TY - JOUR
T1 - Expanding the clinical-pathological and genetic spectrum of RYR1-related congenital myopathies with cores and minicores: an Italian population study
AU - Fusto, Aurora
AU - Cassandrini, Denise
AU - Fiorillo, Chiara
AU - Fiorillo, Claudio
AU - Codemo, Valentina
AU - Astrea, Guja
AU - D’Amico, Adele
AU - D'Amico, Adele
AU - Maggi, Lorenzo
AU - Magri, Francesca
AU - Pane, Marika
AU - Tasca, Giorgio
AU - Sabbatini, Daniele
AU - Bello, Luca
AU - Battini, Roberta
AU - Bernasconi, Pia
AU - Fattori, Fabiana
AU - Fattori, Francesco
AU - Bertini, Enrico Silvio
AU - Comi, Giacomo
AU - Messina, Sonia
AU - Mongini, Tiziana
AU - Moroni, Isabella
AU - Panicucci, Chiara
AU - Berardinelli, Angela
AU - Donati, Alice
AU - Nigro, Vincenzo
AU - Pini, Antonella
AU - Giannotta, Melania
AU - Dosi, Claudia
AU - Ricci, Enzo
AU - Mercuri, Eugenio Maria
AU - Minervini, Giovanni
AU - Tosatto, Silvio
AU - Santorelli, Filippo
AU - Bruno, Claudio
AU - Pegoraro, Elena
PY - 2022
Y1 - 2022
N2 - Mutations in the RYR1 gene, encoding ryanodine receptor 1 (RyR1), are a well-known cause of Central Core Disease (CCD) and Multi-minicore Disease (MmD). We screened a cohort of 153 patients carrying an histopathological diagnosis of core myopathy (cores and minicores) for RYR1 mutation. At least one RYR1 mutation was identified in 69 of them and these patients were further studied. Clinical and histopathological features were collected. Clinical phenotype was highly heterogeneous ranging from asymptomatic or paucisymptomatic hyperCKemia to severe muscle weakness and skeletal deformity with loss of ambulation. Sixty-eight RYR1 mutations, generally missense, were identified, of which 16 were novel. The combined analysis of the clinical presentation, disease progression and the structural bioinformatic analyses of RYR1 allowed to associate some phenotypes to mutations in specific domains. In addition, this study highlighted the structural bioinformatics potential in the prediction of the pathogenicity of RYR1 mutations. Further improvement in the comprehension of genotype–phenotype relationship of core myopathies can be expected in the next future: the actual lack of the human RyR1 crystal structure paired with the presence of large intrinsically disordered regions in RyR1, and the frequent presence of more than one RYR1 mutation in core myopathy patients, require designing novel investigation strategies to completely address RyR1 mutation effect.
AB - Mutations in the RYR1 gene, encoding ryanodine receptor 1 (RyR1), are a well-known cause of Central Core Disease (CCD) and Multi-minicore Disease (MmD). We screened a cohort of 153 patients carrying an histopathological diagnosis of core myopathy (cores and minicores) for RYR1 mutation. At least one RYR1 mutation was identified in 69 of them and these patients were further studied. Clinical and histopathological features were collected. Clinical phenotype was highly heterogeneous ranging from asymptomatic or paucisymptomatic hyperCKemia to severe muscle weakness and skeletal deformity with loss of ambulation. Sixty-eight RYR1 mutations, generally missense, were identified, of which 16 were novel. The combined analysis of the clinical presentation, disease progression and the structural bioinformatic analyses of RYR1 allowed to associate some phenotypes to mutations in specific domains. In addition, this study highlighted the structural bioinformatics potential in the prediction of the pathogenicity of RYR1 mutations. Further improvement in the comprehension of genotype–phenotype relationship of core myopathies can be expected in the next future: the actual lack of the human RyR1 crystal structure paired with the presence of large intrinsically disordered regions in RyR1, and the frequent presence of more than one RYR1 mutation in core myopathy patients, require designing novel investigation strategies to completely address RyR1 mutation effect.
KW - Central core disease
KW - Genotype–phenotype correlations
KW - Multi-minicore disease
KW - Neuromuscular disorder
KW - Protein modelling
KW - RYR1-related myopathies
KW - Central core disease
KW - Genotype–phenotype correlations
KW - Multi-minicore disease
KW - Neuromuscular disorder
KW - Protein modelling
KW - RYR1-related myopathies
UR - http://hdl.handle.net/10807/205830
U2 - 10.1186/s40478-022-01357-0
DO - 10.1186/s40478-022-01357-0
M3 - Article
SN - 2051-5960
VL - 10
SP - N/A-N/A
JO - Acta neuropathologica communications
JF - Acta neuropathologica communications
ER -