Characterization of MTM1 mutations in 31 Japanese families with myotubular myopathy, including a patient carrying 240kb deletion in Xq28 without male hypogenitalism

Tsai, T L; Horinouchi, Hideo; Noguchi, S.; Minami, Narihiro; Murayama, Kumiko; Hayashi, Yukiko; Nonaka, Ikuya; Nishino, Ichizo

doi:10.1016/j.nmd.2004.12.005

Cited by 48 publications

(36 citation statements)

References 19 publications

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“…Tsai et al also suggested that exon 3, which encodes 80% of the protein, is required for normal CXorf6 function (18). These authors reported a case of chimeric CXorf6-MTMR1 fusion transcript including exon 3 in a child without genital malformation.…”

Section: Discussionmentioning

confidence: 97%

Mutations of CXorf6 are associated with a range of severities of hypospadias

Kalfa

Liu

Klein

et al. 2008

European Journal of Endocrinology

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Objective: Mutations in chromosome X open reading frame 6 (CXorf6), a recently described candidate gene involved in the development of male genitalia, have been found in patients with complex 46,XYdisorders of sexual development (46,XY DSD) including micropenis, bifid scrotum, and penoscrotal hypospadias. The objective of this work was to identify genomic variants of CXorf6 in patients with isolated hypospadias, severe or non-severe. Design and methods: Forty-one patients with glandular to perineal hypospadias and thirty controls were studied. Direct sequencing for coding exons 3-6 of CXorf6 and their flanking splice sites was performed on DNA extracted from foreskin collected from surgery. Secondary and tertiary structures of the protein were predicted using NNpredict and Protein Homology/analogY Recognition Engine engines. Results: Four mutations (9.7% of cases) were identified. One missense mutation (1295TOC, V432A) and two deletions (325delG, predicted to cause a stop codon L121X) occurred in patients with penoscrotal and proximal hypospadias. One patient with subcoronal hypospadias had CAG-repeat amplification in the second polyglutamine domain of CXorf6. Secondary structure prediction indicated that this insertion occurred in a helix element of the protein. The tertiary structure prediction showed an alteration of the shape of the protein and crowding between domains. Conclusion: CXorf6 mutations are associated with isolated hypospadias of varying severity. However, the pathophysiology of these mutations and the function of the CXorf6 gene product remain to be investigated. European Journal of Endocrinology 159 453-458

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Section: Discussionmentioning

confidence: 97%

Mutations of CXorf6 are associated with a range of severities of hypospadias

Kalfa

Liu

Klein

et al. 2008

European Journal of Endocrinology

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“…10,35 The largest proportion (93.3%) of pathogenic sequence variants described to date in MTM1 is that comprising small mutations. Since the last published MTM1 mutation update, 23 there has been a disproportional increase of missense and splicing mutations reported in MTM1.…”

Section: Database Content Analysismentioning

confidence: 99%

Expanding the MTM1 mutational spectrum: novel variants including the first multi-exonic duplication and development of a locus-specific database

Oliveira

Kreß

et al. 2012

Eur J Hum Genet

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Myotubular myopathy (MIM#310400), the X-linked form of Centronuclear myopathy (CNM) is mainly characterized by neonatal hypotonia and inability to maintain unassisted respiration. The MTM1 gene, responsible for this disease, encodes myotubularin -a lipidic phosphatase involved in vesicle trafficking regulation and maturation. Recently, it was shown that myotubularin interacts with desmin, being a major regulator of intermediate filaments. We report the development of a locus-specific database for MTM1 using the Leiden Open Variation database software (http://www.lovd.nl/MTM1), with data collated for 474 mutations identified in 472 patients (by June 2012). Among the entries are a total of 25 new mutations, including a large deletion encompassing introns 2-15. During database implementation it was noticed that no large duplications had been reported. We tested a group of eight uncharacterized CNM patients for this specific type of mutation, by multiple ligationdependent probe amplification (MLPA) analysis. A large duplication spanning exons 1-5 was identified in a boy with a mild phenotype, with results pointing toward possible somatic mosaicism. Further characterization revealed that this duplication causes an in-frame deletion at the mRNA level (r.343_444del). Results obtained with a next generation sequencing approach suggested that the duplication extends into the neighboring MAMLD1 gene and subsequent cDNA analysis detected the presence of a MTM1/MAMLD1 fusion transcript. A complex rearrangement involving the duplication of exon 10 has since been reported, with detection also enabled by MLPA analysis. It is thus conceivable that large duplications in MTM1 may account for a number of CNM cases that have remained genetically unresolved.

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“…To date, more than 200 different mutations in MTM1 have been reported in about 450 families, most of which lead to a strong reduction of MTM1 protein (6)(7)(8)(9). Mtm1-knockout mice or mice with knockin of a patient mutation both recapitulate the CNM phenotype with classical histological features including abnormal organelle positioning, mislocalization of nuclei, and muscle atrophy, associated with a corresponding reduction in muscle strength (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Reducing dynamin 2 expression rescues X-linked centronuclear myopathy

Cowling¹,

Chevremont²,

Prokić³

et al. 2014

J. Clin. Invest.

122

147

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Centronuclear myopathies (CNM) are congenital disorders associated with muscle weakness and abnormally located nuclei in skeletal muscle. An autosomal dominant form of CNM results from mutations in the gene encoding dynamin 2 (DNM2), and loss-of-function mutations in the gene encoding myotubularin (MTM1) result in X-linked CNM (XLCNM, also called myotubular myopathy), which promotes severe neonatal hypotonia and early death. Currently, no effective treatments exist for XLCNM. Here, we found increased DNM2 levels in XLCNM patients and a mouse model of XLCNM (Mtm1 -/y ). Generation of Mtm1 -/y mice that were heterozygous for Dnm2 revealed that reduction of DNM2 in XLCNM mice restored life span, whole-body strength, and diaphragm function and increased muscle strength. Additionally, classic CNM-associated histological features, including fiber atrophy and nuclei mispositioning, were absent or reduced. Ultrastructural analysis revealed improvement of sarcomere organization and triad structures. Skeletal muscle-specific decrease of Dnm2 during embryogenesis or in young mice after disease onset revealed that the rescue associated with downregulation of Dnm2 is cell autonomous and is able to stop and potentially revert XLCNM progression. These data indicate that MTM1 and DNM2 regulate muscle organization and force through a common pathway. Furthermore, despite DNM2 being a key mechanoenzyme, its reduction is beneficial for XLCNM and represents a potential therapeutic approach for patients.

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Characterization of MTM1 mutations in 31 Japanese families with myotubular myopathy, including a patient carrying 240kb deletion in Xq28 without male hypogenitalism

Cited by 48 publications

References 19 publications

Mutations of CXorf6 are associated with a range of severities of hypospadias

Mutations of CXorf6 are associated with a range of severities of hypospadias

Expanding the MTM1 mutational spectrum: novel variants including the first multi-exonic duplication and development of a locus-specific database

Reducing dynamin 2 expression rescues X-linked centronuclear myopathy

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