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Published on: July 15, 2014
Truncating mutations in C-terminal titin may cause more severe tibial muscular dystrophy (TMD)
Peter Hackman1, Sylvie Marchand, Jaakko Sarparanta
1Folkhälsan Institute of Genetics, Department of Medical Genetics, University of Helsinki, Haartmaninkatu 8, Pb 63, 00014 Helsinki, Finland. peter.hackman@helsinki.fi
Abstract:
Mutations in C-terminal titin cause autosomal dominant tibial muscular dystrophy (TMD) as reported previously. Samples from 25 new families and 25 sporadic new distal myopathy cases were screened for titin mutations. Three novel mutations were discovered in two families from Spain and two families from France. Two mutations, g.292998delT and g.293376delA lead to frameshift and premature stop codons in the second last and the last titin gene (TTN) exons, Mex5 and Mex6, respectively. The third was a nonsense mutation g.293379C>T (p.Q33396X) in Mex6. Patients with the upstream Mex5 mutation showed a more severe phenotype with earlier onset implying a genotype-phenotype correlation.
Insights
New titin gene (TTN) mutations cause autosomal dominant tibial muscular dystrophy (TMD). Researchers identified three novel TTN mutations in European families, with one mutation linked to a more severe disease phenotype.
Area of Science:
- Genetics
- Molecular Biology
- Neurology
Background:
- Autosomal dominant tibial muscular dystrophy (TMD) is linked to mutations in the C-terminal titin gene (TTN).
- Previous studies have established the role of titin mutations in TMD etiology.
Purpose of the Study:
- To screen for novel titin mutations in patients with distal myopathy.
- To investigate the genotype-phenotype correlation in patients with newly identified TTN mutations.
Main Methods:
- Genetic screening of 25 new families and 25 sporadic distal myopathy cases for titin mutations.
- Analysis of mutation types, including frameshift and nonsense mutations, and their location within TTN exons (Mex5, Mex6).
Main Results:
- Three novel titin gene (TTN) mutations were identified in families from Spain and France.
- Two mutations (g.292998delT, g.293376delA) caused frameshifts and premature stop codons in Mex5 and Mex6.
- A nonsense mutation (g.293379C>T) was found in Mex6. Patients with the Mex5 mutation exhibited a more severe phenotype and earlier disease onset.
Conclusions:
- Novel mutations in the titin gene (TTN) are associated with autosomal dominant tibial muscular dystrophy (TMD).
- The location of TTN mutations, particularly in the Mex5 exon, correlates with disease severity and onset, suggesting a genotype-phenotype relationship.
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