Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026850 (muscular dystrophy)
 5,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The O-mannosyl glycan is present in a limited number of glycoproteins of brain, nerve, and skeletal muscle. alpha-Dystroglycan is one of the O-mannosylated proteins and is a central component of the dystrophin-glycoprotein complex that has been shown to be related to the onset of muscular dystrophy. We have identified and characterized glycosyltransferases, protein O-mannose beta1,2-N-acetylglucosaminyltransferase (POMGnT1) and protein O-mannosyltransferase 1 (POMT1), involved in the biosynthesis of O-mannosyl glycans. We subsequently found that loss of function of the POMGnT1 gene is responsible for muscle-eye-brain disease (MEB). It has also been reported that the POMT1 gene is responsible for Walker-Warburg syndrome (WWS). MEB and WWS are autosomal recessive disorders characterized by congenital muscular dystrophies with neuronal migration disorders. Therefore, the ability to assay enzyme activities of mammalian O-mannosylation would facilitate progress in the identification of other O-mannosylated proteins, the elucidation of their functional roles, and the understanding of muscular dystrophies. This protocol describes assay methods for the mammalian POMT and POMGnT.
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PMID:O-mannosylation in mammalian cells. 1707 3

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

Walker--Warburg syndrome (WWS), the most severe alpha-dystroglycanopathy, is characterized by brain and eye anomalies, and congenital muscular dystrophy (CMD). So far at least four genes (POMT1, POMT2, Fukutin, and FKRP gene) have been implicated in WWS, accounting for about 30% of all cases. We report a male patient with WWS resulting from a homozygous nonsense mutation (R514X) in the POMT1 gene. The patient had congenital hydrocephalus which was detected at 29 weeks of gestation. A brain MRI obtained after birth revealed type II lissencephaly, hydrocephalus, and pontocerebellar hypoplasia. The case also exhibited severe ocular malformations and muscular hypotonia due to CMD.
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PMID:A case of Walker-Warburg syndrome resulting from a homozygous POMT1 mutation. 1716 65

The Walker-Warburg syndrome is a rare and lethal autosomal recessive disorder. We report a newborn male infant with the Walker-Warburg syndrome. He had typical clinical features, including lissencephaly, congenital muscular dystrophy and an ocular abnormality associated with cleft lip and palate without hydrocephalus.
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PMID:The Walker-Warburg syndrome with cleft lip and palate. 1730 84

Intragenic homozygous deletions in the Large gene are associated with a severe neuromuscular phenotype in the myodystrophy (myd) mouse. These mutations result in a virtual lack of glycosylation of alpha-dystroglycan. Compound heterozygous LARGE mutations have been reported in a single human patient, manifesting with mild congenital muscular dystrophy (CMD) and severe mental retardation. These mutations are likely to retain some residual LARGE glycosyltransferase activity as indicated by residual alpha-dystroglycan glycosylation in patient cells. We hypothesized that more severe LARGE mutations are associated with a more severe CMD phenotype in humans. Here we report a 63-kb intragenic LARGE deletion in a family with Walker-Warburg syndrome (WWS), which is characterized by CMD, and severe structural brain and eye malformations. This finding demonstrates that LARGE gene mutations can give rise to a wide clinical spectrum, similar as for other genes that have a role in the post-translational modification of the alpha-dystroglycan protein.
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PMID:Intragenic deletion in the LARGE gene causes Walker-Warburg syndrome. 1743 19

Walker-Warburg syndrome (WWS) is the most severe of a group of congenital disorders that have in common defects in the O-glycosylation of alpha-dystroglycan. WWS is characterized by congenital muscular dystrophy coupled with severe ocular and brain malformations. Moreover, in at least one-fifth of the reported cases, mutations in the POMT1 gene are responsible for this disease. During embryonic development (E8.5 to E11.5), the mouse Pomt1 gene is expressed in the tissues most severely affected in WWS, the muscle, eye, and brain. In this study, we show that mPomt1 expression is maintained in the muscle and eye in later developmental stages and, notably, that its expression is particularly strong in regions of brain and cerebellum that, when affected, could generate the defects observed in patients with WWS. We show that the Pomt1 protein is localized to the sarcoplasmic reticulum of muscle tissue cells in adult mice, where alpha-dystroglycan is O-glycosylated. Furthermore, the Pomt1 protein is localized to the acrosome of maturing spermatids, where alpha-dystroglycan is not glycosylated, so that Pomt1 might have a different target for O-mannosylation in the testes. This expression pattern in the testes could also be related to the gonadal anomalies observed in some patients with WWS.
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PMID:Expression of the murine Pomt1 gene in both the developing brain and adult muscle tissues and its relationship with clinical aspects of Walker-Warburg syndrome. 1745 71

