Recessive truncating titin gene, <i>TTN</i> , mutations presenting as centronuclear myopathy

TLDR

TTN encodes the giant sarcomeric protein titin, a myofibrillar backbone distinct from the excitation‑contraction coupling genes that underlie classic centronuclear myopathies. The study aimed to identify causative genes for centronuclear myopathies by applying next‑generation sequencing of whole exomes and genomes. Whole‑exome or genome sequencing was performed on 29 CNM patients, followed by immunofluorescence, splicing assays, and protein gel electrophoresis to assess the molecular impact of identified variants. Autosomal recessive truncating mutations in TTN were found in five patients, leading to increased titin degradation and truncated proteins, establishing TTN as a novel cause of congenital myopathy presenting as CNM and broadening its phenotypic spectrum.

Abstract

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. 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. 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. 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.