Expanding the clinical-pathological and genetic spectrum of RYR1-related congenital myopathies with cores and minicores: an Italian population study
Abstract 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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2022-04-01
|
| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40478-022-01357-0 |
| _version_ | 1818481252655693824 |
|---|---|
| author | Aurora Fusto Denise Cassandrini Chiara Fiorillo Valentina Codemo Guja Astrea Adele D’Amico Lorenzo Maggi Francesca Magri Marika Pane Giorgio Tasca Daniele Sabbatini Luca Bello Roberta Battini Pia Bernasconi Fabiana Fattori Enrico Silvio Bertini Giacomo Comi Sonia Messina Tiziana Mongini Isabella Moroni Chiara Panicucci Angela Berardinelli Alice Donati Vincenzo Nigro Antonella Pini Melania Giannotta Claudia Dosi Enzo Ricci Eugenio Mercuri Giovanni Minervini Silvio Tosatto Filippo Santorelli Claudio Bruno Elena Pegoraro |
| author_facet | Aurora Fusto Denise Cassandrini Chiara Fiorillo Valentina Codemo Guja Astrea Adele D’Amico Lorenzo Maggi Francesca Magri Marika Pane Giorgio Tasca Daniele Sabbatini Luca Bello Roberta Battini Pia Bernasconi Fabiana Fattori Enrico Silvio Bertini Giacomo Comi Sonia Messina Tiziana Mongini Isabella Moroni Chiara Panicucci Angela Berardinelli Alice Donati Vincenzo Nigro Antonella Pini Melania Giannotta Claudia Dosi Enzo Ricci Eugenio Mercuri Giovanni Minervini Silvio Tosatto Filippo Santorelli Claudio Bruno Elena Pegoraro |
| author_sort | Aurora Fusto |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-10T11:32:30Z |
| format | Article |
| id | doaj.art-3ed5f40b63494afb99f982bee9a3292a |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-10T11:32:30Z |
| publishDate | 2022-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-3ed5f40b63494afb99f982bee9a3292a2022-12-22T01:50:31ZengBMCActa Neuropathologica Communications2051-59602022-04-0110112010.1186/s40478-022-01357-0Expanding the clinical-pathological and genetic spectrum of RYR1-related congenital myopathies with cores and minicores: an Italian population studyAurora Fusto0Denise Cassandrini1Chiara Fiorillo2Valentina Codemo3Guja Astrea4Adele D’Amico5Lorenzo Maggi6Francesca Magri7Marika Pane8Giorgio Tasca9Daniele Sabbatini10Luca Bello11Roberta Battini12Pia Bernasconi13Fabiana Fattori14Enrico Silvio Bertini15Giacomo Comi16Sonia Messina17Tiziana Mongini18Isabella Moroni19Chiara Panicucci20Angela Berardinelli21Alice Donati22Vincenzo Nigro23Antonella Pini24Melania Giannotta25Claudia Dosi26Enzo Ricci27Eugenio Mercuri28Giovanni Minervini29Silvio Tosatto30Filippo Santorelli31Claudio Bruno32Elena Pegoraro33Department of Neurosciences DNS, University of PadovaMolecular Medicine Unit, IRCCS Fondazione Stella MarisPaediatric Neurology and Neuromuscular Disorders Unit, IRCCS Istituto Giannina Gaslini, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of GenovaDepartment of Neurosciences DNS, University of PadovaDepartment of Neuroscience, IRCCS Fondazione Stella MarisMolecular Medicine Unit, Ospedale Bambin GesùNeuroimmunology and Neuromuscular Disorders Unit, Foundation IRCCS Neurological Institute “C. Besta”Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, I.R.C.C.S. Foundation Cà Granda, Ospedale Maggiore PoliclinicoDepartment of Paediatric Neurology, Catholic UniversityUnità Operativa Complessa Di Neurologia, Fondazione Policlinico Universitario A. Gemelli IRCCSDepartment of Neurosciences DNS, University of PadovaDepartment of Neurosciences DNS, University of PadovaMolecular Medicine Unit, IRCCS