Mutations in dynamin 2 cause dominant centronuclear myopathy

Abstract

Autosomal dominant centronuclear myopathy is a rare congenital myopathy characterized by delayed motor milestones and muscular weakness. In 11 families affected by centronuclear myopathy, we identified recurrent and de novo missense mutations in the gene dynamin 2 (DNM2, 19p13.2), which encodes a protein involved in endocytosis and membrane trafficking, actin assembly and centrosome cohesion. The transfected mutants showed reduced labeling in the centrosome, suggesting that DNM2 mutations might cause centronuclear myopathy by interfering with centrosome function.

Dynamin 2 homozygous mutation in humans with a lethal congenital syndrome

“…Two autosomal dominant disorders have been associated with heterozygous mutations within the DNM2 gene; autosomal dominant centronuclear myopathy (ADCNM) and dominant intermediate or type 2M Charcot-Marie-Tooth neuropathies (CMT-DIB). [4][5][6] Functional analyses support the pathological impact of the novel p.Phe379Val mutation, and downregulation experiments in zebrafish highlight a pleiotropic role for DNM2 during vertebrate development. These findings identify this congenital syndrome as allelic to dominant ADCNM and CMT-DIB.…”

“…Within the 141 genes mapped in this region, the DNM2 gene was selected as a candidate based on the congenital myopathy component in patient AFB2 and the suggestion of peripheral nerve involvement in AFB3 and AFB4, as distinct DNM2 heterozygous mutations were previously linked to autosomal dominant CMT peripheral neuropathy and to ADCNM. 4,6 Direct sequencing revealed a single point mutation (c.1135 T4G Genbank NM_001005360) in exon 9 at the homozygous state in all affected children (Figure 1b). Parents and unaffected children were all heterozygous for the mutation.…”

Clinical utility gene card for: Centronuclear and myotubular myopathies

“…34 For instance, a triad of morphological abnormalities is usually found in DNM2-related CNM: increased numbers of central and internal nuclei, radiating sarcoplasmic strands with oxidative enzyme reactions (so called 'spokes on a wheel') and type 1 muscle fibre predominance and hypotrophy. 15,35,36 In MTM1-related CNM, an increased number of centralized nuclei and type 1 muscle fibre predominance and hypotrophy are reported and may be accompanied by the presence of necklace fibers, at least in adult cases. 37 To get the best of the morphological study of CNM, one should analyze the muscle biopsies with both histoenzymology and electron microscopy.…”

“…14 DNM2: Thirteen heterozygous missense changes or in-frame deletions or insertions have been reported with hotspots at position 368, 369, 465, 522, 618 and 619. 5,[15][16][17][18][19][20] In the middle domain, the recurrent p.R465W mutation is most common, likely accounting for B25% of families, whereas p.E368K and p.R369W are found in B20% and B10% of families, respectively. The PH domain mutation p.R522H is found in roughly 10% of families, whereas mutations of residues 618 and 619 account for about 15% of families.…”

Mutations de l’amphiphysine 2 (BIN1) dans les myopathies centronucléaires récessives

“…Les CNM sont classiquement répertoriées en trois formes : la forme liée au chromosome X aussi appelée myopathie myotubulaire qui est la plus fré-quente et la plus sévère avec une hypotonie généralisée néonatale, la forme intermé-diaire autosomique récessive apparaissant dans l'enfance, et la forme autosomique dominante la plus légère apparaissant à l'âge adulte avec une hypotonie lentement progressive [1]. Des mutations dans le gène codant pour la myotubularine (MTM1) sont responsables de la forme liée au chromosome X [2], et des mutations dans la dynamine 2 (DNM2) ont été identifiées dans la majorité des cas de CNM autosomiques dominantes [3]. La myotubularine est une phosphatase à phosphoinositides impliquée dans le trafic membranaire et l'endocytose.…”