POMT2 mutations cause  -dystroglycan hypoglycosylation and Walker-Warburg syndrome

Reeuwijk, Jeroen van; Janssen, Mirian C. H.; Elzen, C. van der; Bernabe, D. Beltran Valero de; Sabatelli, Patrizia; Merlini, Luciano; Boon, M. E.; Scheffer, Hans; Brockington, M; Muntoni, Francesco; Huynen, Martijn A.; Verrips, Aad; Walsh, Christopher A.; Barth, P. G.; Brunner, Han G.; Bokhoven, Hans van

doi:10.1136/jmg.2005.031963

Cited by 384 publications

(225 citation statements)

References 33 publications

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“…12 It is the main CNS feature of CMDs with O-glycosylation defects of ␣-dystroglycan, even though it is difficult to differentiate the genetic causes on the basis of brain MRI because of overlapping phenotypes. [19][20][21][22][23] Cerebral, cerebellar, and brainstem abnormalities have been well documented in the major phenotypes: FCMD, WWS, and MEB. WWS displays severe cerebral cortical dysplasia, hypomyelination, dysplastic tectum, pontomedullary kink, severe hypoplasia of the vermis, and dysplastic cerebellar hemispheres.…”

Section: Resultsmentioning

confidence: 99%

Midbrain–hindbrain involvement in lissencephalies

Jissendi-Tchofo¹,

Kara²,

Barkovich³

2009

Neurology

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Objectives:To determine the involvement of the midbrain and hindbrain (MHB) in the groups of classic (cLIS), variant (vLIS), and cobblestone complex (CBSC) lissencephalies and to determine whether a correlation exists between the cerebral malformation and the MHB abnormalities.Methods: MRI scans of 111 patients (aged 1 day to 32 years; mean 5 years 4 months) were retrospectively reviewed. After reviewing the brain involvement on MRI, the cases were reclassified according to known mutation (LIS1, DCX, ARX, VLDLR, RELN, MEB, WWS) or mutation phenotype (LIS1-P, DCX-P, RELN-P, ARX-P, VLDLR-P) determined on the basis of characteristic MRI features. Abnormalities in the MHB were then recorded. For each structure, a score was assigned, ranging from 0 (normal) to 3 (severely abnormal). The differences between defined groups and the correlation between the extent of brain agyria/pachygyria and MHB involvement were assessed using Kruskal-Wallis and 2 McNemar tests. Results:There was a significant difference in MHB appearance among the three major groups of cLIS, vLIS, and CBSC. The overall score showed a severity gradient of MHB involvement: cLIS (0 or 1), vLIS (7), and CBSC (11 or 12). The extent of cerebral lissencephaly was significantly correlated with the severity of MHB abnormalities (p ϭ 0.0029). Conclusion: GLOSSARYA ϭ autosomal; ACC ϭ agenesis of corpus callosum; AD ϭ autosomal dominant; AP ϭ anteroposterior; AR ϭ autosomal recessive; CBL ϭ cerebellar; CBSC ϭ cobblestone complex; cLIS ϭ classic lissencephaly; CMD ϭ congenital muscular dystrophy; CSZ ϭ cell-sparse zone; DV ϭ dorsal-ventral; FCMD ϭ Fukuyama congenital muscular dystrophy; IVH ϭ inferior vermis hypoplasia; LV ϭ lateral ventricle; m ϭ medulla; M ϭ midbrain; MDS ϭ Miller-Dieker syndrome; MEB ϭ muscle-eyebrain; MHB ϭ midbrain and hindbrain; MR ϭ magnetic resonance; ND ϭ not determined; P ϭ pons; RC ϭ rostrocaudal; SCBH ϭ subcortical band heterotopia; SELH ϭ subependymal linear heterotopia; V ϭ vermis; vLIS ϭ variant lissencephaly; WI ϭ weighted image; WWS ϭ Walker-Warburg syndrome; XLD ϭ X-linked dominant; XLR ϭ X-linked recessive.The term lissencephaly (smooth outer brain surface) refers to a paucity of gyral and sulcal development. 1 It encompasses a spectrum of gyral malformations ranging from complete agyria to regional pachygyria and includes subcortical band heterotopia. Lissencephaly has been traditionally classified in two distinct groups: classic (cLIS, formerly called lissencephaly type 1) and cobblestone complex (CBSC, formerly called lissencephaly type 2) based on both brain imaging and pathology. To date, five genes have been identified as causing or contributing to human cLIS: LIS1, 14-3-3 in Miller-Dieker syndrome (MDS), DCX, RELN, and ARX. [1][2][3][4][5][6] A new classification has recently been proposed defining four groups of cLIS differing from each other by genetics and neuropathologic features of the cerebral cortex, cerebellum, and brainstem. 3 1)

