Gene/Protein Disease Symptom Drug Enzyme Compound
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Construction of animal models of human inherited diseases is particularly important for testing gene therapy approaches. Towards this end, we constructed a mouse model for Charcot-Marie-Tooth disease type 1A by pronuclear injection of a YAC containing the human PMP22 gene. In one transgenic line, the YAC DNA is integrated in about eight copies and the PMP22 gene is strongly expressed to give a peripheral neuropathy closely resembling the human pathology. The disorder is dominant, causes progressive weakness of the hind legs, and there is severe demyelination in the peripheral nervous system including the presence of onion bulb formations. This approach will be valuable for pathologies produced by over-expression of a gene including trisomy and amplification in cancer. Such models will be particularly useful for testing gene therapy approaches if the transgene is human.
Hum Mol Genet 1996 May
PMID:Construction of a mouse model of Charcot-Marie-Tooth disease type 1A by pronuclear injection of human YAC DNA. 873 21

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant, neuromuscular disorder characterized by progressive weakness of muscles in the face, shoulder and upper arm. Deletion of integral copies of a 3.3 kb repeated unit from the subtelomeric region on chromosome 4q35 has been shown to be associated with FSHD. These repeated units which are apparently not transcribed, map very close to the 4q telomere and belong to a 3.3 kb repeat family dispersed over heterochromatic regions of the genome. Hence, position effect variegation (PEV), inducing allele-specific transcriptional repression of a gene located more centromeric, has been postulated as the underlying genetic mechanism of FSHD. This hypothesis has directed the search for the FSHD gene to the region centromeric to the repeated units. A CpG island was identified and found to be associated with the 5' untranslated region of a novel human gene, FRG1 (FSHD Region Gene 1). This evolutionary conserved gene is located about 100 kb proximal to the repeated units and belongs to a multigene family with FRG1 related sequences on multiple chromosomes. The mature chromosome 4 FRG1 transcript is 1042 bp in length and contains nine exons which encode a putative protein of 258 amino acid residues. Transcription of FRG1 was detected in several human tissues including placenta, lymphocytes, brain and muscle. To investigate a possible PEV mechanism, allele-specific FRG1 steady-state transcript levels were determined using RNA-based single-strand conformation polymorphism (SSCP) analysis. A polymorphic fragment contained within the first exon of FRG1 was amplified from reverse transcribed RNA from lymphocytes and muscle biopsies of patients and controls. No evidence for PEV mediated repression of allelic transcription was obtained in these tissues. However, detection of PEV in FSHD patients may require analysis of more specific cell types at particular developmental stages.
Hum Mol Genet 1996 May
PMID:Identification of the first gene (FRG1) from the FSHD region on human chromosome 4q35. 873 23

Velo-cardio-facial syndrome (VCFS) and DiGeorge syndrome (DGS) are developmental disorders characterized by a spectrum of phenotypes including velopharyngeal insufficiency, conotruncal heart defects and facial dysmorphology among others. Eighty to eighty-five percent of VCFS/DGS patients are hemizygous for a portion of chromosome 22. It is likely that the genes encoded by this region play a role in the etiology of the phenotypes associated with the disorders. Using a cDNA selection protocol, we isolated a novel clathrin heavy chain cDNA (CLTD) from the VCFS/DGS minimally deleted interval. The cDNA encodes a protein of 1638 amino acids. CLTD shares significant homology, but is not identical to the ubiquitously expressed clathrin heavy chain gene. The CLTD gene also shows a unique pattern of expression, having its maximal level of expression in skeletal muscle. Velopharyngeal insufficiency and muscle weakness are common features of VCFS patients. Based on the location and expression pattern of CLTD, we suggest hemizygosity at this locus may play a role in the etiology of one of the VCFS-associated phenotypes.
Hum Mol Genet 1996 May
PMID:Isolation of a new clathrin heavy chain gene with muscle-specific expression from the region commonly deleted in velo-cardio-facial syndrome. 873 28

Limb-girdle muscular dystrophies (LGMDs) represent a clinically heterogeneous group of genetic diseases characterised by progressive weakness of the pelvic and shoulder girdle muscles. An autosomal dominant form (LGMD1A) has been mapped at 5q22.3-31.3, while five genes responsible for the autosomal recessive forms were mapped respectively at: 15q15.1 (LGMD2A), 2p12-p16 (LGMD2B), 13q12 (LGMD2C), 17q12-q21.33 (LGMD2D) and 4q12 (LGMD2E). Among 17 autosomal recessive (AR) LGMD Brazilian families with at least three affected sibs, we were able to exclude four families (one mild and three severe) from all these five known loci as well as from the dystroglycan and syntrophin genes. Therefore, we have performed a genome-wide search in two of the severely affected families, which are alpha-sarcoglycan negative. We demonstrate linkage of these two Duchenne muscular dystrophy-like families to 5q33-34, and propose to classify them as LGMD2F. In addition, linkage analysis in the other two genealogies that are alpha-sarcoglycan positive suggests that there is at least one other gene which causes AR LGMD.
Hum Mol Genet 1996 Jun
PMID:Linkage analysis in autosomal recessive limb-girdle muscular dystrophy (AR LGMD) maps a sixth form to 5q33-34 (LGMD2F) and indicates that there is at least one more subtype of AR LGMD. 877 97

