Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disorder. The FSHD locus has been linked to the most distal genetic markers on the long arm of chromosome 4. An EcoRI fragment length polymorphism segregates with the disease in most FSHD families. Within the EcoRI fragment lies a tandem array of 3.2 kb repeats. Deletions of integral copies of this repeat have been associated with the disease. The 3.2 kbp repeat has recently been shown to cross-hybridize to several regions of heterochromatin in the human genome and DNA sequence analysis reveals strong homology to a class of heterochromatin repeats, LSau. In this report, we demonstrate that the 3.2 kbp tandem repeat lies adjacent to a subtelomeric sequence, which is within 5-14 kb of the telomeric repeat (TTAGGG)n. Direct visual fluorescence hybridization to linearly extended strands of DNA enabled the visualization of this subtelomeric sequence as a short string of signals at the end of a longer string of signals from the differentially labeled 3.2 kbp tandem repeat. Furthermore, in support of our data showing that the 3.2 kbp repeat lies in close proximity to the telomere of 4q, we demonstrated the lack of hybridization of total human DNA to this same region. Our results indicate that the tandem array of 3.2 kbp repeats, disrupted in FSHD, lies immediately adjacent to the telomere of 4q and that the gene responsible for FSHD is likely located proximal to the tandem repeat.
Hum Mol Genet 1994 Oct
PMID:High resolution fluorescence in situ hybridization to linearly extended DNA visually maps a tandem repeat associated with facioscapulohumeral muscular dystrophy immediately adjacent to the telomere of 4q. 784 3

The gene for the common recessive neuromuscular disorder spinal muscular atrophy (SMA) has been previously mapped to chromosome 5q. We report here linkage disequilibrium analyses of two polymorphic simple tandem repeat (STR) sequences which map into the critical region of 5q13 containing the SMA gene. The polymorphisms presented are constituents of CATT-1, a complex STR which is present in as many as four or more copies per chromosome 5. The PCR can amplify as many as eight CATT-1 products of different sizes from genomic DNA samples due to differing numbers of CA dinucleotides at each STR location (sublocus). Oligonucleotide primers for two of these subloci have been developed for specific PCR assays; a variety of allele sizes can be generated with each assay and, in some cases, no amplification products are detected due to null alleles. The genotyping of 149 SMA Type 1 chromosomes and 142 normal chromosomes from Canadian and American kindreds reveals the presence of significant linkage disequilibrium between the null allele of the sublocus referred to as CATT-40G1 and mutation(s) causing SMA Type 1 (Werdnig-Hoffmann disease). Allele 2 of the second sublocus, CATT-192F7, is also in linkage disequilibrium with SMA Type 1 although the degree of this association is less than that found for CATT-40G1. The proximal and distal STRs from the critical region, D5S435 and D5S351, showed no linkage disequilibrium with SMA. The data presented here will serve as a framework for future linkage disequilibrium analyses, expediting the final stage of the search for the SMA gene.
Hum Mol Genet 1994 Nov
PMID:Two 5q13 simple tandem repeat loci are in linkage disequilibrium with type 1 spinal muscular atrophy. 787 11

Spinal muscular atrophy (SMA) is, after Duchenne muscular dystrophy, the most common neuromuscular disorder in childhood. The gene responsible for childhood SMA has been mapped to the q11.2-q13.3 region of chromosome 5. We have extended our linkage studies of SMA in the French-Canadian population to include microsatellite markers at the D5S125, D5S351, D5S435, JK53CA1/2 and MAP1B loci. These markers span about 4 cM of the SMA candidate region. We observed significant evidence for linkage between SMA and all the markers tested. The analysis of recombinant chromosomes provide evidence for the following genetic order: D5S125-D5S435-MAP1B-3'-JK53CA1/2 and places D5S351 proximal to JK53CA1/2. Furthermore, we confirm the current localization of the SMA gene distal to D5S435. Finally, we provide demonstration of significant linkage disequilibrium between childhood-onset SMA and four of the five marker loci, D5S125, D5S435, D5S351 and JK53CA1/2. Analysis of SMA-region haplotypes suggests that there may be a predominant SMA allele that is present on about 17% of SMA chromosomes in this sample of the French-Canadian population. We conclude that the observed linkage disequilibrium is likely due to genetic drift among regions of Quebec, consistent with this population's early history.
Hum Mol Genet 1994 Mar
PMID:Linkage disequilibrium analysis of childhood-onset spinal muscular atrophy (SMA) in the French-Canadian population. 801 58

