Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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We studied a large Danish family of seven generations in which autosomal dominant retinitis pigmentosa (adRP), a heterogeneous genetic form of retinal dystrophy, was segregating. After linkage had been excluded to all known adRP loci on chromosomes 3q, 6p, 7p, 7q, 8q, 17p, 17q and 19q, a genome screening was performed. Positive lod scores suggestive of linkage with values ranging between Z = 1.58-5.36 at theta = 0.04-0.20 were obtained for eight loci on proximal 1p and 1q. Close linkage without recombination and a maximum lod score of 7.22 at theta = 0.00 was found between the adRP locus (RP18) in this family and D1S498 which is on 1q very near the centromere. Analysis of multiply informative meioses suggests that in this family D1S534 and D1S305 flank RP18 in interval 1p13-q23. No linkage has been found to loci from this chromosomal region in six other medium sized adRP families in which the disease locus has been excluded from all known chromosomal regions harbouring an adRP gene or locus suggesting that there is (at least) one further adRP locus to be mapped in the future.
Hum Mol Genet 1996 Aug
PMID:A ninth locus (RP18) for autosomal dominant retinitis pigmentosa maps in the pericentromeric region of chromosome 1. 884 40

The function of the retina is to detect light and to send appropriate signals to the brain in response. Inherited diseases that cause the retina to degenerate, leading to either partial or total blindness, affect approximately 1 in 3000 people. Rapid progress is being made in identifying the genetic causes of common, inherited retinal diseases, such as retinitis pigmentosa and macular degeneration, as well as some of the rare forms of retinal disease. Linkage studies of large families and candidate-gene screening of known retinal genes have already identified 59 independent genetic loci that can cause retinal degeneration. The astounding genetic and clinical heterogeneity that is being revealed is a 'nightmare' for those interested in molecular diagnostics but, at the same time, provides great insight into functional aspects of the normal retina.
Mol Med Today 1996 Sep
PMID:Inherited retinal degeneration: exceptional genetic and clinical heterogeneity. 888 57

Usher syndrome (USH) is a clinically and genetically heterogeneous disorder characterized by congenital hearing loss combined with retinitis pigmentosa. This dual sensorineural deficiency is transmitted in an autosomal recessive mode. Usher syndrome type I (USH1) is the most severe form. Four loci responsible for USH1 (USH1A, 1B, 1C and 1D) have previously been mapped, among which only the USH1B gene has been cloned. Using homozygosity mapping in a consanguineous family from Morocco, we identified a novel locus for USH1, USH1E, mapping to chromosome band 21q21. The delimited 15 cM interval is flanked by the loci D21S1905 and D21S1913. Subsequent segregation analysis of two families affected by USH1, in which the A, B, C and D loci had been excluded, also excluded the involvement of the USH1E locus, therefore indicating the existence of at least one more locus for USH1.
Hum Mol Genet 1997 Jan
PMID:A newly identified locus for Usher syndrome type I, USH1E, maps to chromosome 21q21. 900 66

Usher syndrome is recognized as the most frequent cause of hereditary deaf-blindness. Usher syndrome type I (USH1), the most severe form of the disease, is characterized by profound congenital sensorineural deafness, constant vestibular dysfunction, and retinitis pigmentosa of prepubertal onset. This form is genetically heterogeneous and five loci (USH1A-E) have been mapped thusfar. However, only the gene responsible for USH1 B (which accounts for approximately 75% of USH1 cases) has been characterized. It encodes a long-tailed unconventional myosin, myosin VIIA, with a predicted 2215 amino acid sequence. Primers covering the complete myosin VIIA coding sequence as well as the 3' non coding sequence were designed, allowing direct sequence analysis of each of the 48 coding exons and flanking splice sites in seven patients affected by USH1. Four novel mutations were thereby identified. The possibility should now be considered of a sequence-based prenatal diagnosis in some of the families affected by this very severe form of Usher syndrome.
Hum Mol Genet 1997 Jan
PMID:Myosin VIIA gene: heterogeneity of the mutations responsible for Usher syndrome type IB. 900 78

