Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UMLS:C0026850 (muscular dystrophy)
5,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have isolated a human gene homologous to Drosophila melanogaster rotated abdomen, rt, a poorly viable recessive mutation causing a clockwise twisted abdomen in affected flies due to defects in embryonic muscle development. The human gene, like rt, encodes a protein with high homology to the yeast mannosyl-transferases (Pmts) and has been named POMT1. POMT1 is expressed as a 3.1-kb transcript in all tissues tested, with highest levels in testis and fetal brain. Alternative splicing of several exons in all tissues predicts the generation of several protein isoforms. The most common mRNA variant encodes a 725-aa protein with 40% identity and 62.5% similarity to rt, as well as 30.5% identity and 54% similarity to yeast Pmts. Computer prediction of protein sorting suggests that the POMT1 product could be an integral protein of the endoplasmic reticulum membrane. Given the strong conservation of protein motifs between POMT1 and the yeast Pmts, POMT1 may function as a mannosyl-transferase involved in O-mannosylation of proteins, being the first of such a class found in mammals. The POMT1 locus has been assigned to human chromosome 9q34.1 by somatic cell hybrids, radiation hybrids, and linkage analysis. On the basis of the rt phenotype, POMT1 could be a candidate for uncharacterized genetic disorders of the muscular system, such as some forms of congenital muscular dystrophy or congenital myopathy.
...
PMID:Identification of a human homolog of the Drosophila rotated abdomen gene (POMT1) encoding a putative protein O-mannosyl-transferase, and assignment to human chromosome 9q34.1. 1036 49

Walker-Warburg syndrome (WWS) is an autosomal recessive developmental disorder characterized by congenital muscular dystrophy and complex brain and eye abnormalities. A similar combination of symptoms is presented by two other human diseases, muscle-eye-brain disease (MEB) and Fukuyama congenital muscular dystrophy (FCMD). Although the genes underlying FCMD (Fukutin) and MEB (POMGnT1) have been cloned, loci for WWS have remained elusive. The protein products of POMGnT1 and Fukutin have both been implicated in protein glycosylation. To unravel the genetic basis of WWS, we first performed a genomewide linkage analysis in 10 consanguineous families with WWS. The results indicated the existence of at least three WWS loci. Subsequently, we adopted a candidate-gene approach in combination with homozygosity mapping in 15 consanguineous families with WWS. Candidate genes were selected on the basis of the role of the FCMD and MEB genes. Since POMGnT1 encodes an O-mannoside N-acetylglucosaminyltransferase, we analyzed the possible implication of O-mannosyl glycan synthesis in WWS. Analysis of the locus for O-mannosyltransferase 1 (POMT1) revealed homozygosity in 5 of 15 families. Sequencing of the POMT1 gene revealed mutations in 6 of the 30 unrelated patients with WWS. Of the five mutations identified, two are nonsense mutations, two are frameshift mutations, and one is a missense mutation. Immunohistochemical analysis of muscle from patients with POMT1 mutations corroborated the O-mannosylation defect, as judged by the absence of glycosylation of alpha-dystroglycan. The implication of O-mannosylation in MEB and WWS suggests new lines of study in understanding the molecular basis of neuronal migration.
...
PMID:Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome. 1236 18

Walker-Warburg syndrome (WWS) is an autosomal recessive disorder characterized by congenital muscular dystrophy, structural eye abnormalities and severe brain malformations. We performed an immunohistochemical and electron microscopy study of a muscle biopsy from a patient affected by WWS carrying a homozygous frameshift mutation in O-mannosyltransferase 1 gene (POMT1). alpha-Dystroglycan glycosylated epitope was not detected in muscle fibers and intramuscular peripheral nerves. Laminin alpha2 chain and perlecan were reduced in muscle fibers and well preserved in intramuscular peripheral nerves. The basal lamina in several muscle fibers showed discontinuities and detachment from the plasmalemma. Most nuclei, including myonuclei and satellite cell nuclei, showed detachment or complete absence of peripheral heterochromatin from the nuclear envelope. Apoptotic changes were detected in 3% of muscle fibers. The particular combination of basal lamina and nuclear changes may suggest that a complex pathogenetic mechanism, affecting several subcellular compartments, underlies the degenerative process in WWS muscle.
...
PMID:Extracellular matrix and nuclear abnormalities in skeletal muscle of a patient with Walker-Warburg syndrome caused by POMT1 mutation. 1275 35

