Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy

Area of Science:

• Genetics
• Molecular Biology
• Neuromuscular Disorders

Background:

• Centronuclear myopathies (CNM) are a group of rare inherited muscle disorders.
• These conditions often manifest in infancy with muscle weakness and hypotonia.
• Previous genetic studies focused on specific genes like MTM1, DNM2, and BIN1.

Purpose of the Study:

• To identify novel causative genes for centronuclear myopathies (CNM).
• Utilized advanced next-generation sequencing (NGS) of whole exomes and genomes.
• Investigated a cohort of unrelated patients with diagnosed CNM or related myopathies.

Main Methods:

• Performed whole-exome and whole-genome sequencing on 29 unrelated patients.
• Excluded patients with known mutations in MTM1, DNM2, and BIN1.
• Conducted immunofluorescence, splicing assays, and protein gel electrophoresis to analyze mutation impact.

Main Results:

• Identified autosomal recessive compound heterozygous truncating mutations in the titin gene (TTN) in 5 individuals.
• Biochemical analyses confirmed increased titin degradation and truncated titin proteins in patient muscle samples.
• Established a direct link between TTN mutations and the observed myopathic phenotype.

Conclusions:

• Truncating TTN mutations are identified as a novel cause of congenital myopathy presenting as CNM.
• Unlike classic CNM genes, TTN encodes a major sarcomeric protein crucial for myofibril structure.
• Expanded the phenotypic spectrum of TTN mutations and recommends TTN analysis for CNM cases lacking mutations in known genes.