Truncating mutations in C-terminal titin may cause more severe tibial muscular dystrophy (TMD)

Hackman, Peter; Marchand, Sylvie; Sarparanta, J.; Vihola, Anna; Pénisson-Besnier, I.; Eymard, B.; Pardal-Fernández, José Manuel; Hammouda, El Hadi; Richard, Isabelle; Illa, Isabel; Udd, Bjarne

doi:10.1016/j.nmd.2008.07.010

Cited by 92 publications

(101 citation statements)

References 19 publications

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“…[10][11][12] Encompassing 363 exons, TTN includes several regions subject to extensive differential splicing, producing a number of different isoforms in cardiac and skeletal muscles. 10,13,14 TTN mutations have previously been implicated in various cardiac and skeletal muscle diseases including adult-onset tibial muscular dystrophy, [15][16][17] limb-girdle muscular dystrophy 2J, 15,18 hereditary myopathy with early respiratory failure, 19,20 and earlyonset myopathy with fatal cardiomyopathy. 21 Heterozygous truncating mutations in TTN have also been shown to be a common cause of dilated cardiomyopathy, accounting for ;25% of cases in one large series.…”

Section: Indirect Immunofluorescence Analysis Of Muscle Biopsiesmentioning

confidence: 99%

“…Electron microscopy demonstrated severe myofibrillar disorganization in fibers with internal nuclei and varying degrees of Z-disk streaming ( figure 1, L-Q Two mutations identified in our patients, c.100185delA and c.32854G.C, have previously been associated with tibial muscular dystrophy and adult-onset cardiomyopathy, respectively, in the heterozygous state. 16,25 Tibial muscular dystrophy presents in the fifth to sixth decades of life with preferential weakness in the tibialis anterior muscles. 16 The mother of patient 1044-1, heterozygous for c.100185delA mutation, was adopted with no known family history, and had no clinical signs of muscle weakness at the age of 34 years.…”

Section: Indirect Immunofluorescence Analysis Of Muscle Biopsiesmentioning

confidence: 99%

“…16,25 Tibial muscular dystrophy presents in the fifth to sixth decades of life with preferential weakness in the tibialis anterior muscles. 16 The mother of patient 1044-1, heterozygous for c.100185delA mutation, was adopted with no known family history, and had no clinical signs of muscle weakness at the age of 34 years. Extensive cardiac and muscle examination performed on the father of patient 314-1, heterozygous for c.32854G.C mutation, showed no evidence of cardiomyopathy or skeletal myopathy at the age of 46.5 years.…”

Section: Indirect Immunofluorescence Analysis Of Muscle Biopsiesmentioning

confidence: 99%

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Recessive truncating titin gene, TTN , mutations presenting as centronuclear myopathy

et al. 2013

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Objective: To identify causative genes for centronuclear myopathies (CNM), a heterogeneous group of rare inherited muscle disorders that often present in infancy or early life with weakness and hypotonia, using next-generation sequencing of whole exomes and genomes.Methods: Whole-exome or -genome sequencing was performed in a cohort of 29 unrelated patients with clinicopathologic diagnoses of CNM or related myopathy depleted for cases with mutations of MTM1, DNM2, and BIN1. Immunofluorescence analyses on muscle biopsies, splicing assays, and gel electrophoresis of patient muscle proteins were performed to determine the molecular consequences of mutations of interest.Results: Autosomal recessive compound heterozygous truncating mutations of the titin gene, TTN, were identified in 5 individuals. Biochemical analyses demonstrated increased titin degradation and truncated titin proteins in patient muscles, establishing the impact of the mutations.Conclusions: Our study identifies truncating TTN mutations as a cause of congenital myopathy that is reported as CNM. Unlike the classic CNM genes that are all involved in excitation-contraction coupling at the triad, TTN encodes the giant sarcomeric protein titin, which forms a myofibrillar backbone for the components of the contractile machinery. This study expands the phenotypic spectrum associated with TTN mutations and indicates that TTN mutation analysis should be considered in cases of possible CNM without mutations in the classic CNM genes.

