL1 in the pathogenesis of the ocular albinism with late-onset sensorineural deafness phenotype.
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PMID:X-linked late-onset sensorineural deafness caused by a deletion involving OA1 and a novel gene containing WD-40 repeats. 1033 Mar 47

Ocular albinism type I (OA1) is an X-linked disorder characterized by severe reduction of visual acuity, strabismus, photophobia and nystagmus. Ophthalmologic examination reveals hypopigmentation of the retina, foveal hypoplasia and iris translucency. Microscopic examination of both retinal pigment epithelium (RPE) and skin melanocytes shows the presence of large pigment granules called giant melanosomes or macromelanosomes. In this study, we have generated and characterized Oa1-deficient mice by gene targeting (KO). The KO males are viable, fertile and phenotypically indistinguishable from the wild-type littermates. Ophthalmologic examination shows hypopigmentation of the ocular fundus in mutant animals compared with wild-type. Analysis of the retinofugal pathway reveals a reduction in the size of the uncrossed pathway, demonstrating a misrouting of the optic fibres at the chiasm, as observed in OA1 patients. Microscopic examination of the RPE shows the presence of giant melanosomes comparable with those described in OA1 patients. Ultrastructural analysis of the RPE cells, suggests that the giant melanosomes may form by abnormal growth of single melanosomes, rather than the fusion of several, shedding light on the pathogenesis of ocular albinism.
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PMID:Oa1 knock-out: new insights on the pathogenesis of ocular albinism type 1. 1109 54

Albinism is a group of inherited conditions in which affected individuals have less than normal pigment in the eyes, skin, and hair compared to others of the same race and ethnic background. The prevalence of all types of albinism in the United States is estimated at 1 in 20,000, based on poor epidemiological data. X-linked Nettleship-Falls ocular albinism (XLOA, OA1) affects approximately 1/150,000 males in the population. XLOA effects reduce visual acuity and nystagmus, result in a mild skin and hair phenotype, and occur mostly in XY males. Female carriers of XLOA have normal visual acuity, but often show iris punctate transillumination and a classic pattern of mosaic retinal pigmentation, coarse and grainy in the macula and becoming increasingly reticular into the periphery of the retinal pigment epithelium. Studies of OA1 have shown linkage of a single gene to markers at Xp22.3-p22.2. About 48% of the reported mutations in the OA1 gene are intragenic deletions and about 43% are point mutations. We present a hierarchical strategy for mutation screening for diagnostic testing for OA1 that comprises two tiers: first, multiplex PCR to detect intragenic deletions in the OA1 gene with denaturing high-performance liquid chromatography (dHPLC), and, second, heteroduplex analysis with dHPLC to scan for mutations, with subsequent sequencing of variants to confirm putative mutations in the OA1 gene. Prenatal diagnosis can be provided for families when the mutation has been firmly identified. We have validated this procedure with positive controls that were identified in patients by Southern blot, single-stranded conformation polymorphism (SSCP), and sequencing. In this hierarchical strategy, these procedures have an analytical sensitivity of > 99%.
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PMID:Diagnostic DNA testing for X-linked ocular albinism (OA1) with a hierarchical mutation screening protocol. 1218 81

Ocular albinism type 1 is an X-linked disorder characterized by severe reduction of visual acuity, retinal hypopigmentation, foveal hypoplasia, optic misrouting and the presence of giant melanosomes (macromelanosomes) in skin melanocytes and retinal pigment epithelium. The protein product of the OA1 gene is a pigment cell specific membrane glycoprotein, displaying structural and functional features of G protein-coupled receptors (GPCRs). However, in contrast to all other previously characterized GPCRs, OA1 is not localized to the plasma membrane, but is targeted to intracellular organelles, namely late endosomes/lysosomes and melanosomes. These unique characteristics suggest that OA1 represents the first example described so far of an exclusively intracellular GPCR and regulates melanosome biogenesis by transducing signals from the organelle lumen to the cytosol. These findings support previous hypotheses that GPCR-mediated signaling might also operate at the internal membranes in mammalian cells.
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PMID:The ocular albinism type 1 (OA1) protein and the evidence for an intracellular signal transduction system involved in melanosome biogenesis. 1602 16

An intronic point mutation was identified in the ocular albinism type 1 (OA1) gene (HUGO symbol, GPR143) in a family with the X-linked form of ocular albinism. Interestingly, the mutation creates a new acceptor splice site in intron 7 of the OA1 gene. In addition to low levels of normally spliced mRNA product of the OA1 gene, the patient samples contained also an aberrantly spliced mRNA with a 165 bp fragment of intron 7 (from position +750 to +914) inserted between exons 7 and 8. The abnormal transcript contained a premature stop codon and was unstable, as revealed by Northern blot analysis. We defined that mutation NC_000023.8:g.25288G>A generated a consensus binding motif for the splicing factor enhancer ASF/SF2, which most likely favored transcription of the aberrant mRNA. Furthermore, it activated a cryptic donor-splice site causing the inclusion between exons 7 and 8 of the 165 bp intronic fragment. Thus, the aberrant splicing is most likely explained by the generation of a de novo splicing enhancer motif. Finally, to rescue OA1 expression in the patient's melanocytes, we designed an antisense morpholino modified oligonucleotide complementary to the mutant sequence. The morpholino oligonucleotide (MO) was able to rescue OA1 expression and restore the OA1 protein level in the patient's melanocytes through skipping of the aberrant inclusion. The use of MO demonstrated that the lack of OA1 was caused by the generation of a new splice site. Furthermore, this technique will lead to new approaches to correct splice site mutations that cause human diseases.
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PMID:Aberrant splicing in the ocular albinism type 1 gene (OA1/GPR143) is corrected in vitro by morpholino antisense oligonucleotides. 1655 May 51


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