Abstract
Next generation sequencing (NGS) has allowed the titin gene (TTN) to be identified as a major contributor to neuromuscular disorders, with high clinical heterogeneity. The mechanisms underlying the phenotypic variability and the dominant or recessive pattern of inheritance are unclear. Titin is involved in the formation and stability of the sarcomeres. The effects of the different TTN variants can be harmless or pathogenic (recessive or dominant) but the interpretation is tricky because the current bioinformatics tools can not predict their functional impact effectively. Moreover, TTN variants are very frequent in the general population. The combination of deep phenotyping associated with RNA molecular analyses, western blot (WB) and functional studies is often essential for the interpretation of genetic variants in patients suspected of titinopathy. In line with the current guidelines and suggestions, we implemented for patients with skeletal myopathy and with potentially disease causing TTN variant(s) an integrated genotype-transcripts-protein-phenotype approach, associated with phenotype and variants segregation studies in relatives and confrontation with published data on titinopathies to evaluate pathogenic effects of TTN variants (even truncating ones) on titin transcripts, amount, size and functionality. We illustrate this integrated approach in four patients with recessive congenital myopathy.
Highlights
titin gene (TTN) encodes titin, a giant sarcomeric protein [1] that plays important functional and structural roles in the sarcomere
Assessing the pathogenicity of the identified variants, in particular missense ones, is often difficult, due to the clinical heterogeneity of the pathology, the large size of the gene, the frequency of TTN variants in the general population and the complexity of gene expression [3]
Specific variants in the last exon and all the truncating variants causing the loss of the Cterminal portion (i.e. M-band truncating variants) causes the loss of the interaction with calpain-3 and its reduction at western blot, may contribute to disease pathogenesis, raising the possibility that the decrease of calpain-3 level may contribute to disease pathogenesis [5,6,7,8,9]
Summary
TTN encodes titin, a giant sarcomeric protein [1] that plays important functional and structural roles in the sarcomere. Different types of mutation have been reported as pathogenic, but their consequences on transcripts and protein, in particular loss or gain of titin function, are not fully elucidated. Several studies demonstrated that TTN truncating mutations are associated with loss function leading to recessive titinopathies, including congenital titinopathies. Interpretation of non-truncating (mainly missense) variants remains more difficult. Their localization in important functional domains (such as the titin kinase domain) and interaction domains (with proteins such as calpain-3, actin, myosin, nebulin, or one of the numerous interacting proteins (for review, see [4])) may suggest a potential pathogenicity. Specific variants in the last exon (including missense variants) and all the truncating variants causing the loss of the Cterminal portion (i.e. M-band truncating variants) causes the loss of the interaction with calpain-3 and its reduction at western blot, may contribute to disease pathogenesis, raising the possibility that the decrease of calpain-3 level may contribute to disease pathogenesis [5,6,7,8,9]
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