A Dystroglycan Mutation Associated with Limb-Girdle Muscular Dystrophy

Hara, Yuji; Balcı-Hayta, Burcu; Yoshida‐Moriguchi, Takako; Kanagawa, Motoi; Bernabé, Daniel Beltrán-Valero de; Gündeşli, Hülya; Willer, Tobias; Satz, Jakob S.; Crawford, Robert W.; Burden, Steven J.; Kunz, Stefan; Oldstone, Michael B. A.; Accardi, Alessio; Talim, Beril; Muntoni, Francesco; Topaloǧlu, Haluk; Dinçer, Pervin; Campbell, Kevin P.

doi:10.1056/nejmoa1006939

Cited by 249 publications

(194 citation statements)

References 25 publications

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“…9 Finally, mutations in DAG1 encoding a-dystroglycan were identified in a patient with a form of limb girdle muscular dystrophy who had normal brain imaging and relatively mild muscular involvement but intellectual disabilities. 10 POMT2 mutations have been associated with a wide spectrum of phenotypes, including some patients without structural CNS involvement and a more benign course of cognitive impairment and microcephaly. 2 Other more severe forms include structural brain abnormalities such as seen in a WWS-like phenotype, 11 a muscle-eyebrain phenotype, 6 and cerebellar hypoplasia with or without cerebral atrophy.…”

Section: Discussionmentioning

confidence: 99%

Novel cardiovascular findings in association with a POMT2 mutation: three siblings with α-dystroglycanopathy

Martinez¹,

Craigen

Ummat

et al. 2013

Eur J Hum Genet

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Dystroglycanopathies are a genetically heterogeneous subset of congenital muscular dystrophies that exhibit autosomal recessive inheritance and are characterized by abnormal glycosylation of a-dystroglycan. In particular, POMT2 (protein O-mannosyltransferase-2) mutations have been identified in congenital muscular dystrophy patients with a wide range of clinical involvement, ranging from the severe muscle-eye-brain disease and Walker-Warburg syndrome to limb girdle muscular dystrophy without structural brain or ocular involvement. Cardiovascular disease is thought to be uncommon in congenital muscular dystrophy, with rare reports of cardiac involvement. We describe three brothers aged 21, 19, and 17 years with an apparently homozygous POMT2 mutation who all presented with congenital muscular dystrophy, intellectual disabilities, and distinct cardiac abnormalities. All three brothers were homozygous for a p.Tyr666Cys missense mutation in exon 19 of the POMT2 gene. On screening echocardiograms, all siblings demonstrated significant dilatation of the aortic root and depressed left ventricular systolic function and/or left ventricular wall motion abnormalities. Our report is the first to document an association between POMT2 mutations and aortopathy with concomitant depressed left ventricular systolic function. On the basis of our findings, we suggest patients with POMT2 gene mutations be screened not only for myocardial dysfunction but also for aortopathy. In addition, given the potential for progression of myocardial dysfunction and/or aortic dilatation, longitudinal surveillance imaging is recommended both for patients with disease as well as those that have normal baseline imaging.

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Section: Discussionmentioning

confidence: 99%

Novel cardiovascular findings in association with a POMT2 mutation: three siblings with α-dystroglycanopathy

Martinez¹,

Craigen

Ummat

et al. 2013

Eur J Hum Genet

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“…muscular dystrophy | eccentric contraction | titin | skeletal muscle | dystroglycan M uscular dystrophies are a heterogenous group of genetic disorders characterized by progressive muscle weakness and wasting (1,2). Mutations in genes encoding proteins of the dystrophin-glycoprotein complex (DGC) are associated with various muscular dystrophies (3)(4)(5)(6)(7)(8)(9)(10). The DGC is a multimeric complex comprising both transmembrane proteins [β-dystroglycan (DG), sarcoglycans (α, β, γ, and δ), and sarcospan] and membrane-associated proteins (α-DG, dystrophin, syntrophin, dystrobrevin, and neuronal nitric oxide synthase).…”

mentioning

confidence: 99%

“…The extracellular matrix receptor function of α-DG is impaired when either DAG1 is itself mutated (limb-girdle muscular dystrophy type 2P) (10,16,17) or genes that encode putative or known glycosyltransferases that act on α-DG are mutated (Walker-Warburg syndrome, muscle-eye-brain disease, Fukuyama congenital muscular dystrophy, congenital muscular dystrophy types 1C and 1D, or limb-girdle muscular dystrophy) (12,18,19). Sarcolemmal expression of α-DG, sarcospan, and the sarcoglycan complex is reduced in patients with distinct sarcoglycan mutations (limb-girdle muscular dystrophy type 2C-F) (3)(4)(5)20).…”

mentioning

confidence: 99%

Role of dystroglycan in limiting contraction-induced injury to the sarcomeric cytoskeleton of mature skeletal muscle

Rader

Turk

Willer

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Dystroglycan (DG) is a highly expressed extracellular matrix receptor that is linked to the cytoskeleton in skeletal muscle. DG is critical for the function of skeletal muscle, and muscle with primary defects in the expression and/or function of DG throughout development has many pathological features and a severe muscular dystrophy phenotype. In addition, reduction in DG at the sarcolemma is a common feature in muscle biopsies from patients with various types of muscular dystrophy. However, the consequence of disrupting DG in mature muscle is not known. Here, we investigated muscles of transgenic mice several months after genetic knockdown of DG at maturity. In our study, an increase in susceptibility to contractioninduced injury was the first pathological feature observed after the levels of DG at the sarcolemma were reduced. The contractioninduced injury was not accompanied by increased necrosis, excitation-contraction uncoupling, or fragility of the sarcolemma. Rather, disruption of the sarcomeric cytoskeleton was evident as reduced passive tension and decreased titin immunostaining. These results reveal a role for DG in maintaining the stability of the sarcomeric cytoskeleton during contraction and provide mechanistic insight into the cause of the reduction in strength that occurs in muscular dystrophy after lengthening contractions. muscular dystrophy | eccentric contraction | titin | skeletal muscle | dystroglycan

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“…Selon le gène impliqué, les −DGpathies sont réparties en deux caté-gories, primaires et secondaires. Des mutations du gène DAG1 qui code la partie protéique du dystroglycan (sous-unités  et ) définissent l'-DGpathie primaire ; seulement quelques patients sont rapportés à ce jour [10,11]. Les -DGpathies secondaires sont donc très majoritaires.…”

Section: Gènes Associés Aux Alpha-dystroglycanopathiesunclassified