We have generated mouse models of human Tay-Sachs and Sandhoff diseases by targeted disruption of the Hexa (alpha subunit) or Hexb (beta subunit) genes, respectively, encoding lysosomal beta-hexosaminidase A (structure, alpha) and B (structure, beta beta). Both mutant mice accumulate GM2 ganglioside in brain, much more so in Hexb -/- mice, and the latter also accumulate glycolipid GA2. Hexa -/- mice suffer no obvious behavioral or neurological deficit, while Hexb -/- mice develop a fatal neurodegenerative disease, with spasticity, muscle weakness, rigidity, tremor and ataxia. The Hexb -/- but not the Hexa -/- mice have massive depletion of spinal cord axons as an apparent consequence of neuronal storage of GM2. We propose that Hexa -/- mice escape disease through partial catabolism of accumulated GM2 via GA2 (asialo-GM2) through the combined action of sialidase and beta-hexosaminidase B.
Hum Mol Genet 1996 Jan
PMID:Dramatically different phenotypes in mouse models of human Tay-Sachs and Sandhoff diseases. 878 34

Exercised mdx mice were used to evaluate the efficacy of two pharmacologic entities, cromolyn and compound 48/80. Beginning at 2 weeks of age, mdx mice were treated with either cromolyn (50 mg/kg/day), prednisone (2mg/kg/day), compound 48/80 (1mg/kg/day), or diluent vehicle. At 4 weeks of age, treated mice were subjected to twice weekly, forced treadmill running which has previously been shown to cause expressed weakness in mdx mice (Hudecki, Pollina et al., 1993). Strength was evaluated weekly through 6 weeks of age using a previously described "pull-test" procedure (Hudecki, Pollina et al., 1993). Serum creatine kinase (CK) and mast cell tryptase activities were evaluated from 6 week blood samples. There was a significant increase in strength in mdx mice treated with cromolyn (p < or = 0.05), while no significant increase in strength was found in mice treated with compound 48/80, or prednisone compared to vehicle controls. While no significant change in tryptase activity was found between treatments, CK activity was significantly increased in the cromolyn group compared to vehicle controls. However, when tryptase and CK were expressed as a combined factor (Tryp x CK), the cromolyn treated group was significantly different from all other groups. The results of this study suggest a possible use for cromolyn-like compounds in the treatment of Duchenne muscular dystrophy.
Res Commun Mol Pathol Pharmacol 1996 Mar
PMID:Cromolyn increases strength in exercised mdx mice. 882 68

Clinical, electrophysiological and genetic linkage studies were performed on a large autosomal dominant family with Charcot-Marie-Tooth axonal neuropathy type 2 (CMT2) with 38 members of which 14 were affected. Onset of the disease was between 16 and 30 years of age with weakness and atrophy of the hands more severe than of the feet with slow progressive course in 12 patients. Deep tendon reflexes were absent in the upper extremities and decreased in the lower extremities. There was distal hypesthesia for touch, proprioception and vibration sense for the hands more than for the feet. Motor nerve conduction velocities showed normal values (48-53 M/s) with normal latencies (2-3 msec) and electromyography revealed signs of denervation. Genetic linkage analysis used 167 short tandem repeat markers (STRPs) spaced throughout the 22 autosomes. Linkage to the short arm of chromosome 7 at 7p14 was found using the marker D7S435 (Z = 4.83 at theta = 0). Flanking markers were D7S1808 and D7S1806 and the genetic distance between them was 6.8 cM. The multipoint linkage analysis gave a peek multipoint lod score of 6.89 between the markers D7S1808 and D7S435. Linkage analysis showed significantly negative lod scores (with values less than -2) with markers of chromosomes 1 and 3 where CMT axonal forms have been previously mapped. PFGE analysis indicated the absence of the CMT1A duplication. Our findings are consistent with a new genetic type of axonal CMT neuropathy designated by us as CMT2D. Potential candidate genes are multiple T-cell gamma receptor genes which map to the same cytogenetic interval as CMT2D neuropathy.
Hum Mol Genet 1996 Sep
PMID:Autosomal dominant Charcot-Marie-Tooth axonal neuropathy mapped on chromosome 7p (CMT2D). 887 80