Fondazione Stella MarisNeuroimmunology and Neuromuscular Disorders Unit, Foundation IRCCS Neurological Institute “C. Besta”Department of Neuroscience, IRCCS Fondazione Stella MarisDepartment of Neuroscience, IRCCS Fondazione Stella MarisDino Ferrari Centre, Department of Neurological Sciences, University of Milan, I.R.C.C.S. Foundation Cà Granda, Ospedale Maggiore PoliclinicoDepartment of Neurosciences, Psychiatry and Anaesthesiology, University of MessinaSG. Battista Hospital, Neuromuscular Center, University of TurinChild Neurology Department, Neurological Institute C. Besta Foundation IRCCSCenter of Translational and Experimental Myology, IRCCS Istituto Giannina Gaslini, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of GenovaChild and Adolescent Unit, IRCCS C. Mondino FoundationMetabolic Disease Unit, AOU Meyer Children Hospital“Luigi Vanvitelli” University and Telethon Institute of Genetics and Medicine (TIGEM)Child Neurology and Psychiatry Unit, IRCCS Istituto Delle Scienze Neurologiche Di BolognaChild Neurology and Psychiatry Unit, IRCCS Istituto Delle Scienze Neurologiche Di BolognaMolecular Medicine Unit, IRCCS Fondazione Stella MarisDepartment of Paediatric Neurology, Catholic UniversityDepartment of Paediatric Neurology, Catholic UniversityDepartment of Biomedical Sciences, University of PadovaDepartment of Biomedical Sciences, University of PadovaMolecular Medicine Unit, IRCCS Fondazione Stella MarisCenter of Translational and Experimental Myology, IRCCS Istituto Giannina Gaslini, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of GenovaDepartment of Neurosciences DNS, University of PadovaAbstract 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.https://doi.org/10.1186/s40478-022-01357-0RYR1-related myopathiesCentral core diseaseMulti-minicore diseaseGenotype–phenotype correlationsNeuromuscular disorderProtein modelling |
| spellingShingle | Aurora Fusto Denise Cassandrini Chiara Fiorillo Valentina Codemo Guja Astrea Adele D’Amico Lorenzo Maggi Francesca Magri Marika Pane Giorgio Tasca Daniele Sabbatini Luca Bello Roberta Battini Pia Bernasconi Fabiana Fattori Enrico Silvio Bertini Giacomo Comi Sonia Messina Tiziana Mongini Isabella Moroni Chiara Panicucci Angela Berardinelli Alice Donati Vincenzo Nigro Antonella Pini Melania Giannotta Claudia Dosi Enzo Ricci Eugenio Mercuri Giovanni Minervini Silvio Tosatto Filippo Santorelli Claudio Bruno Elena Pegoraro Expanding the clinical-pathological and genetic spectrum of RYR1-related congenital myopathies with cores and minicores: an Italian population study Acta Neuropathologica Communications RYR1-related myopathies Central core disease Multi-minicore disease Genotype–phenotype correlations Neuromuscular disorder Protein modelling |
| title | Expanding the clinical-pathological and genetic spectrum of RYR1-related congenital myopathies with cores and minicores: an Italian population study |
| title_full | Expanding the clinical-pathological and genetic spectrum of RYR1-related congenital myopathies with cores and minicores: an Italian population study |
| title_fullStr | Expanding the clinical-pathological and genetic spectrum of RYR1-related congenital myopathies with cores and minicores: an Italian population study |
| title_full_unstemmed | Expanding the clinical-pathological and genetic spectrum of RYR1-related congenital myopathies with cores and minicores: an Italian population study |
| title_short | Expanding the clinical-pathological and genetic spectrum of RYR1-related congenital myopathies with cores and minicores: an Italian population study |