Walker-Warburg syndrome (WWS) is an autosomal recessive disorder characterized by the combined involvement of the central nervous and skeletal muscle systems. Although the molecular basis of WWS remains unknown, defects in the muscle fibre basal lamina are characteristic of other forms of congenital muscular dystrophy (CMD). In agreement with this, some forms of CMD, due to glycosyltransferase defects, display a reduction in the immunolabelling of alpha-dystroglycan, whilst beta-dystroglycan labelling appears normal. Here we describe an almost complete absence of alpha-dystroglycan using both immunohistochemistry and immunoblotting in two patients with WWS. In addition, there was a mild reduction of laminin-alpha 2. In contrast, immunohistochemical labelling of perlecan and collagen VI was normal. Linkage analysis excluded the recently identified POMT1 locus, responsible for a proportion of WWS cases. These results confirm that WWS is a genetically heterogeneous condition and suggest that disruption of the alpha-dystroglycan/laminin-alpha 2 axis in the basal lamina may play a role in the degeneration of muscle fibres in WWS-also in cases not due to POMT1 defects.
...
PMID:Profound skeletal muscle depletion of alpha-dystroglycan in Walker-Warburg syndrome. 1278 39

Recently, post-translational modification of proteins has been defined as a new area of focus for muscular dystrophy research by the identification of a group of disease genes that encode known or putative glycosylation enzymes. Walker-Warburg Syndrome (WWS) and muscle-eye-brain disease (MEB) are caused by mutations in two genes involved in O-mannosylation, POMT1 and POMGnT1, respectively. Fukuyama muscular dystrophy (FCMD) is due to mutations in fukutin, a putative phospholigand transferase. Congenital muscular dystrophy type 1C and limb girdle muscular dystrophy type 2I are allelic, both being due to mutations in the gene-encoding fukutin-related protein (FKRP). Finally, the causative gene in the myodystrophy (myd) mouse is a putative bifunctional glycosyltransferase (Large). WWS, MEB, FCMD and the myd mouse are also associated with neuronal migration abnormalities (often type II lissencephaly) and ocular or retinal defects. A deficiency in post-translational modification of alpha-dystroglycan is a common feature of all these muscular dystrophies and is thought to involve O-glycosylation pathways. This abnormally modified alpha-dystroglycan is deficient in binding to extracellular matrix ligands, including laminin and agrin. Selective deletion of dystroglycan in the central nervous system (CNS) produces brain abnormalities with striking similarities to WWS, MEB, FCMD and the myd mouse. Thus, impaired dystroglycan function is strongly implicated in these diseases. However, it is unlikely that these five glycosylation enzymes only have a role in glycosylation of alpha-dystroglycan and it is important that other protein targets are identified.
...
PMID:Glycosylation defects: a new mechanism for muscular dystrophy? 1292 72

The congenital muscular dystrophies (CMD) are a heterogeneous group of autosomal recessive disorders. A new pathomechanism has recently been identified in a group of these disorders in which known or putative glycosyltransferases are defective. Common to all these conditions is the hypoglycosylation of alpha-dystroglycan. Fukuyama CMD, muscle-eye-brain disease and Walker-Warburg syndrome, each associated with eye abnormalities and neuronal migration defects, result from mutations in fukutin, POMGnT1 and POMT1, respectively, while mutations in the fukutin-related protein (FKRP) gene cause congenital muscular dystrophy 1C, typically lacking brain involvement. Another putative glycosyltransferase, Large, is mutated in the myodystrophy mouse. The human homologue of this gene is therefore a strong candidate for involvement in novel forms of muscular dystrophy. We studied 36 patients with muscular dystrophy and either mental retardation, structural brain changes or abnormal alpha-dystroglycan immunolabelling, unlinked to any reported CMD loci. Linkage analysis in seven informative families excluded involvement of LARGE but sequencing of this gene in the remaining 29 families identified one patient with a G1525A (Glu509Lys) missense mutation and a 1 bp insertion, 1999insT. This 17-year-old girl presented with congenital muscular dystrophy, profound mental retardation, white matter changes and subtle structural abnormalities on brain MRI. Her skeletal muscle biopsy showed reduced immunolabelling of alpha-dystroglycan. Immunoblotting with an antibody to a glycosylated epitope demonstrated a reduced molecular weight form of alpha-dystroglycan that retained some laminin binding activity. This is the first description of mutations in the human LARGE gene and we propose to name this new disorder MDC1D.
...
PMID:Mutations in the human LARGE gene cause MDC1D, a novel form of congenital muscular dystrophy with severe mental retardation and abnormal glycosylation of alpha-dystroglycan. 1296 29

