A novel dynamin-2 gene mutation associated with a late-onset centronuclear myopathy with necklace fibres

Casar‐Borota, Olivera; Jacobsson, Johan; Libelius, Rolf; Oldfors, Carola Hedberg; Malfatti, Edoardo; Romero, Norma B.; Oldfors, Anders

doi:10.1016/j.nmd.2015.01.001

Cited by 14 publications

(10 citation statements)

References 19 publications

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“…We also describe unusual muscle pathology associated with mutations in SCN4A. The muscle biopsy for Sibling 2 has features reminiscent of necklace fibres, previously described only in centronuclear myopathies [8][9][10][11]. However, the muscle pathology we describe differs from the classic necklace fibres reported initially by Bevilacqua et.al.…”

Section: Discussionsupporting

confidence: 45%

Congenital myopathy with “corona” fibres, selective muscle atrophy, and craniosynostosis associated with novel recessive mutations in SCN4A

Gonorazky

Marshall

Almurshed

et al. 2017

Neuromuscular Disorders

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We describe two brothers with lower facial weakness, highly arched palate, scaphocephaly due to synostosis of the sagittal and metopic sutures, axial hypotonia, proximal muscle weakness, and mild scoliosis. The muscle MRI of the younger sibling revealed a selective pattern of atrophy of the gluteus maximus, adductor magnus and soleus muscles. Muscle biopsy of the younger sibling revealed myofibres with internalized nuclei, myofibrillar disarray, and "corona" fibres. Both affected siblings were found to be compound heterozygous for c.3425G>A (p.Arg1142Gln) and c.1123T>C (p.Cys375Arg) mutations in SCN4A on exome sequencing, and the parents were confirmed carriers of one of the mutations. Electrophysiological characterization of the mutations revealed the Cys375Arg confers full and Arg1142Gln mild partial loss-of-function.Loss of function of the Nav1.4 channel leads to a decrement of the action potential and subsequent reduction of muscle contraction. The unusual muscle biopsy features suggest a more complex pathomechanism, and broaden the phenotype associated with SCN4A mutations. Gonorazky et al. 3

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Section: Discussionsupporting

confidence: 45%

Congenital myopathy with “corona” fibres, selective muscle atrophy, and craniosynostosis associated with novel recessive mutations in SCN4A

Gonorazky

Marshall

Almurshed

et al. 2017

Neuromuscular Disorders

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“…Consistently, our patients with reported variants were compatible with those features (Figure 3f). In contrast, the patients with novel variants were remarkably late‐onset (Figure 3f) consistent with a few previous reports about late‐onset DNM2 ‐CNM patients (Casar‐Borota et al, 2015; Fattori et al, 2015).…”

Section: Resultssupporting

confidence: 90%

“…Diverse clinical manifestations among CNM patients are mainly attributed to the functions of these different responsible genes and the individual mutations. In DNM2 , 26 pathogenic variants have been reported to date as being responsible for an autosomal dominant form of CNM with relatively mild and slowly progressive symptoms (Biancalana et al, 2018; Bohm et al, 2012; Casar‐Borota et al, 2015; Hohendahl et al, 2016). DNM2 encodes the ubiquitous isoform of dynamin, dynamin 2, a GTPase essential for membrane fission in endocytosis (Antonny et al, 2016; Ferguson & De Camilli, 2012).…”

Section: Introductionmentioning

confidence: 99%

Imaging‐based evaluation of pathogenicity by novel DNM2 variants associated with centronuclear myopathy

et al. 2021

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A centronuclear myopathy (CNM) is a group of inherited congenital diseases showing clinically progressive muscle weakness associated with the presence of centralized myonuclei, diagnosed by genetic testing and muscle biopsy. The gene encoding dynamin 2, DNM2, has been identified as a causative gene for an autosomal dominant form of CNM. However, the information of a DNM2 variant alone is not always sufficient to gain a definitive diagnosis as the pathogenicity of many gene variants is currently unknown. In this study, we identified five novel DNM2 variants in our cohort. To establish the pathogenicity of these variants without using clinicopathological information, we used a simple in cellulo imaging‐based assay for T‐tubule‐like structures to provide quantitative data that enable objective determination of pathogenicity by novel DNM2 variants. With this assay, we demonstrated that the phenotypes induced by mutant dynamin 2 in cellulo are well correlated with biochemical gain‐of‐function features of mutant dynamin 2 as well as the clinicopathological phenotypes of each patient. Our approach of combining an in cellulo assay with clinical information of the patients also explains the course of a disease progression by the pathogenesis of each variant in DNM2‐associated CNM.

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“…Although the EMG suggested a feature of axonal sensory-motor neuropathy, the appearance of necklace fibres seen in muscle biopsy is an intriguing feature observed in our index patient, which was not observed in the previous SBF1 -related cases. Necklace fibres with nuclear internalisation have been reported as a histological hallmark of X-linked myotubular myopathy related to mutations in the phosphoinositide phosphatase myotubularin 1 ( MTM1 ) gene and also a late-onset dynamin-2 ( DNM2 ) gene-related centronuclear myopathy [ 11 , 12 ]. These fibres were usually described to be small and obliquely oriented with an increased density of mitochondria and sarcoplasmic reticulum profiles, and internal nuclei usually aligned like the necklace [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

A novel frameshift deletion in autosomal recessive SBF1-related syndromic neuropathy with necklace fibres

et al. 2020

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Objective To identify the genetic cause of complex neuropathy in two siblings from a consanguineous family. Methods The patients were recruited from our clinic. Muscle biopsy and whole-exome sequencing (WES) were performed. Fibroblasts cell lines from the index patient, unaffected parents, and three normal controls were used for cDNA analysis and western blot. Results The index patient was a 29-year-old male with clinical phenotype of syndactyly, pes cavus, swallowing difficulties, vision problem, imbalance, and muscle weakness. The sibling had similar, but milder symptoms. Nerve conduction studies and electromyography of both patients suggested sensory-motor axonal neuropathy. Muscle biopsy showed a feature of necklace fibres. WES identified a novel homozygous frameshift deletion (c.5477-5478del; p.1826-1826del) in exon 40 of the SBF1 gene in the two siblings, while both parents and the unaffected sibling were heterozygous carriers. Functional analysis showed a markedly reduced level of MTMR5 protein encoded by SBF1 in the index case. The levels of MTMR5 protein in unaffected parents were similar to those found in controls. Conclusion A novel homozygous frameshift deletion in SBF1 was identified in this family. Sensory-motor axonal neuropathy and necklace fibres in biopsy were the major features expanding the phenotypic spectrum of SBF1-related recessive syndromic neuropathy.

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A novel dynamin-2 gene mutation associated with a late-onset centronuclear myopathy with necklace fibres

Cited by 14 publications

References 19 publications

Congenital myopathy with “corona” fibres, selective muscle atrophy, and craniosynostosis associated with novel recessive mutations in SCN4A

Congenital myopathy with “corona” fibres, selective muscle atrophy, and craniosynostosis associated with novel recessive mutations in SCN4A

Imaging‐based evaluation of pathogenicity by novel DNM2 variants associated with centronuclear myopathy

A novel frameshift deletion in autosomal recessive SBF1-related syndromic neuropathy with necklace fibres

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