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

Walker-Warburg syndrome (WWS) is an autosomal recessive disorder of infancy characterized by hydrocephalus, agyria, retinal dysplasia, congenital muscular dystrophy, and over migration of neurons through a disrupted pial surface resulting in leptomeningeal heterotopia. Although previous work identified mutations in the o-mannosyl transferase, POMT1, in 6 out of 30 WWS families [Beltran-Valero de Bernabe et al., 2002], the incidence of POMT1 mutations in WWS is not known. We sequenced the entire coding region of POMT1 in 30 consecutive, unselected patients with classic WWS. Two novel heterozygous mutations were found in two patients from non-consanguineous parents, whereas 28 other patients failed to show any POMT1 mutations. One patient was found to be heterozygous for a transition, g.1233T > A, which predicts p.Y352X. A second patient was found also to be heterozygous for a transition g.1790C > G, which predicts p.S537R. As an additional determination of the frequency of the POMT1 mutations in WWS, we tested for linkage of WWS to POMT1 in six consanguineous families. All six demonstrated heterozygosity and negative LOD scores at the POMT1 locus. From these data we show that POMT1 is an uncommon cause of WWS, the incidence of coding region mutations in this population of WWS being less than 7%. We conclude that while the incidence of POMT1 mutations in WWS can be as high as 20% as reported by Beltran-Valero de Bernabe et al. [2002] and it can be as low as approximately 7%, as reported here.
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PMID:Mutations in POMT1 are found in a minority of patients with Walker-Warburg syndrome. 1563 32

Walker-Warburg syndrome (WWS) is the most severe of a group of multiple congenital anomaly disorders known as the cobblestone lissencephalies. These are characterized by congenital muscular dystrophy in conjunction with severe brain malformation and ocular abnormalities. In the last 3 years, important progress has been made towards the elucidation of the genetic causes of these disorders. Mutations in three genes, POMT1, fukutin and FKRP, have been described for WWS, which together account for approximately 20% of patients with Walker-Warburg. It has become evident that some of the underlying genes may cause a broad spectrum of phenotypes, ranging from limb girdle muscular dystrophy type 2I to WWS. In some cases, a genotype-phenotype correlation can be recognized. In line with the known or proposed functions of the resolved genes, all patients with cobblestone lissencephaly show defects in the O-linked glycosylation of the glycoprotein alpha-dystroglycan. Perhaps, the missing genes underlying the remainder of the unexplained WWS patients have also to be sought in the pathways involved in O-linked protein glycosylation.
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PMID:Glyc-O-genetics of Walker-Warburg syndrome. 1573 61

Mutations of the protein O-mannosyltransferase (POMT1) gene affect glycosylation of alpha-dystroglycan, leading to Walker-Warburg syndrome, a lethal disorder in early life with severe congenital muscular dystrophy, and brain and eye malformations. Recently, we described a novel form of recessive limb girdle muscular dystrophy with mild mental retardation, associated with an abnormal alpha-dystroglycan pattern in the muscle, suggesting a glycosylation defect. Here, we present evidence that this distinct phenotype results from a common mutation (A200P) in the POMT1 gene. Our findings further expand the phenotype of glycosylation disorders linked to POMT1 mutations. Furthermore, the A200P mutation is part of a conserved core haplotype, indicating an ancestral founder mutation.
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PMID:An autosomal recessive limb girdle muscular dystrophy (LGMD2) with mild mental retardation is allelic to Walker-Warburg syndrome (WWS) caused by a mutation in the POMT1 gene. 1579 65

The myodystrophy (Large(myd)) mouse has a spontaneous loss of function mutation in a putative glycosyltransferase gene (Large). Mutations in the human gene (LARGE) have been described in congenital muscular dystrophy type 1D (MDC1D). Mutations in four other genes that encode known or putative glycosylation enzymes (POMT1, POMGnT1, fukutin and FKRP) are also associated with muscular dystrophy. In all these diseases hypoglycosylation of alpha-dystroglycan, and consequent loss of ligand binding, is a common pathomechanism. Currently, the Large(myd) mouse is the principal animal model for studying the underlying molecular mechanisms of this group of disorders. Over-expression of LARGE in cells from patients with mutations in POMT1 or POMGnT1 results in hyperglycosylation of alpha-dystroglycan and restoration of laminin binding. Thus, LARGE is a potential therapeutic target. Here, we define the intronic deletion breakpoints of the Large(myd) mutation and describe a simple, PCR-based diagnostic assay, facilitating the study of this important animal model.
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PMID:A rapid PCR method for genotyping the Large(myd) mouse, a model of glycosylation-deficient congenital muscular dystrophy. 1583 24

