Mutation spectrum in the large GTPase dynamin 2, and genotype-phenotype correlation in autosomal dominant centronuclear myopathy

Abstract

Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei. Autosomal dominant CNM is due to mutations in the large GTPase dynamin 2 (DNM2), a mechanochemical enzyme regulating cytoskeleton and membrane trafficking in cells. To date, 40 families with CNM-related DNM2 mutations have been described, and here we report 60 additional families encompassing a broad genotypic and phenotypic spectrum. In total, 18 different mutations are reported in 100 families and our cohort harbors nine known and four new mutations, including the first splice-site mutation. Genotype–phenotype correlation hypotheses are drawn from the published and new data, and allow an efficient screening strategy for molecular diagnosis. In addition to CNM, dissimilar DNM2 mutations are associated with Charcot–Marie–Tooth (CMT) peripheral neuropathy (CMTD1B and CMT2M), suggesting a tissue-specific impact of the mutations. In this study, we discuss the possible clinical overlap of CNM and CMT, and the biological significance of the respective mutations based on the known functions of dynamin 2 and its protein structure. Defects in membrane trafficking due to DNM2 mutations potentially represent a common pathological mechanism in CNM and CMT.

Dynamin 2 homozygous mutation in humans with a lethal congenital syndrome

“…To date, only heterozygous DNM2 mutations that cause relatively mild pathologies and display tissue specificity have been identified. 5,6 The p.Phe379Val change is very likely to be the disease-causing mutation as DNM2 is located in the best linked region, the mutation segregates with the disease, biochemical and in vitro tests demonstrate an impact of this change on different aspects of DNM2 function, patient fibroblasts depict an alteration in DNM2-dependent transferrin endocytosis and an adult heterozygous carrier shows signs of CNM. DNM2 deletion in mice causes embryonic lethality (8-12 days post coitum), suggesting that DNM2 is essential for embryonic development.…”

“…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.…”

Triadopathies: An Emerging Class of Skeletal Muscle Diseases

“…Some individuals with RYR1-related CNM present with severe symptoms that phenocopy those seen with MTM1 mutations. The next most common cause of CNM is mutations in DNM2, which present as either de novo or dominant mutations [45,46]. There is a mild adult onset form of DNM2-related CNM, usually caused by mutations within the middle domain of DNM2.…”

Clinical utility gene card for: Centronuclear and myotubular myopathies

“…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.…”