Facioscapulohumeral muscular dystrophy (FSHD) is a neuromuscular disorder characterized by progressive weakness of the facial, shoulder and upper arm muscles. The disease is associated with DNA rearrangements which are detectable using probe p13E-11 (D4F104S1) in DNA digested with EcoRI or other restriction enzymes. We have cloned and characterized the rearranged EcoRI fragment of four unrelated FSHD patients. Restriction fragment mapping and DNA sequence analysis showed that the proximal and distal parts of the EcoRI fragment, which flank a region of tandemly repeated 3.2 kb units, are identical in normal and rearranged EcoRI fragments. These results strongly support the hypothesis that the FSHD associated rearrangements are due to deletions of integral copies of the 3.2 kb repeated unit. Since these repeated units are likely to form part of the FSHD transcription unit, the variation in repeat unit number might affect the function of the gene product. Hence, our data confine the FSHD gene region and thus provide a starting point for cloning the FSHD gene.
Hum Mol Genet 1993 Dec
PMID:FSHD associated DNA rearrangements are due to deletions of integral copies of a 3.2 kb tandemly repeated unit. 811 71

Facioscapulohumeral muscular dystrophy is an important autosomal dominant neuromuscular disorder that has been localised to 4q35. We have analysed our extensive panel of 45 families with a new DNA marker p13E-11. The findings, based on multiply informative individual meioses and multipoint mapping, suggest that probe p13E-11 is the closest marker for the disorder and it is likely to be located proximal to the disease locus as are all the other present markers. In nine of the ten new mutations studied, a new smaller EcoRI fragment which was not present in either of the parents was detected, indicating that a de novo DNA rearrangement is indeed associated with the development of the disease state. However, in view of the difficulty in defining the size of over 30kb alleles and the recombinant events observed with p13E-11, we suggest that it should be used in combination with another VNTR marker until a close distal flanking marker for this condition is identified or the gene itself is isolated.
Hum Mol Genet 1993 Jul
PMID:Molecular analysis of British facioscapulohumeral dystrophy families for 4q DNA rearrangements. 836 81

Proximal spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder characterized by degeneration of anterior horn cells in the spinal cord leading to weakness and wasting of voluntary muscles. Here we present the molecular analysis of both SMA candidate genes, the survival motor neuron gene (SMN; exons 7 and 8) and the neuronal apoptosis inhibitory protein gene (NAIP; exons 5, 6 and 13), in 195 patients and 348 parents of SMA families mainly of German origin. The SMN gene is homozygously deleted for both exons 7 and 8 or exon 7 only in 96% of type I SMA, 94% of type II SMA and 82% of type III SMA as well as in 0.3% of SMA parents. The NAIP gene is homozygously deleted in 46% of type I SMA, 17% of type II SMA, 7% of type III SMA and 2% of SMA parents. The frequencies of deletions in patients for both genes, SMN and NAIP, correspond to those for the NAIP gene only. SMA patients of this series who did not show deletions were clinically indistinguishable from deleted patients. In addition to one unaffected mother of a type II SMA patient, we found homozygous deletions of the SMN gene exons 7 and 8 in six further unaffected individuals, all sibs of type II and III patients. These belonged to four families with affected and unaffected sibs who showed identical haplotypes for all SMA flanking markers; therefore, we had regarded these families as chromosome 5 unlinked. All seven unaffected individuals in whom we detected SMA deletions do not show any signs of muscle weakness and are physically inconspicuous. The largest divergence between age at onset of an affected subject and the present age of unaffected deleted sibs is four decades now. The occurrence of SMN deletions in unaffected individuals suggests that other genes or mechanisms may be necessary to produce the SMA phenotype.
Hum Mol Genet 1995 Oct
PMID:Molecular analysis of candidate genes on chromosome 5q13 in autosomal recessive spinal muscular atrophy: evidence of homozygous deletions of the SMN gene in unaffected individuals. 859 17

