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

Ozge Ceyhan-Birsoy, Pankaj B. Agrawal, Carlos Hidalgo, Klaus Schmitz-Abe, Elizabeth T. Dechene, Lindsay C. Swanson, Rachel Soemedi, Nasim Vasli, Susan T. Iannaccone, Perry B. Shieh, Natasha Shur, Jane M. Dennison, Michael W. Lawlor, Jocelyn Laporte, Kyriacos Markianos, William G. Fairbrother, Henk Granzier, Alan H. Beggs

Research output: Contribution to journalArticle

105 Citations (Scopus)

Abstract

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 TTNmutations as a cause of congenitalmyopathy that is reported as CNM.Unlike the classic CNMgenes 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 contractilemachinery. This study expands the phenotypic spectrumassociated with TTN mutations and indicates that TTN mutation analysis should be considered in cases of possible CNM without mutations in the classic CNM genes.

Original languageEnglish (US)
Pages (from-to)1205-1214
Number of pages10
JournalNeurology
Volume81
Issue number14
DOIs
StatePublished - Oct 1 2013

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Congenital Structural Myopathies
Connectin
Mutation
Genes
Exome
Muscular Diseases
Genome
Excitation Contraction Coupling
Muscles
Muscle Hypotonia
Muscle Proteins
Gene
Fluorescent Antibody Technique
Electrophoresis
Proteins
Gels
Biopsy

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)

Cite this

Ceyhan-Birsoy, O., Agrawal, P. B., Hidalgo, C., Schmitz-Abe, K., Dechene, E. T., Swanson, L. C., ... Beggs, A. H. (2013). Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy. Neurology, 81(14), 1205-1214. https://doi.org/10.1212/WNL.0b013e3182a6ca62

Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy. / Ceyhan-Birsoy, Ozge; Agrawal, Pankaj B.; Hidalgo, Carlos; Schmitz-Abe, Klaus; Dechene, Elizabeth T.; Swanson, Lindsay C.; Soemedi, Rachel; Vasli, Nasim; Iannaccone, Susan T.; Shieh, Perry B.; Shur, Natasha; Dennison, Jane M.; Lawlor, Michael W.; Laporte, Jocelyn; Markianos, Kyriacos; Fairbrother, William G.; Granzier, Henk; Beggs, Alan H.

In: Neurology, Vol. 81, No. 14, 01.10.2013, p. 1205-1214.

Research output: Contribution to journalArticle

Ceyhan-Birsoy, O, Agrawal, PB, Hidalgo, C, Schmitz-Abe, K, Dechene, ET, Swanson, LC, Soemedi, R, Vasli, N, Iannaccone, ST, Shieh, PB, Shur, N, Dennison, JM, Lawlor, MW, Laporte, J, Markianos, K, Fairbrother, WG, Granzier, H & Beggs, AH 2013, 'Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy', Neurology, vol. 81, no. 14, pp. 1205-1214. https://doi.org/10.1212/WNL.0b013e3182a6ca62
Ceyhan-Birsoy O, Agrawal PB, Hidalgo C, Schmitz-Abe K, Dechene ET, Swanson LC et al. Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy. Neurology. 2013 Oct 1;81(14):1205-1214. https://doi.org/10.1212/WNL.0b013e3182a6ca62
Ceyhan-Birsoy, Ozge ; Agrawal, Pankaj B. ; Hidalgo, Carlos ; Schmitz-Abe, Klaus ; Dechene, Elizabeth T. ; Swanson, Lindsay C. ; Soemedi, Rachel ; Vasli, Nasim ; Iannaccone, Susan T. ; Shieh, Perry B. ; Shur, Natasha ; Dennison, Jane M. ; Lawlor, Michael W. ; Laporte, Jocelyn ; Markianos, Kyriacos ; Fairbrother, William G. ; Granzier, Henk ; Beggs, Alan H. / Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy. In: Neurology. 2013 ; Vol. 81, No. 14. pp. 1205-1214.
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AU - Ceyhan-Birsoy, Ozge

AU - Agrawal, Pankaj B.

AU - Hidalgo, Carlos

AU - Schmitz-Abe, Klaus

AU - Dechene, Elizabeth T.

AU - Swanson, Lindsay C.

AU - Soemedi, Rachel

AU - Vasli, Nasim

AU - Iannaccone, Susan T.

AU - Shieh, Perry B.

AU - Shur, Natasha

AU - Dennison, Jane M.

AU - Lawlor, Michael W.

AU - Laporte, Jocelyn

AU - Markianos, Kyriacos

AU - Fairbrother, William G.

AU - Granzier, Henk

AU - Beggs, Alan H.

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N2 - 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 TTNmutations as a cause of congenitalmyopathy that is reported as CNM.Unlike the classic CNMgenes 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 contractilemachinery. This study expands the phenotypic spectrumassociated with TTN mutations and indicates that TTN mutation analysis should be considered in cases of possible CNM without mutations in the classic CNM genes.

AB - 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 TTNmutations as a cause of congenitalmyopathy that is reported as CNM.Unlike the classic CNMgenes 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 contractilemachinery. This study expands the phenotypic spectrumassociated 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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