Increasing Role of Titin Mutations in Neuromuscular Disorders

Abstract

The TTN gene with 363 coding exons encodes titin, a giant muscle protein spanning from the Z-disk to the M-band within the sarcomere. Mutations in the TTN gene have been associated with different genetic disorders, including hypertrophic and dilated cardiomyopathy and several skeletal muscle diseases.Before the introduction of next generation sequencing (NGS) methods, the molecular analysis of TTN has been laborious, expensive and not widely used, resulting in a limited number of mutations identified. Recent studies however, based on the use of NGS strategies, give evidence of an increasing number of rare and unique TTN variants. The interpretation of these rare variants of uncertain significance (VOUS) represents a challenge for clinicians and researchers.The main aim of this review is to describe the wide spectrum of muscle diseases caused by TTN mutations so far determined, summarizing the molecular findings as well as the clinical data, and to highlight the importance of joint efforts to respond to the challenges arising from the use of NGS. An international collaboration through a clinical and research consortium and the development of a single accessible database listing variants in the TTN gene, identified by high throughput approaches, may be the key to a better assessment of titinopathies and to systematic genotype– phenotype correlation studies.

Untangling the complexity of limb‐girdle muscular dystrophies

“…TTN exon 344, encoding for an A‐band titin, is the mutation hot spot for TTN MFM. TTN exon 364, encoding for an M‐band titin, is the mutation hot spot for late‐onset, autosomal dominant distal myopathy, with preferential involvement of the anterior leg compartment (tibial muscular dystrophy) as well as early‐onset LGMD2 (LGMD2J) . Not all TTN myopathies show MFM pathology.…”

Centronuclear myopathy with cardiomyopathy due to recessive titinopathy

“…Titin gene ( TTN ) mutations, specifically truncating mutations, account for 25% of familial dilated cardiomyopathy cases . TTN mutations also occur in several skeletal muscle disorders, with variable inheritance and pathologic findings, including late‐onset dominant or early‐onset recessive distal myopathy, limb girdle muscular dystrophy type 2 J, hereditary myopathy with early respiratory failure, Emery‐Dreifuss‐like muscular dystrophy without cardiac involvement, early‐onset myopathy with fatal cardiomyopathy, multiminicore disease with heart disease, and recessive centronuclear myopathy . Our case below further highlights the phenotypic variability and cardiac involvement in recessive titinopathy.…”

“…Titin is a protein involved in sarcomere assembly and maintenance of passive sarcomeric tension, interacting with multiple scaffolding proteins including calpain‐3 and nebulin . Titin gene ( TTN ) mutations, specifically truncating mutations, account for 25% of familial dilated cardiomyopathy cases .…”

Neuromuscular transmission defects in myopathies: Rare but worth searching for

“…It is interesting that both centronuclear myopathy and distal myopathy patients carry a single but different truncating variant in titin ( TTN ). TTN mutations are known to cause a wide variety of myopathies, including centronuclear myopathy and distal myopathy, although the severe involvement of calf muscles observed in patient 2 is not typical of TTN ‐distal myopathy . Truncating TTN mutations are known so far to cause only autosomal recessive muscle diseases; therefore, the significance of the single truncating TTN variant identified in both patients remain unknown.…”