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.

Keywords: Childhood-juvenile onset Emery-Dreifuss-like phenotype without cardiomyopathy; Congenital centronuclear myopathy (CNM); Early-onset myopathy with fatal cardiomyopathy (EOMFC); Hereditary myopathy with early respiratory failure (HMERF); Late-onset autosomal dominant tibial muscular dystrophy (TMD); Limb-girdle muscular dystrophy (LGMD); Multi-minicore disease with heart disease (MmDHD); TTN; neuromuscular disorders; titin.

Fig.1

Top: A schematic view of the sarcomere, with titin filaments shown in red. One titin molecule, extending from the Z-disc to M-band, is highlighted. Middle: The modular structure of the titin protein (theoretical meta isoform). Titin is mostly comprised of repeated immunoglobulin-like (Ig; red) and fibronectin type 3-like (FN3; white) domains. Selected domains are labeled above the diagram with the classical titin nomenclature (sarcomere region Z/I/A/M+domain number; Bang et al. 2001), followed in parentheses by the alternative numbering scheme (domain type Ig/FN3 + domain number), and with the corresponding exon number. Also indicated are other structural features: the Z-repeats, the Novex-1 and Novex-2 exons, the N2B and N2A elements, the PEVK (proline/glutamate/valine/lysine-rich) region, and the alternatively spliced M-band is7 (M-is7) region. Protein interactions of the different parts of titin are summarized below the diagram. Bottom: Exon inclusion in NCBI RefSeq database sequences representing the main titin isoform classes. The bars align to the protein diagram of the meta isoform above, except for the alternative C-terminal exon of the Novex-3 isoform (grey). Note that within each class there is further developmental, anatomical, and physiological variation in exon inclusion, mostly in the proximal tandem-Ig and PEVK regions.

Fig.2

Skeletal muscle disease mutations in titin. Symbols below the diagram depict mutations associated with neuromuscular diseases, with the symbol shape indicating mutation type and symbol color indicating the predominant clinical phenotype.