Mobility shift of beta-dystroglycan as a marker of<i>GMPPB</i>gene-related muscular dystrophy

Sárközy, Anna; Torelli, Silvia; Mein, R.; Henderson, Matt; Phadke, Rahul; Feng, Lucy; Sewry, C.; Ala, Pierpaolo; Yau, Michael; Bértoli, Marta; Willis, Tracey; Hammans, Simon; Sframeli, Maria; Norwood, Fiona; Rakowicz, Wojtek; Radunović, Aleksandar; Vaidya, Sujit; Parton, Matt; Walker, Mark S.; Marino, Silvia; Offiah, Curtis; Farrugia, Maria Elena; Mamutse, Godwin; Marini‐Bettolo, Chiara; Wraige, Elizabeth; Beeson, David; Lochmüller, Hanns; Straub, Volker; Bushby, Kate; Barresi, Rita; Muntoni, Francesco

doi:10.1136/jnnp-2017-316956

Cited by 17 publications

(17 citation statements)

References 28 publications

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“…Recently, defective N‐glycosylation of skeletal muscle βDG was reported as a specific marker for GMPPB deficiency, but the N‐glycosylation of βDG in other DPM synthesis defects has remained unassessed . Here, we found the same shift of βDG in all three DPM3‐CDG patients.…”

Section: Discussionsupporting

confidence: 64%

“…However, PNGase F treatment lowered the molecular weight of βDG in skeletal muscle of patients with mutations in DPM3 even further, demonstrating that βDG is partly N‐glycosylated in DPM3‐CDG. Previously, a N‐glycosylation defect of βDG was consistently found in skeletal muscle from patients carrying mutations in GMPPB . The findings presented above suggest the presence of more than one N‐glycan on processed βDG.…”

Section: Resultsmentioning

confidence: 57%

“…Here, we found the same shift of βDG in all three DPM3‐CDG patients. Sarkozy et al did not observe this shift in dystroglycanopathy patients with mutations in POMT1 , POMT2 , POMGNT1 , B3GALNT2 , and FKTN , which encode glycosyltransferases. These glycosyltransferases synthesize the O‐mannosyl glycans on αDG, and are thus not expected to affect N‐glycosylation.…”

Section: Discussionmentioning

confidence: 95%

“…Previously, a N-glycosylation defect of βDG was consistently found in skeletal muscle from patients carrying mutations in GMPPB. 7,33 The findings presented above suggest the presence of more than one N-glycan on processed βDG. Using the dystroglycan preprotein sequence, we used the NetNGlyc tool to predict potential Nglycosylation sites in Asn-Xaa-Ser/Thr sequons.…”

Section: Alpha-dystroglycan and β-Dystroglycan Are Hypoglycosylatedmentioning

confidence: 87%

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Toward understanding tissue‐specific symptoms in dolichol‐phosphate‐mannose synthesis disorders; insight from DPM3‐CDG

Tol

Michelakakis

Georgiadou

et al. 2019

J of Inher Metab Disea

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The congenital disorders of glycosylation (CDG) are inborn errors of metabolism with a great genetic heterogeneity. Most CDG are caused by defects in the N‐glycan biosynthesis, leading to multisystem phenotypes. However, the occurrence of tissue‐restricted clinical symptoms in the various defects in dolichol‐phosphate‐mannose (DPM) synthesis remains unexplained. To deepen our understanding of the tissue‐specific characteristics of defects in the DPM synthesis pathway, we investigated N‐glycosylation and O‐mannosylation in skeletal muscle of three DPM3‐CDG patients presenting with muscle dystrophy and hypo‐N‐glycosylation of serum transferrin in only two of them. In the three patients, O‐mannosylation of alpha‐dystroglycan (αDG) was strongly reduced and western blot analysis of beta‐dystroglycan (βDG) N‐glycosylation revealed a consistent lack of one N‐glycan in skeletal muscle. Recently, defective N‐glycosylation of βDG has been reported in patients with mutations in guanosine‐diphosphate‐mannose pyrophosphorylase B (GMPPB). Thus, we suggest that aberrant O‐glycosylation of αDG and N‐glycosylation of βDG in skeletal muscle is indicative of a defect in the DPM synthesis pathway. Further studies should address to what extent hypo‐N‐glycosylation of βDG or other skeletal muscle proteins contribute to the phenotype of patients with defects in DPM synthesis. Our findings contribute to our understanding of the tissue‐restricted phenotype of DPM3‐CDG and other defects in the DPM synthesis pathway.