Scapuloperoneal (SP) syndromes are heterogeneous neuromuscular disorders which are characterized by weakness in the distribution of shoulder girdle and peroneal muscles. SP syndromes can resemble facioscapulohumeral muscular dystrophy (FSH) due to scapular weakness or Charcot-Marie-Tooth disease (CMT) due to atrophy of peroneal muscles. Both neurogenic and myopathic SP syndromes have been described. Locus for the myopathic form of SP syndrome (scapuloperoneal muscular dystrophy, SPMD) has recently been assigned to chromosome 12q. We previously described a large New England kindred exhibiting an autosomal dominant neurogenic SP syndrome (scapuloperoneal spinal muscular atrophy, SPSMA). Disease expression was more severe and progressive in successive generations, which suggested genetic anticipation. We performed genetic linkage analysis of this family with microsatellite markers and excluded the loci for FSH, CMT, SPMD and SMA (spinal muscular atrophy) in our family. Linkage in our SPSMA family (lod score > 3) was established to seven microsatellite markers that map to chromosome 12q24.1-q24.31. The highest lod score with two-point linkage analysis was 6.67 (theta = 0.00) with marker D12S353. Multipoint analysis gave maximum lod scores of 7.38 between D12S354 and D12S79, and also 7.38 between D12S369 and NOS1 (neuronal nitric oxide synthase). The gene for SPSMA lies within the 19 cM interval between D12S338 and D12S366. This report establishes a locus for the neurogenic form of SP syndrome approximately 20 cM telomeric to the one described for the myopathic form of SP syndrome.
Hum Mol Genet 1996 Sep
PMID:Linkage of scapuloperoneal spinal muscular atrophy to chromosome 12q24.1-q24.31. 887 81

Charcot-Marie-Tooth (CMT) disease is the most frequent inherited peripheral motor and sensory neuropathy characterised by chronic distal weakness with progressive muscular atrophy and sensory loss of the distal extremities. The dominant form of the disease is genetically heterogeneous but only one locus has been identified on chromosome 8q13-q21.1 for autosomal recessive CMT. By homozygosity mapping in a large Algerian kindred, we have assigned a second locus for autosomal recessive CMT to chromosome 5q23-33. Linkage analysis demonstrated that the same locus is involved in a second Algerian family with a demyelinating CMT. Haplotype reconstruction and determination of the minimal region of homozygosity restricts the candidate region to a 4 cM interval.
Hum Mol Genet 1996 Oct
PMID:Homozygosity mapping of an autosomal recessive form of demyelinating Charcot-Marie-Tooth disease to chromosome 5q23-q33. 889 8

A novel mtDNA point mutation was detected in the tRNAleu(CUN) gene (G to A at position 12315) in a sporadic patient with chronic progressive external ophthalmoplegia, ptosis, limb weakness, sensorineural hearing loss and a pigmentary retinopathy. The mutation disrupts base pairing in the T psi C stem at a site which has been conserved throughout evolution. Although the other mtDNA tRNAleu gene (UUR) is a hotspot for mutation, this is the first pathogenic mutation to be reported in the gene coding for tRNAleu(CUN). MtDNAs carrying the mutation constituted 94% of total mtDNAs in two separate muscle biopsies. Single fibre analysis showed that skeletal muscle fibres without detectable cytochrome c oxidase activity (COX-ve fibres) contained predominantly mutant mtDNAs (93-98%) while fibres with apparently normal COX activity had up to 90% mutant mtDNAs, demonstrating that the G12315A mutation is functionally recessive. Immunofluorescence studies with specific antibodies to mtDNA- or nuclear-encoded subunits of COX were consistent with a defect in mitochondrial protein translation. The mutation was not present in blood cells or cultured fibroblasts and surprisingly, it could not be detected in satellite cells cultured from the patient's muscle. This pattern, which may by typical of patients who have inherited new germline pathogenic mtDNA mutations, possibly reflects loss of the mutation by random genetic drift in mitotic tissues and proliferation of mitochondria containing the mutant mtDNA in post-mitotic cells. The absence of mtDNA carrying the mutation in satellite cells suggests that regeneration of skeletal muscle fibres from satellite cells could restore a wild-type mtDNA genotype and normal muscle function.
Hum Mol Genet 1996 Nov
PMID:A novel heteroplasmic tRNAleu(CUN) mtDNA point mutation in a sporadic patient with mitochondrial encephalomyopathy segregates rapidly in skeletal muscle and suggests an approach to therapy. 892 13


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