Bardet-Biedl syndrome (BBS) is a clinically and genetically heterogeneous autosomal recessive disorder characterized by retinitis pigmentosa, polydactyly, obesity, hypogenitalism, mental retardation, and renal anomalies. To detect linkage to BBS loci, 29 BBS families, of mixed but predominantly European ethnic origin, were typed with 37 microsatellite markers on chromosomes 2, 3, 11, 15, 16, and 17. The results show that an estimated 36-56% of the families are linked to the 11q13 chromosomal site (BBS1) previously described by M. Leppert et al. (1994, Nature Genet. 7, 108-112), with the gene order cen-D11S480-5 cM-BBS1-3 cM-D11S913/D11S987-qter. A further 32-35% of the families are linked to the BBS4 locus, reported by R. Carmi et al. (1995, Hum. Mol. Genet. 4, 9-13) in chromosomal region 15q22.3-q23, with the gene order cen-D15S125-5 cM-BBS4-2 cM-D15S131/D15S204-qter. Three consanguineous BBS families are homozygous for three adjacent chromosome 15 markers, consistent with identity by descent for this region. In one of these families haplotype analysis supports a localization for BBS4 between D15S131 and D15S114, a distance of about 2 cM. Weak evidence of linkage to the 16q21 (BBS2) region reported by A. E. Kwitek-Black et al. (1993, Nature Genet. 5, 392-396) was observed in 24-27% of families with the gene order cen-D16S408-2 cM-BBS2-5 cM-D16S400. A fourth group of families, estimated at 8%, are unlinked to all three of the above loci, showing that at least one other BBS locus remains to be found. No evidence of linkage was found to markers on chromosome 3, corresponding to the BBS3 locus, reported by V. C. Sheffield et al. (1994, Hum. Mol. Genet. 3, 1331-1335), or on chromosome 2 or 17, arguing against the involvement of a BBS locus in a patient with a t(2;17) translocation.
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PMID:Linkage mapping in 29 Bardet-Biedl syndrome families confirms loci in chromosomal regions 11q13, 15q22.3-q23, and 16q21. 912 87

In this paper, an attempt is made to highlight some of the recent developments in genetics to understand the group of inherited eye disorders referred to as retinitis pigmentosa (RP). Of the seven genes identified, six are expressed specifically in the photoreceptor cells and four encode the enzymes involved in the phototransduction pathway. A short discussion is presented of the tremendous phenotypic heterogeneity. An understanding of RP requires knowledge of other genetic and environmental factors as well as tests to measure the status of the patient's photoreceptor cells in various disease stages.
Cell Mol Life Sci 1997 May
PMID:Signal transduction in the retina and inherited retinopathies. 917 60

Nineteen patients (9 females, 10 males) with mitochondrial encephalomyopathies (ME) were studied. The diagnosis was established according to clinical and histopathological criteria. Leading clinical features were chronic progressive external ophthalmoplegia (CPEO) and muscle weakness in 95% of the patients. Pigmentary retinopathy was seen in 63%, and was always associated with CPEO. Hypacusis was present in 47% and cerebellar ataxia in 63% of patients. Clinical or electrophysiological signs of involvement of the central nervous system (CNS) were found in 21% of the patients. In muscle biopsy ragged red fibers were the predominant histopathological findings (100% of the patients), while COX-negative fibers were seen in 74%, deletions of the mitochondrial DNA in 42%, and defects of the respiratory chain in 32% of the patients. Increased blood lactate levels were found in 79% of the patients. Needle electromyography revealed myopathic features in 74%, features of denervation in 16%, and was normal in the remainder. Imaging studies showed cerebral atrophy in 58%, cerebellar atrophy in 16%, and hyperintense lesions of the white matter, pyramidal tract or extrapyramidal system in 16% of the cases. It is concluded that the clinical manifestations of ME can be very variable. Diagnosis of ME should be always considered in young patients presenting with CPEO and muscle weakness. In most cases, diagnosis can be made by a few selected investigations, while detection of genetic abnormalities may lead to the diagnosis in the remaining cases.
Mol Cell Biochem 1997 Sep
PMID:Clinical, morphological, biochemical, and neuroradiological features of mitochondrial encephalomyopathies. Presentation of 19 patients. 930 3