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Section: Discussionsupporting

confidence: 64%

Section: Resultsmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 95%

Section: Alpha-dystroglycan and β-Dystroglycan Are Hypoglycosylatedmentioning

confidence: 87%

See 2 more Smart Citations

Toward understanding tissue‐specific symptoms in dolichol‐phosphate‐mannose synthesis disorders; insight from DPM3‐CDG

Tol

Michelakakis

Georgiadou

et al. 2019

J of Inher Metab Disea

View full text Add to dashboard Cite

show abstract

“…The most severely affected patients present in infancy with a congenital muscular dystrophy with brain and eye abnormalities . Less severely affected patients present between childhood and the 4th decade with a spectrum of limb‐girdle muscular dystrophy, CMS, and recurrent rhabdomyolysis . These milder phenotypes are characterized by proximal weakness, which is usually progressive .…”

Section: Hereditary Muscle Diseases With Neuromuscular Transmission Dmentioning

confidence: 99%

Trouble at the junction: When myopathy and myasthenia overlap

2019

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Although myopathies and neuromuscular junction disorders are typically distinct, their coexistence has been reported in several inherited and acquired conditions. Affected individuals have variable clinical phenotypes but typically display both a decrement on repetitive nerve stimulation and myopathic findings on muscle biopsy. Inherited causes include myopathies related to mutations in BIN1, DES, DNM2, GMPPB, MTM1, or PLEC and congenital myasthenic syndromes due to mutations in ALG2, ALG14, COL13A1, DOK7, DPAGT1, or GFPT1. Additionally, a decrement due to muscle fiber inexcitability is observed in certain myotonic disorders. The identification of a defect of neuromuscular transmission in an inherited myopathy may assist in establishing a molecular diagnosis and in selecting patients who would benefit from pharmacological correction of this defect. Acquired cases meanwhile stem from the co‐occurrence of myasthenia gravis or Lambert‐Eaton myasthenic syndrome with an immune‐mediated myopathy, which may be due to paraneoplastic disorders or exposure to immune checkpoint inhibitors.

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Lysosomal degradation of GMPPB is associated with limb‐girdle muscular dystrophy type 2T

Tian

Zhou

Zhan

et al. 2019

Ann Clin Transl Neurol

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Objective GDP‐mannose pyrophosphorylase B (GMPPB) related phenotype spectrum ranges widely from congenital myasthenic syndrome (CMS), limb‐girdle muscular dystrophy type 2T (LGMD 2T) to severe congenital muscle‐eye‐brain syndrome. Our study investigates the clinicopathologic features of a patient with novel GMPPB mutations and explores the pathogenetic mechanism. Methods The patient was a 22‐year‐old woman with chronic proximal limb weakness for 9 years without cognitive deterioration. Weakness became worse after fatigue. Elevated serum creatine kinase and decrements on repetitive nerve stimulation test were recorded. MRI showed fatty infiltration in muscles of lower limbs and shoulder girdle on T1 sequence. Open muscle biopsy and genetic analysis were performed. Results Muscle biopsy showed myogenic changes. Two missense mutations in GMPPB gene (c.803T>C and c.1060G>A) were identified in the patient. Western blotting and immunostaining showed GMPPB and α‐dystroglycan deficiency in the patient's muscle. In vitro, mutant GMPPB forming cytoplasmic aggregates completely colocalized with microtubule‐associated protein 1 light chain 3‐II (LC3‐II), a classical marker of autophagosome. Degradation of GMPPB was accompanied by an upregulation of LC3‐II, which could be restored by lysosomal inhibitor leupeptin. Interpretation We identified two novel GMPPB mutations causing overlap phenotype between LGMD 2T and CMS. We provided the initial evidence that mutant GMPPB colocalizes with autophagosome at subcellular level. GMPPB mutants degraded by autophagy‐lysosome pathway is associated with LGMD 2T. This study shed the light into the enzyme replacement which could become one of the therapeutic targets in the future study.

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Mobility shift of beta-dystroglycan as a marker ofGMPPBgene-related muscular dystrophy

Abstract: Our data demonstrate that a change in β-DG electrophoretic mobility in patients with dystroglycanopathy is a distinctive marker of the molecular defect in

Cited by 17 publications

References 28 publications

Toward understanding tissue‐specific symptoms in dolichol‐phosphate‐mannose synthesis disorders; insight from DPM3‐CDG

Toward understanding tissue‐specific symptoms in dolichol‐phosphate‐mannose synthesis disorders; insight from DPM3‐CDG

Trouble at the junction: When myopathy and myasthenia overlap

Lysosomal degradation of GMPPB is associated with limb‐girdle muscular dystrophy type 2T

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