The Large(myd) mouse has a loss-of-function mutation in the putative glycosyltransferase gene Large. Mutations in the human homolog (LARGE) have been described in a form of congenital muscular dystrophy (MDC1D). Other genes (POMT1, POMGnT1, fukutin, and FKRP) that encode known or putative glycosylation enzymes are also causally associated with human congenital muscular dystrophies. All these diseases are associated with hypoglycosylation of the membrane protein alpha-dystroglycan (alpha-DG) and consequent loss of extracellular ligand binding. Hence, they are termed dystroglycanopathies. A paralogous gene for LARGE (LARGE2 or GYLTL1B) may also have a role in DG glycosylation. Using database interrogation and reverse-transcriptase polymerase chain reaction (RT-PCR), we identified vertebrate orthologs of each of these LARGE genes in many vertebrates, including human, mouse, dog, chicken, zebrafish, and pufferfish. However, within invertebrate genomes, we were able to identify only single homologs. We suggest that vertebrate LARGE orthologs be referred to as LARGE1. RT-PCR, dot-blot, and northern analysis indicated that LARGE2 has a more restricted tissue-expression profile than LARGE1. Using epitope-tagged proteins, we show that both LARGE1 and LARGE2 localize to the Golgi apparatus. The high similarity between the LARGE paralogs suggests that LARGE2 may also act on DG. Overexpression of LARGE2 in mouse C2C12 myoblasts results in increased glycosylation of alpha-DG accompanied by an increase in laminin binding. Thus, there may be functional redundancy between LARGE1 and LARGE2. Consistent with this idea, we show that alpha-DG is still fully glycosylated in kidney (a tissue that expresses a high level of LARGE2 mRNA) of Large(myd) mutant mice.
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PMID:Characterization of the LARGE family of putative glycosyltransferases associated with dystroglycanopathies. 1595 17

Fukuyama congenital muscular dystrophy (FCMD), Walker-Warburg syndrome (WWS), and muscle-eye-brain (MEB) disease are similar disorders characterized by congenital muscular dystrophy, brain and eye anomalies. We previously identified the genes for FCMD and MEB, which encode fukutin and POMGnT1. Recent studies have revealed that posttranslational modification of alpha-dystroglycan is associated with congenital muscular dystrophy with brain malformations. Since hypoglycosylation of alpha-dystroglycan is common amongst several other disorders, a new clinical entity called alpha-dystroglycanopathy is proposed. However, only POMGnT1 (MEB) and POMT1 (WWS) are shown to have a definite enzymatic activity, and no enzymatic activity has been detected in fukutin. We show positive interactions between fukutin and POMGnT1. Fukutin may form a protein complex with POMGnT1 and modulate POMGnT1's enzymatic activity. Through cDNA microarray, we also show aberrant neuromuscular junction formation and delayed muscle fiber maturation in alpha-dystroglycanopathies, suggesting a new pathomechanism.
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PMID:[Alpha-dystroglycanopathy (FCMD, MEB, etc): abnormal glycosylation and muscular dystrophy]. 1644 66

The importance of O-glycosylation of alpha-dystroglycan (alpha-DG) is evident from the identification of POMT1 mutations in Walker-Warburg syndrome (WWS). Approximately one-fifth of the WWS patients show mutations in POMT1, which result in complete loss of protein mannosyltransferase activity. WWS patients are characterized by congenital muscular dystrophy (CMD) with severe brain and eye abnormalities. This suggests a crucial role for alpha-DG during development of these organs and tissues. Here we report new POMT1 mutations and polymorphisms in WWS patients. In addition, we report different compound heterozygous POMT1 mutations in four unrelated families that result in a less severe phenotype than WWS, characterized by CMD with calf hypertrophy, microcephaly, and mental retardation. Compared to WWS patients, these patients have milder structural brain abnormalities, and eye abnormalities were absent, except for myopia in some cases. In these patients we postulate that one or both transcripts for POMT1 confer residual protein O-mannosyltransferase activity. Our data suggest the existence of a disease spectrum of CMD including brain and eye abnormalities resulting from POMT1 mutations.
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PMID:The expanding phenotype of POMT1 mutations: from Walker-Warburg syndrome to congenital muscular dystrophy, microcephaly, and mental retardation. 1657 35