Protein O-mannosylation represents an evolutionarily conserved, essential posttranslational modification with immense impact on a variety of cellular processes. In humans, O-mannosylation defects result in Walker-Warburg syndrome, a severe recessive congenital muscular dystrophy associated with defects in neuronal migration that produce complex brain and eye abnormalities. In mouse and yeasts, loss of O-mannosylation causes lethality. Protein O-mannosyltransferases (PMTs) initiate the assembly of O-mannosyl glycans. The evolutionarily conserved PMT family is classified into PMT1, PMT2, and PMT4 subfamilies, which mannosylate distinct target proteins. In contrast to other types of glycosylation, signal sequences for O-mannosylation have not been identified to date. In the present study, we identified signals that determine PMT4-dependent O-mannosylation. Using specific model proteins, we demonstrate that in yeast Pmt4p mediates O-mannosylation of Ser/Thr-rich membrane-attached proteins. The nature of the membrane-anchoring sequence is nonrelevant, as long as it is flanked by a Ser/Thr-rich domain facing the endoplasmic reticulum lumen. Our work shows that, in contrast to several other types of glycosylation, PMT4 O-mannosylation signals are not just linear protein's primary structure sequences but rather are highly complex. Based on these findings, we performed in silico analyses of the Saccharomyces cerevisiae proteome and identified previously undescribed Pmt4p substrates. This tool for proteome-wide identification of O-mannosylated proteins is of general interest because several of these proteins are major players of a wide variety of cellular processes.
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PMID:Membrane association is a determinant for substrate recognition by PMT4 protein O-mannosyltransferases. 1747 Aug 20

Mutations in the fukutin-related protein gene (FKRP) are associated with a spectrum of diseases from mild limb-girdle muscular dystrophy type 2I to severe congenital muscular dystrophy type 1C, muscle-eye-brain disease (MEB), and Walker-Warburg syndrome (WWS). The effect of mutations on the transportation of the mutant proteins may constitute the underlying mechanisms for the pathogenesis of these diseases. Here we examined the subcellular localization of mouse and human normal and mutant FKRP proteins in cells and in muscle in vivo. Both normal human and mouse FKRPs localize in part of the Golgi apparatus in muscle fibers. Mutations in the FKRP gene invariably altered the localization of the protein, leading to endoplasmic reticulum retention within cells and diminished Golgi localization in muscle fibers. Our results therefore suggest that an individual missense point mutation can confer at least two independent effects on the protein, causing (1) reduction or loss of the presumed glycosyltransferase activity directly and (2) mislocalization that could further alter the function of the protein. The complexity of the effect of individual missense point mutations may partly explain the wide variation of the FKRP-related myopathies.
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PMID:Fukutin-related protein localizes to the Golgi apparatus and mutations lead to mislocalization in muscle in vivo. 1755 98

Type II lissencephaly (type II LIS) is a group of autosomal recessive congenital muscular dystrophies (CMD) associated with defects in alpha-DG O-glycosylation, which comprises Walker-Warburg syndrome, Fukuyama cerebral and muscular dystrophy, or muscle-eye-brain disease. The most severe forms of these diseases often have a fetal presentation and lead to a pregnancy termination. We report here the first molecular study on fetal type II LIS in a series of 47 fetuses from 41 unrelated families. Sequencing of the different genes known to be involved in alpha-DG O-glycosylation allowed the molecular diagnosis in 22 families: involvement of POMT1 was demonstrated in 32% of cases, whereas POMGNT1 and POMT2 were incriminated in 15% and in 7% of cases, respectively. We found 30 different mutations in these three genes, 25 were described herein for the first time, 15 in POMT1, and five in POMT2 and POMGNT1. Despite sequencing of FKRP, FCMD, and LARGE, no definitive molecular diagnosis could be made for the other half of our cases. Preliminary results concerning genotype-phenotype correlations show that the choice of the first gene sequenced should depend on the clinical severity of the type II LIS; POMT1 and POMT2 for severest clinical picture and POMGNT1 for milder disease. The other genes, FKRP, FCMD, and LARGE, seem not to be implicated in the fetal form of CMD.
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PMID:Molecular heterogeneity in fetal forms of type II lissencephaly. 1755 86

Muscle-eye-brain (MEB) disease is an autosomal recessive disorder characterized by a broad clinical spectrum including congenital muscular dystrophy, ocular abnormalities, and brain malformation (type-II lissencephaly). Herein, we report on two Turkish siblings with a homozygous mutation in the POMGnT1 gene. A 6-year-old sibling has a severe form of MEB disease, which in some aspects is more suitable with the diagnosis of Walker-Warburg syndrome. However, the same mutation resulted in a less severe form of MEB in the older sibling, who is 14 years old. These two cases suggest that POMGnT1 mutations may cause MEB disease with different phenotypes even in the same family.
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PMID:Severe muscle-eye-brain disease is associated with a homozygous mutation in the POMGnT1 gene. 1788 Dec 66


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