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

Balcı, Burcu; Uyanık, Gökhan; Dinçer, Pervin; Groß, Claudia; Willer, Tobias; Talim, Beril; Haliloğlu, Göknur; Kale, Gülsev; Hehr, Ute; Winkler, Jürgen; Topaloǧlu, Haluk

doi:10.1016/j.nmd.2005.01.013

Cited by 158 publications

(85 citation statements)

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“…33 Patients 2 and 3, conversely, differ from the classical LGMD2K, which usually includes overt mental retardation. 7,8 It has been hypothesized that mutations, which completely disrupt mannosyltransferase activity, are associated with more severe phenotypes (WWS), while those allowing residual enzyme activity are linked to milder ones (CMD-MR/LGMD2K). 4,7 Recent findings suggest that this correlation is weaker with regard to putative glycosyltransferase genes, such as FKTN or FKRP, but stronger for genes with a known enzyme product, such as POMT1.…”

Section: Discussionmentioning

confidence: 99%

“…4 POMT1 mutations result in a reduction in a-DG glycosylation in skeletal muscles [5][6][7] and the clinical spectrum of the phenotype ranges from severe Walker-Warburg syndrome (WWS, OMIM 236670) 5 to milder forms of congenital muscular dystrophy (CMD) with microcephaly and mental retardation without eye abnormalities (CMD-MR, OMIM 613155), 6 and to limb-girdle muscular dystrophy (LGMD) with normal brain structure and mental retardation (LGMD2K, OMIM 609308). 7,8 Five other genes -POMT2, protein o-mannose b-1, 2-N-acetylglucosaminyltransferase (POMGnT1, OMIM *606822), fukutin (FKTN, OMIM *607440), FKTN-related protein (FKRP, OMIM *606596) and like-glycosyltransferase (LARGE, OMIM *608840) -are involved in a-DG glycosylation and their mutations lead to heterogeneous phenotypes characterized by combinations of muscular, cerebral and ophthalmic involvement. 9 Cardiac involvement has until now been reported only in patients with FKRP 10-13 and FKTN 14 gene mutations.…”

Section: Introductionmentioning

confidence: 99%

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Cardiomyopathy in patients with POMT1-related congenital and limb-girdle muscular dystrophy

et al. 2012

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Protein-o-mannosyl transferase 1 (POMT1) is a glycosyltransferase involved in a-dystroglycan (a-DG) glycosylation. Clinical phenotype in POMT1-mutated patients ranges from congenital muscular dystrophy (CMD) with structural brain abnormalities, to limb-girdle muscular dystrophy (LGMD) with microcephaly and mental retardation, to mild LGMD. No cardiac involvement has until now been reported in POMT1-mutated patients. We report three patients who harbored compound heterozygous POMT1 mutations and showed left ventricular (LV) dilation and/or decrease in myocardial contractile force: two had a LGMD phenotype with a normal or close-to-normal cognitive profile and one had CMD with mental retardation and normal brain MRI. Reduced or absent a-DG immunolabeling in muscle biopsies were identified in all three patients. Bioinformatic tools were used to study the potential effect of POMT1-detected mutations. All the detected POMT1 mutations were predicted in silico to interfere with protein folding and/or glycosyltransferase function. The report on the patients described here has widened the clinical spectrum associated with POMT1 mutations to include cardiomyopathy. The functional impact of known and novel POMT1 mutations was predicted with a bioinformatics approach, and results were compared with previous in vitro studies of protein-o-mannosylase function.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cardiomyopathy in patients with POMT1-related congenital and limb-girdle muscular dystrophy

et al. 2012

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“…2 A recent report, however, identified a POMT1 mutation (A200P) as causing a far milder limb-girdle muscular dystrophy with mental retardation (LGMD2K). 26 Similarly, recent findings by Toda and colleagues have expanded the clinical spectrum of POMGnT1 mutations to include FCMD-like and WWS-like phenotypes in addition to MEB. 27 Perhaps the most intriguing development of the past year has been the finding of Topaloglu and colleagues of a patient with a defect in the POMGnT1 gene (IVS17-2A→G), in whom severe autistic features were the dominant presenting sign.…”

Section: The Dystroglycanopathies: Clinical and Genetic Findingsmentioning

confidence: 94%

Mechanisms of Disease: congenital muscular dystrophies—glycosylation takes center stage

Martin

2006

Nat Rev Neurol

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SUMMARYRecent studies have defined a group of muscular dystrophies, now termed the dystroglycanopathies, as novel disorders of glycosylation. These conditions include Walker-Warburg syndrome, muscleeye-brain disease, Fukuyama-type congenital muscular dystrophy, congenital muscular dystrophy types 1C and 1D, and limb-girdle muscular dystrophy type 2I. Although clinical findings can be highly variable, dystroglycanopathies are all characterized by cortical malformations and ocular defects at the more severe end of the clinical spectrum, in addition to muscular dystrophy. All of these disorders are defined by the underglycosylation of α-dystroglycan. Defective glycosylation of dystroglycan severs the link between this important cell adhesion molecule and the extracellular matrix, thereby contributing to cellular pathology. Recent experiments indicate that glycosylation might not only define forms of muscular dystrophy but also provide an avenue to the development of therapies for these disorders.