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

High resolution respirometry in combination with the skinned fiber technique offers the possibility to study mitochondrial function routinely in small amounts of human muscle. During a period of 2 years, we investigated mitochondrial function in skeletal muscle tissue of 13 patients (average age = 5.8 years). In all of them, an open muscle biopsy was performed for diagnosis of their neuromuscular disorder. Mitochondrial oxidation rates were measured with a highly sensitive respirometer. Multiple substrate-inhibitor titration was applied for investigation of mitochondrial function. About 50 mg fibers were sufficient to obtain maximal respiratory rates for seven different substrates (pyruvate/malate, glutamate/malate, octanoylcarnitine/malate, palmitoylcarnitine/malate, succinate, durochinol and ascorbate/TMPD). Decreased respiration rates with reference to the wet weight of the permeabilized fiber could immediately be detected during the course of measurements. In 4 patients with mitochondrial encephalomyopathy (MEM) the respiration pattern indicated a specific mitochondrial enzyme defect, which was confirmed in every patient by measurements of the individual enzymes (one patient with PDHC deficiency, one with complex I deficiency and two patients with combined complex I and IV deficiency). In the 6 patients with spinal muscular atrophy (SMA) oxidation rates were found to be decreased of 23 +/- 5% of controls. The normalized respiration pattern was comparable to that of the controls indicating a decreased content of mitochondria in SMA muscle with normal functional properties. Also in the 3 patients with Duchenne muscular dystrophy (DMD) decreased oxidation rates (42 +/- 5%) were detected. In addition a low RCI (1.2) indicated a loose coupling of oxidative phosphorylation in the mitochondria of these patients. It is concluded that investigation of mitochondrial function in saponin skinned muscle fibers using high resolution respirometry in combination with multiple substrate titration offers a valuable tool for evaluation of mitochondrial alterations in muscle biopsies of children suffering from neuromuscular disorders.
Mol Cell Biochem 1997 Sep
PMID:High resolution respirometry of permeabilized skeletal muscle fibers in the diagnosis of neuromuscular disorders. 930 68

Myotonic dystrophy (DM) is an autosomal dominant neuromuscular disorder characterized by a great variability in its clinical manifestations. The mutational basis underlying DM consists of an unstable (CTG)n trinucleotide repeat in the 3' untranslated region of the myotonic dystrophy protein kinase gene (DMPK). Conflicting results on DMPK gene expression in congenitally affected infants (CDM) have been published. Moreover, the prominence of satellite cells seen in muscle of CDM infants supports the notion that the congenital form is associated with an arrest in muscle development and suggests a role for the DMPK gene during differentiation and maturation of muscle. In order to clarify these findings, a comparative study of DMPK and myogenic factor mRNA levels was performed in developing mouse muscle tissues and cultured muscle cells at different developmental stages. Results show that DMPK gene expression is upregulated at a late stage of muscular development. This upregulation does not seem to depend on a given muscle specific bHLH factor.
Cell Mol Biol (Noisy-le-grand) 1997 Sep
PMID:Expression of myotonic dystrophy protein kinase gene during in vivo and in vitro mouse myogenesis. 935 35

Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder characterized by degeneration of motor neurons of the spinal cord and muscular atrophy. SMA is caused by alterations to the survival of motor neuron (SMN) gene, the function of which has hitherto been unclear. Here, we present immunoblot analyses showing that normal SMN protein expression undergoes a marked decay in the postnatal period compared with fetal development. Morphological and immunohistochemical analyses of the SMN protein in human fetal tissues showed a general distribution in the cytoplasm, except in muscle cells, where SMN protein was immunolocalized to large cytoplasmic dot-like structures and was tightly associated with membrane-free heavy sedimenting complexes. These cytoplasmic structures were similar in size to gem. The SMN protein was markedly deficient in tissues derived from type I SMA fetuses, including skeletal muscles and, as previously shown, spinal cord. While our data do not help decide whether SMA results from impaired SMN expression in spinal cord, skeletal muscle or both, they suggest a requirement for SMN protein during embryo-fetal development.
Hum Mol Genet 1998 Nov
PMID:The distribution of SMN protein complex in human fetal tissues and its alteration in spinal muscular atrophy. 981 37


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