TY - JOUR
T1 - Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy
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.
PY - 2013/10/1
Y1 - 2013/10/1
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.
UR - http://www.scopus.com/inward/record.url?scp=84886409449&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84886409449&partnerID=8YFLogxK
U2 - 10.1212/WNL.0b013e3182a6ca62
DO - 10.1212/WNL.0b013e3182a6ca62
M3 - Article
C2 - 23975875
AN - SCOPUS:84886409449
SN - 0028-3878
VL - 81
SP - 1205
EP - 1214
JO - Neurology
JF - Neurology
IS - 14
ER -