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Section: Indirect Immunofluorescence Analysis Of Muscle Biopsiesmentioning

confidence: 99%

Section: Indirect Immunofluorescence Analysis Of Muscle Biopsiesmentioning

confidence: 99%

Section: Indirect Immunofluorescence Analysis Of Muscle Biopsiesmentioning

confidence: 99%

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Recessive truncating titin gene, TTN , mutations presenting as centronuclear myopathy

et al. 2013

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“…Un domaine en émergence Ana Ferreiro 1,2 , J. Andoni Urtizberea 3 Les titinopathies sont des maladies rares, d'origine génétique, qui se transmettent selon un mode autosomique dominant ou autosomique récessif. Elles sont dues à la présence d'une ou plusieurs anomalies (mutations) du gène TTN codant une protéine musculaire de très grande taille, la titine.…”

Section: Pathologies Musculaires Liées à La Titineunclassified

“…En matière de titinopathie, on note quelques particularités ethno-géo-graphiques. En Finlande, par exemple, une mutation fondatrice est à l'origine d'une titinopathie singulière : la dystrophie musculaire tibiale de type Udd (TMD) représente la maladie musculaire la plus fréquente dans cette population, avec une prévalence de 1/5 000 [3]. 500 à 1 000 personnes seraient ainsi concernées.…”

Section: Dossierunclassified

Pathologies musculaires liées à la titine

Ferreiro

Urtizberea

2017

Med Sci (Paris)

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Interpreting Genetic Variants in Titin in Patients With Muscle Disorders

Savarese

Maggi²,

Vihola

et al. 2018

JAMA Neurol

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IMPORTANCE Mutations in the titin gene (TTN) cause a wide spectrum of genetic diseases. The interpretation of the numerous rare variants identified in TTN is a difficult challenge given its large size. OBJECTIVE To identify genetic variants in titin in a cohort of patients with muscle disorders. DESIGN, SETTING, AND PARTICIPANTS In this case series, 9 patients with titinopathy and 4 other patients with possibly disease-causing variants in TTN were identified. Titin mutations were detected through targeted resequencing performed on DNA from 504 patients with muscular dystrophy, congenital myopathy, or other skeletal muscle disorders. Patients were enrolled from 10 clinical centers in April 2012 to December 2013. All of them had not received a diagnosis after undergoing an extensive investigation, including Sanger sequencing of candidate genes. The data analysis was performed between September 2013 and January 2017. Sequencing data were analyzed using an internal custom bioinformatics pipeline. MAIN OUTCOMES AND MEASURES The identification of novel mutations in the TTN gene and novel patients with titinopathy. We performed an evaluation of putative causative variants in the TTN gene, combining genetic, clinical, and imaging data with messenger RNA and/or protein studies. RESULTS Of the 9 novel patients with titinopathy, 5 (55.5%) were men and the mean (SD) age at onset was 25 (15.8) years (range, 0-46 years). Of the 4 other patients (3 men and 1 woman) with possibly disease-causing TTN variants, 2 (50%) had a congenital myopathy and 2 (50%) had a slowly progressive distal myopathy with onset in the second decade. Most of the identified mutations were previously unreported. However, all the variants, even the already described mutations, require careful clinical and molecular evaluation of probands and relatives. Heterozygous truncating variants or unique missense changes are not sufficient to make a diagnosis of titinopathy. CONCLUSIONS AND RELEVANCE The interpretation of TTN variants often requires further analyses, including a comprehensive evaluation of the clinical phenotype (deep phenotyping) as well as messenger RNA and protein studies. We propose a specific workflow for the clinical interpretation of genetic findings in titin.

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Truncating mutations in C-terminal titin may cause more severe tibial muscular dystrophy (TMD)

Cited by 92 publications

References 19 publications

Recessive truncating titin gene, TTN , mutations presenting as centronuclear myopathy

Recessive truncating titin gene, TTN , mutations presenting as centronuclear myopathy

Pathologies musculaires liées à la titine

Interpreting Genetic Variants in Titin in Patients With Muscle Disorders

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