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ABSTRACT: Aberrant glycosylation of α-dystroglycan is associated with a subset of clinically heterogeneous muscular dystrophies collectively referred to as the dystroglycanopathies. These autosomal-recessive disorders span a wide spectrum of clinical severity ranging from Walker-Warburg syndrome, with severe brain and eye abnormalities, to mild adult-onset limb-girdle muscular dystrophy. To date, seven causative genes have been identified in the dystroglycanopathies, yet studies have suggested that a significant proportion of patients harbor mutations in novel genes.
A homozygous missense alteration in the gene encoding ubiquitin ligase WW domain-containing protein 1 (WWP1), has recently been identified in the dystroglycanopathy chicken. We therefore investigated whether mutations in the human ortholog were present in a cohort of 33 dystroglycanopathy patients.
No clear pathogenic mutations were identified.
The present findings indicate that WWP1 is not a common cause of human dystroglycanopathy.
Muscle & Nerve 09/2011; 44(3):388-92. · 2.37 Impact Factor
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ABSTRACT: A common group of muscular dystrophies is associated with the aberrant glycosylation of α-dystroglycan. These clinically heterogeneous disorders, collectively termed dystroglycanopathies, are often associated with central nervous system and more rarely eye pathology. Defects in a total of eight putative and demonstrated glycosyltransferases or accessory proteins of glycosyltransferases have been shown to cause a dystroglycanopathy phenotype. In recent years the systematic analysis of large patient cohorts has uncovered a complex relationship between the underlying genetic defect and the resulting clinical phenotype. These studies have also drawn attention to the high proportion of patients that remain without a genetic diagnosis implicating novel genes in the pathogenesis of dystroglycanopathies. Recent glycomic analyses of α-dystroglycan have reported complex patterns of glycan composition and have uncovered novel glycan modifications. The exact glycan synthesis and modification pathways involved, as well as their role in ligand binding, remain only partially characterised. This review will focus on recent studies that have extended our knowledge of the mechanisms underlying dystroglycanopathies and have further characterised this patient population.
Current opinion in genetics & development 03/2011; 21(3):278-85. · 8.99 Impact Factor
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Emma Clement,
Eugenio Mercuri, Caroline Godfrey,
Janine Smith,
Stephanie Robb,
Maria Kinali,
Volker Straub,
Kate Bushby,
Adnan Manzur,
Beril Talim, [......],
Andrea Klein,
Cheryl Longman,
Robert McWilliam,
Haluk Topaloglu,
Rachael Mein,
Stephen Abbs,
Kathryn North,
A James Barkovich,
Mary Rutherford,
Francesco Muntoni
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ABSTRACT: To assess the range and severity of brain involvement, as assessed by magnetic resonance imaging, in 27 patients with mutations in POMT1 (4), POMT2 (9), POMGnT1 (7), Fukutin (4), or LARGE (3), responsible for muscular dystrophies with abnormal glycosylation of dystroglycan (dystroglycanopathies).
Blinded review of magnetic resonance imaging brain scans from 27 patients with mutations in 1 of these 5 genes.
Brain magnetic resonance images were normal in 3 of 27 patients; in another 5, only nonspecific abnormalities (ventricular dilatation, periventricular white matter abnormalities, or both) were seen. The remaining 19 patients had a spectrum of structural defects, ranging from complete lissencephaly in patients with Walker-Warburg syndrome to isolated cerebellar involvement. Cerebellar cysts and/or dysplasia and hypoplasia were the predominant features in four patients. Polymicrogyria (11/27) was more severe in the frontoparietal regions in 6, and had an occipitofrontal gradient in 2. Pontine clefts, with an unusual appearance to the corticospinal tracts, were seen in five patients with a muscle-eye-brain-like phenotype, three patients with POMGnT1, one with LARGE, and one with POMT2 mutations. Prominent cerebellar cysts were always seen with POMGnT1 mutations, but rarely seen in POMT1 and POMT2. Brainstem and pontine abnormalities were common in patients with POMT2, POMGnT1, and LARGE mutations.
