C‐terminal titin deletions cause a novel early‐onset myopathy with fatal cardiomyopathy

@article{Carmignac2007CterminalTD,
  title={C‐terminal titin deletions cause a novel early‐onset myopathy with fatal cardiomyopathy},
  author={Virginie Carmignac and Mustafa A. M. Salih and S. Quijano-roy and Sylvie Marchand and M Al Rayess and Maowia M. Mukhtar and J Andoni Urtizberea and Siegfried Labeit and Pascale Guicheney and France Leturcq and Mathias Gautel and Michel Gustave Jules Fardeau and Kevin P. Campbell and Isabelle Richard and Brigitte Estournet and Ana Ferreiro},
  journal={Annals of Neurology},
  year={2007},
  volume={61}
}
The giant protein titin is essential for striated muscle development, structure, and elasticity. All titin mutations reported to date cause late‐onset, dominant disorders involving either skeletal muscle or the heart. Our aim was to delineate the phenotype and determine the genetic defects in two consanguineous families with an early‐onset, recessive muscle and cardiac disorder. 
Atypical phenotypes in titinopathies explained by second titin mutations
TLDR
This study aimed to clarify the molecular cause of the variant phenotypes in 8 patients of 7 European families with previously reported titin gene (TTN) mutations causing tibial muscular dystrophy.
Novel heterozygous truncating titin variants affecting the A‐band are associated with cardiomyopathy and myopathy/muscular dystrophy
TLDR
Recent reports show pathogenic variants in TTN may result in a broader phenotypic spectrum than previously recognized, and this work is the first to show this.
Truncating mutations in C-terminal titin may cause more severe tibial muscular dystrophy (TMD)
A ‘second truncation’ in TTN causes early onset recessive muscular dystrophy
Myopathies caused by homozygous titin mutations: limb-girdle muscular dystrophy 2J and variations of phenotype
TLDR
A French family with an autosomal-dominant late-onset distal myopathy of the tibial muscular dystrophy phenotype segregating in several members of the family was described and the early phenotype in a newly identified young patient with homozygous Finnish C-terminal titin mutation (FINmaj) was detailed.
Titin in muscular dystrophy and cardiomyopathy: Urinary titin as a novel marker.
Removal of the calpain 3 protease reverses the myopathology in a mouse model for titinopathies.
TLDR
By crossing the FINmaj model with a calpain 3-deficient model, the TMD phenotype was corrected, demonstrating a participation of cal pain 3 in the pathogenesis of this disease.
The first Italian family with tibial muscular dystrophy caused by a novel titin mutation
TLDR
Since the introduction of a proline in the last domain of titin was previously known to cause TMD in French families, it can conclude that this missense mutation is the obvious pathogenetic mutation in the affected patients.
Hereditary myopathy with early respiratory failure associated with a mutation in A-band titin.
TLDR
A novel and the first disease-causing mutation in A-band titin associated with hereditary myopathy with early respiratory failure is demonstrated and the typical histopathological features with prominent myofibrillar lesions and inclusions in muscle and respiratory failure early in the clinical course should be incentives for analysis of TTN mutations.
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References

SHOWING 1-10 OF 39 REFERENCES
Mutations in dynamin 2 cause dominant centronuclear myopathy
TLDR
In 11 families affected by centronuclear myopathy, recurrent and de novo missense mutations in the gene dynamin 2 (DNM2), which encodes a protein involved in endocytosis and membrane trafficking, actin assembly and centrosome cohesion, were identified.
Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy
TLDR
It is shown that mutations in the gene encoding giant-muscle filament titin (TTN) cause autosomal dominant DCM linked to chromosome 2q31 (CMD1G; MIM 604145), and the identification of TTN mutations in individuals with C MD1G should provide further insights into the pathogenesis of familial forms of CHF and myofibrillar titin turnover.
Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin.
TLDR
Immunohistochemical analysis using two exon-specific antibodies directed to the M-line region of titin demonstrated the specific loss of carboxy-terminal titin epitopes in the TMD muscle samples that were studied, thus implicating a functional defect of theM-line titin in the genesis of the T MD disease phenotype.
Tibial muscular dystrophy in a Belgian family
TLDR
A Belgian family with autosomal dominant, late‐onset, distal myopathy with selective foot extensor muscle involvement of the lower legs and a disease‐specific, heterozygous point mutation in the last exon, Mex6, of the titin gene is reported, suggesting that titinopathies may occur in various populations.
Titinopathies and extension of the M-line mutation phenotype beyond distal myopathy and LGMD2J
TLDR
Large variability of phenotypic expression caused by just one mutation, the Finnish FINmaj, suggests that no certain phenotype of myopathy/dystrophy can be excluded from being caused by mutated titin.
Titin mutations as the molecular basis for dilated cardiomyopathy.
TLDR
Observations suggest that titin mutations may cause DCM in a subset of the patients, and one of them was a nonsense mutation presumably encoding for a truncated nonfunctional molecule.
Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy
TLDR
This work has mapped the locus for EDMD-AD to an 8-cM interval on chromosome 1q11-q23 in a large French pedigree, and found that the EMD phenotype in four other small families was potentially linked to this locus, and identified four mutations in LMNA that co-segregate with the disease phenotype in the five families.
Structural analysis of the titin gene in hypertrophic cardiomyopathy: identification of a novel disease gene.
TLDR
A G to T transversion in codon 740, from CGC to CTC, replacing Arginine with Leucine was found in a patient, suggesting that the titin mutation may cause HCM in this patient via altered affinity to alpha-actinin.
Mutations of the selenoprotein N gene, which is implicated in rigid spine muscular dystrophy, cause the classical phenotype of multiminicore disease: reassessing the nosology of early-onset myopathies.
TLDR
The present study represents the first identification of a gene responsible for classical MmD, demonstrates its genetic heterogeneity, and reassesses the nosological boundaries between Mmd and RSMD.
Conditional Expression of Mutant M-line Titins Results in Cardiomyopathy with Altered Sarcomere Structure*
TLDR
An important role for MEx1 and MEx2 in early cardiac development as well as postnatally when disruption of M-line titin leads to muscle weakness and death at ∼5 weeks of age is demonstrated.
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