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Section: Resultsmentioning

confidence: 99%

Midbrain–hindbrain involvement in lissencephalies

Jissendi-Tchofo¹,

Kara²,

Barkovich³

2009

Neurology

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“…act as glycosyltransferases. The recognition of the involvement of other two glycosyltransferases, PoMT1 and PoMT2, in the pathogenesis of CMDs came soon after [155][156] . During the last seven years, many have discussed and elucidated the pathogenesis of the defective glycosylation of alpha-DG, and the particular cortical involvement that is observed in many of them 5,711,13,15,17,18,30,33,34,[36][37][38][39][40][41][42][43][44][45][46][47][157][158][159][160][161] .…”

Section: Disorders Of Glycosylation Of Alphadg (Alpha-dystroglycanopamentioning

confidence: 99%

“…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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“…To unravel the genetic basis of WWS, a genome-wide linkage analysis and a candidate-gene approach were performed, which identified mutations in the gene encoding O-mannosyltransferase 1 (POMT1) in 6 of 30 unrelated WWS cases (Beltran-Valero de Bernabe et al 2002). Recently, mutations of the POMT2, a homologue of POMT1 with 33% of identity, in WWS patients were also reported (van Reeuwijk et al 2005). POMT1 is homologous to members of the family of protein O-mannosyltransferases (PMT) in yeast.…”

Section: Dystroglycan and Dystroglycanopathymentioning

confidence: 99%

The genetic and molecular basis of muscular dystrophy: roles of cell–matrix linkage in the pathogenesis

2006

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Muscular dystrophies are a heterogeneous group of genetic disorders. In addition to genetic information, a combination of various approaches such as the use of genetic animal models, muscle cell biology, and biochemistry has contributed to improving the understanding of the molecular basis of muscular dystrophy's etiology. Several lines of evidence confirm that the structural linkage between the muscle extracellular matrix and the cytoskeleton is crucial to prevent the progression of muscular dystrophy. The dystrophin-glycoprotein complex links the extracellular matrix to the cytoskeleton, and mutations in the component of this complex cause Duchenne-type or limb-girdle-type muscular dystrophy. Mutations in laminin or collagen VI, muscle matrix proteins, are known to cause a congenital type of muscular dystrophy. Moreover, it is not only the primary genetic defects in the structural or matrix proteins, but also the primary mutations of enzymes involved in the protein glycosylation pathway that are now recognized to disrupt the matrix-cell interaction in a certain group of muscular dystrophies. This group of diseases is caused by the secondary functional defects of dystroglycan, a transmembrane matrix receptor. This review considers recent advances in understanding the molecular pathogenesis of muscular dystrophies that can be caused by the disruption of the cell-matrix linkage.

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POMT2 mutations cause -dystroglycan hypoglycosylation and Walker-Warburg syndrome

Cited by 384 publications

References 33 publications

Midbrain–hindbrain involvement in lissencephalies

Midbrain–hindbrain involvement in lissencephalies

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

The genetic and molecular basis of muscular dystrophy: roles of cell–matrix linkage in the pathogenesis

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