Mammalian O-mannosylation, although an uncommon type of protein modification, is essential for normal brain and muscle development. Defective O-mannosylation causes congenital muscular dystrophy with abnormal neuronal migration [Walker-Warburg syndrome (WWS)]. Here, we have identified and cloned rat Pomt1 and Pomt2, which are homologues of human POMT1 and POMT2, with identities of 86 and 90%, respectively, at the amino acid level. Coexpression of both genes was found to be necessary for enzymatic activity, as is the case with human POMT1 and POMT2. Northern blot and reverse transcriptase polymerase chain reaction (RT-PCR) analyses revealed that rat Pomt1 and Pomt2 are expressed in all tissues but most strongly in testis. In situ hybridization histochemistry of rat brain revealed that Pomt1 and Pomt2 mRNA are coexpressed in neurons (dentate gyrus and CA1-CA3 region of the hippocampus and cerebellar Purkinje cells). Two transcription-initiation sites were observed in rat Pomt2, resulting in two forms: a testis form and a somatic form. The two forms had equal protein O-mannosyltransferase activity when coexpressed with rat Pomt1. Coexpression studies also showed that the human and rat protein O-mannosyltransferases are interchangeable, providing further evidence for the closeness of their structures.
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PMID:Molecular cloning and characterization of rat Pomt1 and Pomt2. 1670 66

Walker-Warburg Syndrome (WWS) is a rare form of autosomal recessive congenital muscular dystrophy associated with brain and eye abnormalities. WWS has a worldwide distribution. The overall incidence is unknown but a survey in North-eastern Italy has reported an incidence rate of 1.2 per 100,000 live births. It is the most severe form of congenital muscular dystrophy with most children dying before the age of three years. WWS presents at birth with generalized hypotonia, muscle weakness, developmental delay with mental retardation and occasional seizures. It is associated with type II cobblestone lissencephaly, hydrocephalus, cerebellar malformations, eye abnormalities and congenital muscular dystrophy characterized by hypoglycosylation of alpha-dystroglycan. Several genes have been implicated in the etiology of WWS, and others are as yet unknown. Several mutations were found in the Protein O-Mannosyltransferase 1 and 2 (POMT1 and POMT2) genes, and one mutation was found in each of the fukutin and fukutin-related protein (FKRP) genes. Laboratory investigations usually show elevated creatine kinase, myopathic/dystrophic muscle pathology and altered alpha-dystroglycan. Antenatal diagnosis is possible in families with known mutations. Prenatal ultrasound may be helpful for diagnosis in families where the molecular defect is unknown. No specific treatment is available. Management is only supportive and preventive.
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PMID:Walker-Warburg syndrome. 1688 26

Walker Warburg syndrome (WWS) is the most severe of a group of multiple congenital disorders known as lissencephaly type II ( LIS Type II) associated with congenital muscular dystrophy and eye abnormalities. The POMT1 gene is the most frequently affected found in 20% of patients with WWS. We describe five fetuses with WWS in three non-related families carrying a same mutation in the POMT1 gene. All fetuses presented with tetra ventricular hydrocephaly, and arachnoidal neuroglial ectopia and cortical dysplasia characteristic of LIS type II. We performed sequencing of the POMT1 gene on fetal DNA. The five fetuses were found to share an insertion of an inversed Alu repeated DNA element within exon 3 of the POMT1 gene, all at the heterozygous state except one at the homozygous state. This mutation was associated with a common transition c.2203 C > T (p.Arg735Cys) in exon 20 on the same allele and similar intragenic haplotype, suggesting that the three families could be related or indicating a possible founder effect in France. Insertions of Alu sequences, which are rarely found in coding regions, have occasionally been reported to cause other genetic diseases. However, this is the first report of a retrotransposon insertion in the POMT1 gene associated with WWS.
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PMID:Detection of an Alu insertion in the POMT1 gene from three French Walker Warburg syndrome families. 1707 74


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