Our results expand the spectrum of brain involvement associated with mutations in LARGE, POMGnT1, POMT1, and POMT2. Pontine clefts were visible in some dystroglycanopathy patients. Infratentorial structures were often affected in isolation, highlighting their susceptibility to involvement in these conditions.
Annals of Neurology 12/2008; 64(5):573-82. · 11.09 Impact Factor
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Cecilia Jimenez-Mallebrera,
Silvia Torelli,
Lucy Feng,
Jihee Kim, Caroline Godfrey,
Emma Clement,
Rachael Mein,
Stephen Abbs,
Susan C Brown,
Kevin P Campbell,
Stephan Kröger,
Beril Talim,
Haluk Topaloglu,
Ros Quinlivan,
Helen Roper,
Anne M Childs,
Maria Kinali,
Caroline A Sewry,
Francesco Muntoni
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ABSTRACT: Hypoglycosylation of alpha-dystroglycan underpins a subgroup of muscular dystrophies ranging from congenital onset of weakness, severe brain malformations and death in the perinatal period to mild weakness in adulthood without brain involvement. Mutations in six genes have been identified in a proportion of patients. POMT1, POMT2 and POMGnT1 encode for glycosyltransferases involved in the mannosylation of alpha-dystroglycan but the function of fukutin, FKRP and LARGE is less clear. The pathological hallmark is reduced immunolabeling of skeletal muscle with antibodies recognizing glycosylated epitopes on alpha-dystroglycan. If the common pathway of these conditions is the hypoglycosyation of alpha-dystroglycan, one would expect a correlation between clinical severity and the extent of hypoglycosylation. By studying 24 patients with mutations in these genes, we found a good correlation between reduced alpha-dystroglycan staining and clinical course in patients with mutations in POMT1, POMT2 and POMGnT1. However, this was not always the case in patients with defects in fukutin and FKRP, as we identified patients with mild limb-girdle phenotypes without brain involvement with profound depletion of alpha-dystroglycan. These data indicate that it is not always possible to correlate clinical course and alpha-dystroglycan labeling and suggest that there might be differences in alpha-dystroglycan processing in these disorders.
Brain Pathology 09/2008; 19(4):596-611. · 3.99 Impact Factor
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Emma M Clement, Caroline Godfrey,
Jenny Tan,
Martin Brockington,
Silvia Torelli,
Lucy Feng,
Susan C Brown,
Cecilia Jimenez-Mallebrera,
Caroline A Sewry,
Cheryl Longman,
Rachael Mein,
Steve Abbs,
Jiri Vajsar,
Harry Schachter,
Francesco Muntoni
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ABSTRACT: Mutations in protein-O-mannose-beta1,2-N-acetylglucosaminyltransferase 1 (POMGnT1) have been found in muscle-eye-brain disease, a congenital muscular dystrophy with structural eye and brain defects and severe mental retardation.
To investigate whether mutations in POMGnT1 could be responsible for milder allelic variants of muscular dystrophy.
Screening for mutations in POMGnT1.
Tertiary neuromuscular unit.
A patient with limb-girdle muscular dystrophy phenotype, with onset at 12 years of age, severe myopia, normal intellect, and decreased alpha-dystroglycan immunolabeling in skeletal muscle.
A homozygous POMGnT1 missense mutation (c.1666G>A, p.Asp556Asn) was identified. Enzyme studies of the patient's fibroblasts showed an altered kinetic profile, less marked than in patients with muscle-eye-brain disease and in keeping with the relatively mild phenotype in our patient.
Our findings widen the spectrum of disorders known to result from mutations in POMGnT1 to include limb-girdle muscular dystrophy with no mental retardation. We propose that this condition be known as LGMD2M. The enzyme assay used to diagnose muscle-eye-brain disease may not detect subtle abnormalities of POMGnT1 function, and additional kinetic studies must be carried out in such cases.
