TITINdb—a computational tool to assess titin’s role as a disease gene

Laddach, Anna; Gautel, Mathias; Fraternali, Franca

doi:10.1093/bioinformatics/btx424

Cited by 37 publications

(38 citation statements)

References 23 publications

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“…As the clinical and pathological features strongly supported the diagnosis of congenital titinopathy, the missense mutation c.91916T>C on the maternal allele was thought to be pathogenic. Further assessment with a computational tool called TITINdb showed mCSM score −1.424 and destabilizing, PolyPhen‐2 score 0.982, and Condel score 0.563794569134, which was deleterious . Besides, this variant was neither found in ExAC nor in 1000G, and the amino acid affected was extremely conserved among species, all suggesting its pathogenicity.…”

Section: Discussionmentioning

confidence: 98%

Novel TTN mutations and muscle imaging characteristics in congenital titinopathy

Zhu

Xie

et al. 2019

Ann Clin Transl Neurol

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Objective We present clinical features, muscle imaging findings, and genetic characteristics of five unrelated Chinese patients with congenital titinopathy, emphasizing the diagnostic role of muscle MRI. Methods Five patients who recessive titinopathies were recruited. All patients received muscle biopsies. Mutations were detected by panel massively parallel sequencing and confirmed by Sanger sequencing. Western blotting of muscle proteins was performed. Leg muscle MRIs were performed in four patients. Results Four patients aged 1–4 years old showed delayed motor development from early infancy, while a 17‐year‐old boy showed only a 1‐year history of exercise intolerance. Physical examination showed proximal weakness in three patients. Muscle biopsies demonstrated multiple myopathological changes, including increased internalized nuclei, multicores, central cores, and dystrophic changes. Genetic sequencing revealed compound heterozygous or homozygous novel TTN mutations, including six frameshift mutations, one nonsense mutation, two missense mutations, one splicing mutation, and one small nonframeshift deletion. Protein analyses revealed significant decrease of full‐length titin in all patients. Thigh muscle MRIs in four patients showed prominent fatty infiltration in the upper portion of semitendinosus and the peripheral portion of gluteus medius, while the sartorius and gracilis were relatively preserved. Interpretation These cases provided further evidence that TTN mutations are likely responsible for an increasing proportion of congenital myopathies than currently recognized. The novel mutations reported expand the mutation spectrum of the TTN gene. There is a characteristic pattern of muscle involvement in congenital titinopathy regardless of clinical or pathological phenotype, providing valuable clues for guiding a genetic diagnosis workup.

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Section: Discussionmentioning

confidence: 98%

Novel TTN mutations and muscle imaging characteristics in congenital titinopathy

Zhu

Xie

et al. 2019

Ann Clin Transl Neurol

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“…For the analysis of amino acid residue conservation in titin's C-zone super-repeats, we defined titin domain boundaries according to Laddach et al [26]. Domain boundaries in Mus musculus titin (Ttn-203, ENSMUST00000099981) were determined by alignment with human Titin (IC isoform, NP_001254479).…”

Section: Titin's C-zone Super-repeats Interface Sequence Analysismentioning

confidence: 99%

“…To determine which amino acids might potentially be involved in cMyBP-C binding, residues with a low alignment score in C0-1 and C1-2 versus cMyBP-C binding interfaces were identified. For those residues, surface exposure was determined utilizing the GETAREA tool [28] based on modelled Titin domain structures [26]. All residues that exceeded a solvent-exposed ratio of 50% were considered to be surface residues.…”

Section: Titin's C-zone Super-repeats Interface Sequence Analysismentioning

confidence: 99%

Fine mapping titin's C-zone: Matching cardiac myosin-binding protein C stripes with titin's super-repeats

Tonino

Kiss

Gohlke

et al. 2019

Journal of Molecular and Cellular Cardiology

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Titin is largely comprised of serially-linked immunoglobulin (Ig) and fibronectin type-III (Fn3) domains. Many of these domains are arranged in an 11 domain super-repeat pattern that is repeated 11 times, forming the sonamed titin C-zone in the A-band region of the sarcomere. Each super-repeat is thought to provide binding sites for thick filament proteins, such as cMyBP-C (cardiac myosin-binding protein C). However, it remains to be established which of titin's 11 C-zone super-repeats anchor cMyBP-C as titin contains 11 super-repeats and cMyBP-C is found in 9 stripes only. To study the layout of titin's C-zone in relation to MyBP-C, immunolabeling studies were performed on mouse skinned myocardium with antibodies to titin and cMyBP-C, using both immuno-electron microscopy and super-resolution optical microscopy. Results indicate that cMyBP-C locates near the interface between titin's C-zone super-repeats. Studies on a mouse model in which two of titin's C-zone repeats have been genetically deleted support that the first Ig domain of a super-repeat is important for anchoring cMyBP-C but also Fn3 domains located at the end of the preceding repeat. Furthermore, not all superrepeat interfaces are equal as the interface between super-repeat 1 and 2 (close to titin's D-zone) does not contain cMyBP-C. Finally, titin's C-zone does not extend all the way to the bare zone but instead terminates at the level of the second myosin crown. This study enhances insights in the molecular layout of the C-zone of titin, its relation to cMyBP-C, and its possible roles in cardiomyopathies.

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“…The MPA score can efficiently prioritize the large number of TTN variants identified in patients. Moreover, TITINdb, a web application that integrates information on titin structure, sequence, isoforms, and variants, 9 is interesting for predicting the potential effect of TTN missense variants. Considering the high number of TTN variants of uncertain significance, it is crucial to include mRNA and protein analyses when assessing the effects of TTN variants on titin transcripts, quantity, size, and functionality.…”

Section: Introductionmentioning

confidence: 99%

A new congenital multicore titinopathy associated with fast myosin heavy chain deficiency

Perrin

Métay

Villanova³

et al. 2020

Ann Clin Transl Neurol

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Congenital titinopathies are myopathies with variable phenotypes and inheritance modes. Here, we fully characterized, using an integrated approach (deep phenotyping, muscle morphology, mRNA and protein evaluation in muscle biopsies), two siblings with congenital multicore myopathy harboring three TTN variants predicted to affect titin stability and titin-myosin interactions. Muscle biopsies showed multicores, type 1 fiber uniformity and sarcomeric structure disruption with some thick filament loss. Immunohistochemistry and Western blotting revealed a marked reduction of fast myosin heavy chain isoforms. This is the first observation of a titinopathy suggesting that titin defect leads to secondary loss of fast myosin heavy chain isoforms. 846

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TITINdb—a computational tool to assess titin’s role as a disease gene

Cited by 37 publications

References 23 publications

Novel TTN mutations and muscle imaging characteristics in congenital titinopathy

Novel TTN mutations and muscle imaging characteristics in congenital titinopathy

Fine mapping titin's C-zone: Matching cardiac myosin-binding protein C stripes with titin's super-repeats

A new congenital multicore titinopathy associated with fast myosin heavy chain deficiency

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