Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy. Neurology 2013 Oct 01;81(14):1205-14
Date
08/27/2013Pubmed ID
23975875Pubmed Central ID
PMC3795603DOI
10.1212/WNL.0b013e3182a6ca62Scopus ID
2-s2.0-84886409449 (requires institutional sign-in at Scopus site) 162 CitationsAbstract
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.
Author List
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 AHAuthor
Michael W. Lawlor MD, PhD Adjunct Professor in the Pathology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Adaptor Proteins, Signal TransducingAdolescent
Adult
Child
Child, Preschool
Cohort Studies
Connectin
Dynamin II
Female
Genes, Recessive
Humans
Male
Mutation
Myopathies, Structural, Congenital
Nuclear Proteins
Phenotype
Protein Tyrosine Phosphatases, Non-Receptor
Single-Blind Method
Tumor Suppressor Proteins
Young Adult
