Dataset Information

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.

SUBMITTER: Bohm J

PROVIDER: S-EPMC3374402 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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

Böhm Johann J Böhm Johann J Biancalana Valérie V Dechene Elizabeth T ET Bitoun Marc M Pierson Christopher R CR Schaefer Elise E Karasoy Hatice H Dempsey Melissa A MA Klein Fabrice F Dondaine Nicolas N Kretz Christine C Haumesser Nicolas N Poirson Claire C Toussaint Anne A Greenleaf Rebecca S RS Barger Melissa A MA Mahoney Lane J LJ Kang Peter B PB Zanoteli Edmar E Vissing John J Witting Nanna N Echaniz-Laguna Andoni A Wallgren-Pettersson Carina C Dowling James J Merlini Luciano L Oldfors Anders A Bomme Ousager Lilian L Melki Judith J Krause Amanda A Jern Christina C Oliveira Acary S B AS Petit Florence F Jacquette Aurélia A Chaussenot Annabelle A Mowat David D Leheup Bruno B Cristofano Michele M Poza Aldea Juan José JJ Michel Fabrice F Furby Alain A Llona Jose E Barcena JE Van Coster Rudy R Bertini Enrico E Urtizberea Jon Andoni JA Drouin-Garraud Valérie V Béroud Christophe C Prudhon Bernard B Bedford Melanie M Mathews Katherine K Erby Lori A H LA Smith Stephen A SA Roggenbuck Jennifer J Crowe Carol A CA Brennan Spitale Allison A Johal Sheila C SC Amato Anthony A AA Demmer Laurie A LA Jonas Jessica J Darras Basil T BT Bird Thomas D TD Laurino Mercy M Welt Selman I SI Trotter Cynthia C Guicheney Pascale P Das Soma S Mandel Jean-Louis JL Beggs Alan H AH Laporte Jocelyn J

Human mutation 20120404 6

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 genot ...[more]

PMID: 22396310

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Project description:BACKGROUND:Autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency (AD EDA-ID) is caused by heterozygous point mutations at or close to serine 32 and serine 36 or N-terminal truncations in I?B? that impair its phosphorylation and degradation and thus activation of the canonical nuclear factor ? light chain enhancer of activated B cells (NF-?B) pathway. The outcome of hematopoietic stem cell transplantation is poor in patients with AD EDA-ID despite achievement of chimerism. Mice heterozygous for the serine 32I mutation in I?B? have impaired noncanonical NF-?B activity and defective lymphorganogenesis. OBJECTIVE:We sought to establish genotype-phenotype correlation in patients with AD EDA-ID. METHODS:A disease severity scoring system was devised. Stability of I?B? mutants was examined in transfected cells. Immunologic, biochemical, and gene expression analyses were performed to evaluate canonical and noncanonical NF-?B signaling in skin-derived fibroblasts. RESULTS:Disease severity was greater in patients with I?B? point mutations than in those with truncation mutations. I?B? point mutants were expressed at significantly higher levels in transfectants compared with truncation mutants. Canonical NF-?B-dependent IL-6 secretion and upregulation of the NF-?B subunit 2/p100 and RELB proto-oncogene, NF-?B subunit (RelB) components of the noncanonical NF-?B pathway were diminished significantly more in patients with point mutations compared with those with truncations. Noncanonical NF-?B-driven generation of the transcriptionally active p100 cleavage product p52 and upregulation of CCL20, intercellular adhesion molecule 1 (ICAM1), and vascular cell adhesion molecule 1 (VCAM1), which are important for lymphorganogenesis, were diminished significantly more in LPS plus ?-lymphotoxin ? receptor-stimulated fibroblasts from patients with point mutations compared with those with truncations. CONCLUSIONS:I?B? point mutants accumulate at higher levels compared with truncation mutants and are associated with more severe disease and greater impairment of canonical and noncanonical NF-?B activity in patients with AD EDA-ID.

Dataset Information

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

Publications

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

Similar Datasets

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