Genetic Disease Clinical Trial
— DIAMYOTITOfficial title:
Improvement of DIAgnostic and Phenotype-genotype Correlation Studies in Patients With MYOpathy Suspected of TITinopathy
Due to the widespread use of NGS, TTN is emerging as a major causative gene in neuromuscular disorders, with high clinical heterogeneity. The mechanisms underlying the phenotypic variability and mode of inheritance (recessive or dominant) of titinopathies are poorly understood. They involve the primordial structural functions of titin on the formation and stability of the sarcomere, as well as its interactions with other proteins. We identified by NGS, in patients with skeletal myopathy (with or without cardiomyopathy), several potentially disease causing TTN variants. The specific aims of the present project are to implement functional studies (transcripts, protein analyses, in vitro protein-protein interaction studies) to evaluate the effect of TTN variants on the transcripts and protein in order to perform phenotype-genotype correlation studies. We participate to the national "titin network" and to international efforts for the understanding of the molecular bases of titinopathies. Genomic characterisation opens the way to develop cellular models of titinopathy, derived from patient biopsies. This is also a mandatory first step for the design of novel therapeutic approaches.
Status | Recruiting |
Enrollment | 50 |
Est. completion date | May 5, 2025 |
Est. primary completion date | December 5, 2024 |
Accepts healthy volunteers | No |
Gender | All |
Age group | N/A and older |
Eligibility | Inclusion Criteria: - Patient followed by a neurologist or a pediatric neurologist. - Child or adult with congenital or progressive, proximal or distal myopathy - Identification by NGS analysis of variant(s) in the potentially pathogenic TTN gene(s) - Muscle biopsy performed previously - Collection of the patient's (or one of his legal representatives if minor) non-opposition to participate in the present study and for the collection of the necessary biological material (muscle) - Patient affiliated to or benefiting from a social security scheme Exclusion Criteria: - Absence of muscle sampling |
Country | Name | City | State |
---|---|---|---|
France | CHU Montpellier | Montpellier |
Lead Sponsor | Collaborator |
---|---|
University Hospital, Montpellier |
France,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Measurement of the relative quantity of titin protein | Evaluated by Western blot: normal or not, characterization of anomalies if any | enrollment | |
Primary | Measurement of the relative size of titin protein | Evaluated by Western blot: normal or not, characterization of anomalies if any | enrollment | |
Secondary | Measurement of consequences on interacting proteins | Evaluation by Western blot: normal or not | during 2 years | |
Secondary | Measurement of the consequences of TTN variants on titin transcripts | Evaluation by RT-PCR studies from muscle biopsies | 2 years | |
Secondary | Phenotype-genotype correlation studies | Correlation of clinicobiological data | 2.5 years | |
Secondary | Analyses of molecular bases of the different mode of inheritance of the disease | Integrated analyses of the complete biological data and correlation with the familial data | 2.5 years | |
Secondary | Mesurement of the level of interactions by in-vitro studies | Evaluation by Western blot: normal or not | during 2 years | |
Secondary | Evaluate the effects of TTN variants on the amount and composition of titin peptides in patient skeletal muscle | By mass spectrometry | during 2 years | |
Secondary | Evaluate the impact of TTN variants on titin expression and splicing in patient skeletal muscle | using the poly-A tail selection protocol for mRNAs | during 2 years | |
Secondary | Evaluate the impact of TTN variants on muscle gene expression levels by expression analysis of RNAseq data | Expression analysis can be performed using R software and DESeq2 software. | during 2 years | |
Secondary | Evaluate the effects of TTN variants on muscle protein partners. | Quantitative proteomic analysis,mass spectrometry, will enable us to assess the quantity of muscle proteins, overall protein profile, in patients' muscle | during 2 years |
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