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

Lookup NU author(s): Dr Lizzie Harris, Dr Ana TopfORCiD, Dr Rita Barresi, Professor Hanns Lochmuller, Emerita Professor Katherine Bushby, Professor Volker StraubORCiD

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Abstract

© 2017 Elsevier B.V. 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.

Publication metadata

Author(s): Harris E, Topf A, Vihola A, Evila A, Barresi R, Hudson J, Hackman P, Herron B, MacArthur D, Lochmuller H, Bushby K, Udd B, Straub V

Publication type: Article

Publication status: Published

Journal: Neuromuscular Disorders

Year: 2017

Volume: 27

Issue: 11

Pages: 1009-1017

Print publication date: 01/11/2017

Online publication date: 22/06/2017

Acceptance date: 19/06/2017

ISSN (print): 0960-8966

ISSN (electronic): 1873-2364

Publisher: Elsevier Ltd

URL: https://doi.org/10.1016/j.nmd.2017.06.013

DOI: 10.1016/j.nmd.2017.06.013

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