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“…however, out of these classical phenotypes, different types and degrees of cortical and posterior fossa malformations have been described 156,[169][170][171][172][173][174] , with or without eye involvement; mental retardation, and calf as well as thigh enlargement has also been related 170,171 . yanagisawa et col 172 hypothesized that patients with PoMT1 and PoMT2 mutations could share the same phenotype because, according to Manya et al 21 , both glycosyltransferases form a heterodimeric complex that is responsible for the catalysis of the first step in O-mannosyl glycan synthesis.…”

Section: Disorders Of Glycosylation Of Alphadg (Alpha-dystroglycanopamentioning

confidence: 99%

Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives

Reed

2009

Arq. Neuro-Psiquiatr.

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-The congenital muscular dystrophies (CMDs) are a group of genetically and clinically heterogeneous hereditary myopathies with preferentially autosomal recessive inheritance, that are characterized by congenital hypotonia, delayed motor development and early onset of progressive muscle weakness associated with dystrophic pattern on muscle biopsy. The clinical course is broadly variable and can comprise the involvement of the brain and eyes. From 1994, a great development in the knowledge of the molecular basis has occurred and the classification of CMDs has to be continuously up dated. In the last number of this journal, we presented the main clinical and diagnostic data concerning the different subtypes of CMD. In this second part of the review, we analyse the main reports from the literature concerning the pathogenesis and the therapeutic perspectives of the most common subtypes of CMD: MDC1A with merosin deficiency, collagen VI related CMDs (Ullrich and Bethlem), CMDs with abnormal glycosylation of alpha-dystroglycan (Fukuyama CMD, Muscleeye-brain disease, Walker Warburg syndrome, MDC1C, MDC1D), and rigid spine syndrome, another much rare subtype of CMDs not related with the dystrophin/glycoproteins/extracellular matrix complex.Key WorDs: congenital muscular dystrophy, MDC1A, collagen VI related disorders, glycosylation of alphadystroglycan, Fukuyama DMC, muscle-eye-brain (MeB) disease, Walker-Warburg syndrome, rigid spine syndrome. distrofia muscular congênita. parte ii: revisão da patogênese e perspectivas terapêuticas resumo -As distrofias musculares congênitas (DMCs) são miopatias hereditárias geralmente, porém não exclusivamente, de herança autossômica recessiva, que apresentam grande heterogeneidade genética e clínica. são caracterizadas por hipotonia muscular congênita, atraso do desenvolvimento motor e fraqueza muscular de início precoce associada a padrão distrófico na biópsia muscular. o quadro clínico, de gravidade variável, pode também incluir anormalidades oculares e do sistema nervoso central. A partir de 1994, os conhecimentos sobre genética e biologia molecular das DMCs progrediram rapidamente, sendo a classificação continuamente atualizada. os aspectos clínicos e diagnósticos dos principais subtipos de DMC foram apresentados no número anterior deste periódico, como primeira parte desta revisão. Nesta segunda parte apresentaremos os principais mecanismos patogênicos e as perspectivas terapêuticas dos subtipos mais comuns de DMC: DMC tipo 1A com deficiência de merosina, DMCs relacionadas com alterações do colágeno VI (Ullrich e Bethlem), e DMCs com anormalidades de glicosilação da alfa-distroglicana (DMC Fukuyama, DMC "Muscle-eye-brain" ou MeB, síndrome de Walker Warburg, DMC tipo 1C, DMC tipo 1D). A DMC com espinha rígida, mais rara e não relacionada com alterações do complexo distrofina-glicoproteínas associadas-matriz extracelular também será abordada quanto aos mesmos aspectos patogênicos e terapêuticos.PAlAVrAs-ChAVes: distrofia muscular congênita, merosina, colágeno VI, glicosila...

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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

Cited by 158 publications

References 20 publications

Cardiomyopathy in patients with POMT1-related congenital and limb-girdle muscular dystrophy

Cardiomyopathy in patients with POMT1-related congenital and limb-girdle muscular dystrophy

Mechanisms of Disease: congenital muscular dystrophies—glycosylation takes center stage

Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives

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