Archives of Neurology 01/2008; 65(1):137-41. · 7.58 Impact Factor
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Caroline Godfrey,
Emma Clement,
Rachael Mein,
Martin Brockington,
Janine Smith,
Beril Talim,
Volker Straub,
Stephanie Robb,
Ros Quinlivan,
Lucy Feng, [......],
Adnan Y Manzur,
Maria Kinali,
Silvia Torelli,
Susan C Brown,
Caroline A Sewry,
Kate Bushby,
Haluk Topaloglu,
Kathryn North,
Stephen Abbs,
Francesco Muntoni
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ABSTRACT: Muscular dystrophies with reduced glycosylation of alpha-dystroglycan (alpha-DG), commonly referred to as dystroglycanopathies, are a heterogeneous group of autosomal recessive conditions which include a wide spectrum of clinical severity. Reported phenotypes range from severe congenital onset Walker-Warburg syndrome (WWS) with severe structural brain and eye involvement, to relatively mild adult onset limb girdle muscular dystrophy (LGMD). Specific clinical syndromes were originally described in association with mutations in any one of six demonstrated or putative glycosyltransferases. Work performed on patients with mutations in the FKRP gene has identified that the spectrum of phenotypes due to mutations in this gene is much wider than originally assumed. To further define the mutation frequency and phenotypes associated with mutations in the other five genes, we studied a large cohort of patients with evidence of a dystroglycanopathy. Exclusion of mutations in FKRP was a prerequisite for participation in this study. Ninety-two probands were screened for mutations in POMT1, POMT2, POMGnT1, fukutin and LARGE. Homozygous and compound heterozygous mutations were detected in a total of 31 probands (34 individuals from 31 families); 37 different mutations were identified, of which 32 were novel. Mutations in POMT2 were the most prevalent in our cohort with nine cases, followed by POMT1 with eight cases, POMGnT1 with seven cases, fukutin with six cases and LARGE with only a single case. All patients with POMT1 and POMT2 mutations had evidence of either structural or functional central nervous system involvement including four patients with mental retardation and a LGMD phenotype. In contrast mutations in fukutin and POMGnT1 were detected in four patients with LGMD and no evidence of brain involvement. The majority of patients (six out of nine) with mutations in POMT2 had a Muscle-Eye-Brain (MEB)-like condition. In addition we identified a mutation in the gene LARGE in a patient with WWS. Our data expands the clinical phenotypes associated with POMT1, POMT2, POMGnT1, fukutin and LARGE mutations. Mutations in these five glycosyltransferase genes were detected in 34% of patients indicating that, after the exclusion of FKRP, the majority of patients with a dystroglycanopathy harbour mutations in novel genes.
Brain 11/2007; 130(Pt 10):2725-35. · 9.46 Impact Factor
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Caroline Godfrey,
Diana Escolar,
Martin Brockington,
Emma M Clement,
Rachael Mein,
Cecilia Jimenez-Mallebrera,
Silvia Torelli,
Lucy Feng,
Susan C Brown,
Caroline A Sewry,
Mary Rutherford,
Yehuda Shapira,
Stephen Abbs,
Francesco Muntoni
[show abstract]
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ABSTRACT: Defects in glycosylation of alpha-dystroglycan are associated with several forms of muscular dystrophy, often characterized by congenital onset and severe structural brain involvement, collectively known as dystroglycanopathies. Six causative genes have been identified in these disorders including fukutin. Mutations in fukutin cause Fukuyama congenital muscular dystrophy. This is the second most common form of muscular dystrophy in Japan and is invariably associated with mental retardation and structural brain defects. The aim of this study was to determine the genetic defect in two white families with a dystroglycanopathy.
The six genes responsible for dystroglycanopathies were studied in three children with a severe reduction of alpha-dystroglycan in skeletal muscle.
We identified pathogenic fukutin mutations in these two families. Affected children had normal intelligence and brain structure and shared a limb girdle muscular dystrophy (LGMD) phenotype, had marked elevation of serum creatine kinase, and were all ambulant with remarkable steroid responsiveness.
Our data suggest that fukutin mutations occur outside Japan and can be associated with much milder phenotypes than Fukuyama congenital muscular dystrophy. These findings significantly expand the spectrum of phenotypes associated with fukutin mutations to include this novel form of limb girdle muscular dystrophy that we propose to name LGMD2L.
Annals of Neurology 12/2006; 60(5):603-10. · 11.09 Impact Factor