Mutations in the peripherin/rds gene have been reported to be associated with different forms of human autosomal dominant retinitis pigmentosa (ADRP) and macular degeneration (MD). To better understand the disruptive role of these mutations, knowledge of the structure-function relationship of the peripherin/rds gene is needed. To facilitate that, genomic clones encoding the mouse gene were isolated using bovine cDNA sequences as probes. Sequence analysis of clone lambda 6-1-1, that contained the entire coding sequence for the mouse peripherin/rds, yielded the exon-intron organization of the gene. The gene is composed of three exons (581, 247, and 213 bp) and two introns with the first and second introns 8.6 kb and 3.7 kb in size, respectively. Two major (1.6 and 2.7 kb) and three minor (4.0, 5.5, 6.5 kb) transcripts were detected on RNA blots. The major transcripts first appeared in the brain at embryonic day 13 and in the retina at postnatal day 1. Transcripts were missing in brain and eye of mice at embryonic day 15. Several transcription start sites were mapped within 26 nucleotides approximately 200 bp upstream from the translation initiation site. However, transcripts varied in the lengths of their 3' untranslated portion as a result of the utilization of different polyadenylation signals.
Somat Cell Mol Genet 1997 May
PMID:Structural and developmental analysis of the mouse peripherin/rds gene. 933 Jun 29

Ophthalmological and molecular genetic studies were performed in a consanguineous family with individuals showing either retinitis pigmentosa (RP) or cone-rod dystrophy (CRD). Assuming pseudodominant (recessive) inheritance of allelic defects, linkage analysis positioned the causal gene at 1p21-p13 (lod score 4.22), a genomic segment known to harbor the ABCR gene involved in Stargardt's disease (STGD) and age-related macular degeneration (AMD). We completed the exon-intron structure of the ABCR gene and detected a severe homozygous 5[prime] splice site mutation, IVS30+1G->T, in the four RP patients. The five CRD patients in this family are compound heterozygotes for the IVS30+1G->T mutation and a 5[prime] splice site mutation in intron 40 (IVS40+5G->A). Both splice site mutations were found heterozygously in two unrelated STGD patients, but not in 100 control individuals. In these patients the second mutation was either a missense mutation or unknown. Since thus far no STGD patients have been reported to carry two ABCR null alleles and taking into account that the RP phenotype is more severe than the STGD phenotype, we hypothesize that the intron 30 splice site mutation represents a true null allele. Since the intron 30 mutation is found heterozygously in the CRD patients, the IVS40+5G->A mutation probably renders the exon 40 5[prime] splice site partially functional. These results show that mutations in the ABCR gene not only result in STGD and AMD, but can also cause autosomal recessive RP and CRD. Since the heterozygote frequency for ABCR mutations is estimated at 0.02, mutations in ABCR might be an important cause of autosomal recessive and sporadic forms of RP and CRD.
Hum Mol Genet 1998 Mar
PMID:Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt's disease gene ABCR. 946 90

A novel splice variant of RGS 9 was isolated from a rat hypothalamus, human retina, and a human kidney (Wilm's) tumor. This variant, termed RGS 9L, differs from the retinal form (termed RGS 9S) identified previously in that it contains a 211- (rat) or 205- (human) amino acid proline-rich domain on the carboxyl terminus. The pattern of RGS 9 mRNA splicing was tissue specific, with striatum, hypothalamus- and nucleus accumbens expressing RGS 9L, whereas retina and pineal expressed RGS 9S almost exclusively. This pattern of mRNA splicing seemed to be highly conserved between human and rodents, suggesting cell-specific differences in the function of these variants. Transient expression of RGS 9L augmented basal and beta-adrenergic receptor-stimulated adenylyl cyclase activity while suppressing dopamine D2 receptor-mediated inhibition. Furthermore, RGS 9L expression greatly accelerated the decay of dopamine D2 receptor-induced GIRK current. These results indicate RGS 9L inhibits heterotrimeric Gi function in vivo, probably by acting as a GTPase-activating protein. The human RGS 9 gene was localized to chromosome 17 q23-24 by radiation hybrid and fluorescent in situ hybridization analyses. The RGS 9 gene is within a previously defined locus for retinitis pigmentosa (RP 17), a disease that has been linked to genes in the rhodopsin/transducin/cGMP signaling pathway.
Mol Pharmacol 1998 Oct
PMID:Molecular characterization of human and rat RGS 9L, a novel splice variant enriched in dopamine target regions, and chromosomal localization of the RGS 9 gene. 976 12


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