The congenital muscular dystrophies (CMD) constitute a clinically and genetically heterogeneous group of autosomal recessive myopathies. Patients show congenital hypotonia, muscle weakness, and dystrophic changes on muscle biopsy. Mutations in four genes (FKT1, POMGnT1, POMT1, FKRP) encoding putative glycosyltransferases have been identified in a subset of patients characterized by a deficient glycosylation of alpha-dystroglycan on muscle biopsy. FKRP mutations account for a broad spectrum of patients with muscular dystrophy, from a severe congenital form with or without mental retardation (MDC1C) to a much milder limb-girdle muscular dystrophy (LGMD2I). We identified two novel homozygous missense FKRP mutations, one, A455D, in six unrelated Tunisian patients and the other, V405L, in an Algerian boy. The patients, between the ages of 3 and 12 years, presented with a severe form of MDC1C with calf hypertrophy and high serum creatine kinase levels. None had ever walked. Two had cardiac dysfunction and one strabismus. They all had mental retardation, microcephaly, cerebellar cysts, and hypoplasia of the vermis. White matter abnormalities were found in five, mostly when cranial magnetic resonance imaging was performed at a young age. These abnormalities were shown to regress in one patient, as has been observed in patients with Fukuyama CMD. Identification of a new microsatellite close to the FKRP gene allowed us to confirm the founder origin of the Tunisian mutation. These results strongly suggest that particular FKRP mutations in the homozygous state induce structural and clinical neurological lesions in addition to muscular dystrophy. They also relate MDC1C to other CMD with abnormal protein glycosylation and disordered brain function.
...
PMID:New FKRP mutations causing congenital muscular dystrophy associated with mental retardation and central nervous system abnormalities. Identification of a founder mutation in Tunisian families. 1465 96

Walker-Warburg syndrome (WWS) is a congenital muscular dystrophy associated with neuronal migration disorder and structural eye abnormalities. The mutations in the O-mannosyltransferase 1 gene (POMT1) were identified recently in 20% of patients with WWS. The authors report on a patient with WWS and a novel POMT1 mutation. Their patient expressed alpha-dystroglycan (alpha-DG) core protein, but fully glycosylated alpha-DG antibody epitopes were absent, associated with the loss of laminin-binding activity.
...
PMID:POMT1 mutation results in defective glycosylation and loss of laminin-binding activity in alpha-DG. 1503 15

O-mannosylation is an important protein modification in eukaryotes that is initiated by an evolutionarily conserved family of protein O-mannosyltransferases. The first mammalian protein O-mannosyltransferase gene described was the human POMT1. Mutations in the hPOMT1 gene are responsible for Walker-Warburg syndrome (WWS), a severe recessive congenital muscular dystrophy associated with defects in neuronal migration that produce complex brain and eye abnormalities. During embryogenesis, the murine Pomt1 gene is prominently expressed in the neural tube, the developing eye, and the mesenchyme. These sites of expression correlate with those in which the main tissue alterations are observed in WWS patients. We have inactivated a Pomt1 allele by gene targeting in embryonic stem cells and produced chimeras transmitting the defect allele to offspring. Although heterozygous mice were viable and fertile, the total absence of Pomt1(-/-) pups in the progeny of heterozygous intercrosses indicated that this genotype is embryonic lethal. An analysis of the mutant phenotype revealed that homozygous Pomt1(-/-) mice suffer developmental arrest around embryonic day (E) 7.5 and die between E7.5 and E9.5. The Pomt1(-/-) embryos present defects in the formation of Reichert's membrane, the first basement membrane to form in the embryo. The failure of this membrane to form appears to be the result of abnormal glycosylation and maturation of dystroglycan that may impair recruitment of laminin, a structural component required for the formation of Reichert's membrane in rodents. The targeted disruption of mPomt1 represents an example of an engineered deletion of a known glycosyltransferase involved in O-mannosyl glycan synthesis.
...
PMID:Targeted disruption of the Walker-Warburg syndrome gene Pomt1 in mouse results in embryonic lethality. 1538 66

An increasing number of genes encoding for putative or demonstrated glycosyltransferases are being associated with muscular dystrophies of variable severity, ranging from severe congenital onset and associated structural eye and brain changes, to relatively mild forms with onset into adulthood. Five of these genes (POMT1; POMGnT1; FXRP; Fukutin; LARGE) encode for proteins involved in the glycosylation of alpha-dystroglycan and, indeed, abnormal glycosylation of this molecule is a common finding in all the respective conditions (Walker Warburg syndrome; Muscle-Eye-Brain disease; congenital muscular dystrophy type 1C and Limb girdle muscular dystrophy type 21; Fukuyama muscular dystrophy; congenital muscular dystrophy type 1D). A 6th gene, GNE, responsible for the hereditary form of inclusion body myositis, encodes for a glycosyltransferase the substrate(s) of which is, however, still unclear. This article provides an overview of the clinical, biochemical and genetic features of this group of disorders.
...
PMID:Journey into muscular dystrophies caused by abnormal glycosylation. 1560 48


1 2 3 4 5 Next >>

---