A 'second truncation' in TTN causes early onset recessive muscular dystrophy

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Harris , E , Töpf , A , Vihola , A , Evilä , A , Barresi , R , Hudson , J , Hackman , P , Herron , B , MacArthur , D , Lochmüller , H , Bushby , K , Udd , B & Straub , V 2017 , ' A 'second truncation' in TTN causes early onset recessive muscular dystrophy ' , Neuromuscular Disorders , vol. 27 , no. 11 , pp. 1009-1017 . https://doi.org/10.1016/j.nmd.2017.06.013

Title: A 'second truncation' in TTN causes early onset recessive muscular dystrophy
Author: Harris, Elizabeth; Töpf, Ana; Vihola, Anna; Evilä, Anni; Barresi, Rita; Hudson, Judith; Hackman, Peter; Herron, Brian; MacArthur, Daniel; Lochmüller, Hanns; Bushby, Kate; Udd, Bjarne; Straub, Volker
Contributor: University of Helsinki, Department of Medical and Clinical Genetics
University of Helsinki, Department of Medical and Clinical Genetics
University of Helsinki, University of Helsinki
University of Helsinki, Medicum
Date: 2017-11
Language: eng
Number of pages: 9
Belongs to series: Neuromuscular Disorders
ISSN: 0960-8966
URI: http://hdl.handle.net/10138/298408
Abstract: Mutations in the gene encoding the giant skeletal muscle protein titin are associated with a variety of muscle disorders, including recessive congenital myopathies cardiomyopathy, limb girdle muscular dystrophy (LGMD) and late onset dominant distal myopathy. Heterozygous truncating mutations have also been linked to dilated cardiomyopathy. The phenotypic spectrum of titinopathies is emerging and expanding, as next generation sequencing techniques make this large gene amenable to sequencing. We undertook whole exome sequencing in four individuals with LGMD. An essential splice site mutation, previously reported in dilated cardiomyopathy, was identified in all families in combination with a second truncating mutation. Affected individuals presented with childhood onset proximal weakness associated with joint contractures and elevated CK. Cardiac dysfunction was present in two individuals. Muscle biopsy showed increased internal nuclei and immunoblotting identified reduction or absence of calpain-3 and demonstrated a marked reduction of C-terminal titin fragments. We confirm the co-occurrence of cardiac and skeletal myopathies associated with recessive truncating titin mutations. Compound heterozygosity of a truncating mutation previously associated with dilated cardiomyopathy and a 'second truncation' in TTN was identified as causative in our skeletal myopathy patients. These findings add to the complexity of interpretation and genetic counselling for titin mutations. (C) 2017 Elsevier B.V. All rights reserved.
Subject: Titin
Titinopathy
Limb girdle muscular dystrophy
Exome sequencing
Dilated cardiomyopathy
C-TERMINAL TITIN
CARDIOMYOPATHY
MYOPATHY
TITINOPATHY
MUTATIONS
GENES
PHENOTYPE
3111 Biomedicine
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