Clinicopathological features of titinopathy from a Chinese neuromuscular center.
TTN gene
myopathy
neuromuscular disorder
pathology
titinopathy
Journal
Neuropathology : official journal of the Japanese Society of Neuropathology
ISSN: 1440-1789
Titre abrégé: Neuropathology
Pays: Australia
ID NLM: 9606526
Informations de publication
Date de publication:
Oct 2021
Oct 2021
Historique:
revised:
17
05
2021
received:
08
04
2021
accepted:
18
05
2021
pubmed:
24
9
2021
medline:
14
1
2022
entrez:
23
9
2021
Statut:
ppublish
Résumé
Titin, one of the largest proteins in humans, is a major component of muscle sarcomeres. Pathogenic variants in the titin gene (TTN) have been reported to cause a range of skeletal muscle diseases, collectively known as titinopathy. Titinopathy is a heterogeneous group of disabling diseases characterized by muscle weakness. In our study, we aimed to establish the clinicopathological-genetic spectrum of titinopathy from a single neuromuscular center. Three patients were diagnosed as having definite titinopathy, and additional three patients were diagnosed as having possible titinopathy according to the diagnostic criteria. All the patients showed initial symptoms from age one to 40 years. Physical examination revealed that five patients had muscle weakness, and that one patient experienced behavioral changes. Muscle biopsy specimens obtained from all six patients demonstrated multiple myopathological changes, including increased fiber size variation, muscle fiber hypertrophy or atrophy, formation of centralized cell nuclei, necklace cytoplasmic bodies, and formation of rimmed vacuoles and cores. Genetic testing revealed 11 different TTN alterations, including missense (6/11), nonsense (2/11), frameshift (2/11), and splicing (1/11) mutations. Our study provides further evidence that TTN mutations are more likely to be responsible for an increasing proportion of various myopathies, such as hereditary myopathy with early respiratory failure (HMERF), core myopathy, and distal myopathy with rimmed vacuoles, than currently recognized mutations. Our findings expand the clinical, pathohistological and genetic spectrum of titinopathy.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
349-356Informations de copyright
© 2021 Japanese Society of Neuropathology.
Références
Chauveau C, Rowell J, Ferreiro A. A rising titan: TTN review and mutation update. Hum Mutat 2014; 35: 1046-1059.
Freiburg A, Trombitas K, Hell W et al. Series of exon-skipping events in the elastic spring region of titin as the structural basis for myofibrillar elastic diversity. Circ Res 2000; 86: 1114-1121.
Bang ML, Centner T, Fornoff F et al. The complete gene sequence of titin, expression of an unusual approximately 700-kDa titin isoform, and its interaction with obscurin identify a novel Z-line to I-band linking system. Circ Res 2001; 89: 1065-1072.
Savarese M, Jonson PH, Huovinen S et al. The complexity of titin splicing pattern in human adult skeletal muscles. Skelet Muscle 2018; 8: 11.
Udd B. The constantly evolving spectrum of phenotypes in titinopathies - will it ever stop? Curr Opin Neurol 2020; 33: 604-610.
Savarese M, Sarparanta J, Vihola A, Udd B, Hackman P. Increasing role of titin mutations in neuromuscular disorders. J Neuromuscul Dis 2016; 3: 293-308.
Yu M, Zhu Y, Xie Z et al. Novel TTN mutations and muscle imaging characteristics in congenital titinopathy. Ann Clin Transl Neurol 2019; 6: 1311-1318.
Savarese M, Johari M, Johnson K et al. Improved criteria for the classification of titin variants in inherited skeletal myopathies. J Neuromuscul Dis 2020; 7: 153-166.
Savarese M, Maggi L, Vihola A et al. Interpreting genetic variants in titin in patients with muscle disorders. JAMA Neurol 2018; 75: 557-565.
Huang K, Li QX, Bi FF et al. Comparative immunoprofiling of polymyositis and dermatomyositis muscles. Int J Clin Exp Pathol 2018; 11: 3984-3993.
Huang K, Duan HQ, Li QX, Luo YB, Yang H. Investigation of adult-onset multiple Acyl-CoA dehydrogenase deficiency associated with peripheral neuropathy. Neuropathology 2020.40: 531-539.
Huang K, Li J, Ito M et al. Gene expression profile at the motor endplate of the neuromuscular junction of fast-twitch muscle. Front Mol Neurosci 2020; 13: 154.
Morais J, Oliveira AA, Pires O, Burmester I, Regadas MJ, Gouveia P. Titinopathy, an atypical respiratory failure. BMJ Case Rep 2020; 13.
Uruha A, Hayashi YK, Oya Y et al. Necklace cytoplasmic bodies in hereditary myopathy with early respiratory failure. J Neurol Neurosurg Psychiatry 2015; 86: 483-489.
Palmio J, Evila A, Chapon F et al. Hereditary myopathy with early respiratory failure: Occurrence in various populations. J Neurol Neurosurg Psychiatry 2014; 85: 345-353.
Ng PC, Henikoff S. SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res 2003; 31: 3812-3814.
Ramensky V, Bork P, Sunyaev S. Human non-synonymous SNPs: Server and survey. Nucleic Acids Res 2002; 30: 3894-3900.
Kaplan JC, Hamroun D. The 2016 version of the gene table of monogenic neuromuscular disorders (nuclear genome). Neuromuscul Disord 2015; 25: 991-1020.
Lange S, Xiang F, Yakovenko A et al. The kinase domain of titin controls muscle gene expression and protein turnover. Science 2005; 308: 1599-1603.
Tang J, Fan Y, Li H et al. Whole-genome sequencing of monozygotic twins discordant for schizophrenia indicates multiple genetic risk factors for schizophrenia. J Genet Genomics 2017; 44: 295-306.
Nguyen DT, Nguyen HH, Nguyen TD et al. Whole genome sequencing of a vietnamese family from a dioxin contamination hotspot reveals novel variants in the son with undiagnosed intellectual disability. Int J Environ Res Public Health 2018; 15.
Oates EC, Jones KJ, Donkervoort S et al. Congenital titinopathy: Comprehensive characterization and pathogenic insights. Ann Neurol 2018; 83: 1105-1124.
Ge L, Fu X, Zhang W et al. Recessive mutations in proximal I-band of TTN gene cause severe congenital multi-minicore disease without cardiac involvement. Neuromuscul Disord 2019; 29: 350-357.
Martinez-Thompson JM, Winder TL, Liewluck T. Centronuclear myopathy with cardiomyopathy due to recessive titinopathy. Muscle Nerve 2019; 59: E26-E27.
Chauveau C, Bonnemann CG, Julien C et al. Recessive TTN truncating mutations define novel forms of core myopathy with heart disease. Hum Mol Genet 2014; 23: 980-991.
Huebsch KA, Kudryashova E, Wooley CM et al. Mdm muscular dystrophy: Interactions with calpain 3 and a novel functional role for titin's N2A domain. Hum Mol Genet 2005; 14: 2801-2811.
Radke MH, Polack C, Methawasin M, Fink C, Granzier HL, Gotthardt M. Deleting full length titin versus the titin M-B and region leads to differential mechanosignaling and cardiac phenotypes. Circulation 2019; 139: 1813-1827.