| title_sort | expanding the clinical pathological and genetic spectrum of ryr1 related congenital myopathies with cores and minicores an italian population study |
| topic | RYR1-related myopathies Central core disease Multi-minicore disease Genotype–phenotype correlations Neuromuscular disorder Protein modelling |
| url | https://doi.org/10.1186/s40478-022-01357-0 |
| work_keys_str_mv | AT aurorafusto expandingtheclinicalpathologicalandgeneticspectrumofryr1relatedcongenitalmyopathieswithcoresandminicoresanitalianpopulationstudy AT denisecassandrini expandingtheclinicalpathologicalandgeneticspectrumofryr1relatedcongenitalmyopathieswithcoresandminicoresanitalianpopulationstudy AT chiarafiorillo expandingtheclinicalpathologicalandgeneticspectrumofryr1relatedcongenitalmyopathieswithcoresandminicoresanitalianpopulationstudy AT valentinacodemo expandingtheclinicalpathologicalandgeneticspectrumofryr1relatedcongenitalmyopathieswithcoresandminicoresanitalianpopulationstudy AT gujaastrea expandingtheclinicalpathologicalandgeneticspectrumofryr1relatedcongenitalmyopathieswithcoresandminicoresanitalianpopulationstudy AT adeledamico expandingtheclinicalpathologicalandgeneticspectrumofryr1relatedcongenitalmyopathieswithcoresandminicoresanitalianpopulationstudy AT lorenzomaggi expandingtheclinicalpathologicalandgeneticspectrumofryr1relatedcongenitalmyopathieswithcoresandminicoresanitalianpopulationstudy AT francescamagri expandingtheclinicalpathologicalandgeneticspectrumofryr1relatedcongenitalmyopathieswithcoresandminicoresanitalianpopulationstudy AT marikapane expandingtheclinicalpathologicalandgeneticspectrumofryr1relatedcongenitalmyopathieswithcoresandminicoresanitalianpopulationstudy AT giorgiotasca expandingtheclinicalpathologicalandgeneticspectrumofryr1relatedcongenitalmyopathieswithcoresandminicoresanitalianpopulationstudy AT danielesabbatini expandingtheclinicalpathologicalandgeneticspectrumofryr1relatedcongenitalmyopathieswithcoresandminicoresanitalianpopulationstudy AT lucabello expandingtheclinicalpathologicalandgeneticspectrumofryr1relatedcongenitalmyopathieswithcoresandminicoresanitalianpopulationstudy AT robertabattini expandingtheclinicalpathologicalandgeneticspectrumofryr1relatedcongenitalmyopathieswithcoresandminicoresanitalianpopulationstudy AT piabernasconi expandingtheclinicalpathologicalandgeneticspectrumofryr1relatedcongenitalmyopathieswithcoresandminicoresanitalianpopulationstudy AT fabianafattori expandingtheclinicalpathologicalandgeneticspectrumofryr1relatedcongenitalmyopathieswithcoresandminicoresanitalianpopulationstudy AT enricosilviobertini expandingtheclinicalpathologicalandgeneticspectrumofryr1relatedcongenitalmyopathieswithcoresandminicoresanitalianpopulationstudy AT giacomocomi expandingtheclinicalpathologicalandgeneticspectrumofryr1relatedcongenitalmyopathieswithcoresandminicoresanitalianpopulationstudy AT soniamessina expandingtheclinicalpathologicalandgeneticspectrumofryr1relatedcongenitalmyopathieswithcoresandminicoresanitalianpopulationstudy AT tizianamongini expandingtheclinicalpathologicalandgeneticspectrumofryr1relatedcongenitalmyopathieswithcoresandminicoresanitalianpopulationstudy AT isabellamoroni expandingtheclinicalpathologicalandgeneticspectrumofryr1relatedcongenitalmyopathieswithcoresandminicoresanitalianpopulationstudy AT chiarapanicucci expandingtheclinicalpathologicalandgeneticspectrumofryr1relatedcongenitalmyopathieswithcoresandminicoresanitalianpopulationstudy AT angelaberardinelli expandingtheclinicalpathologicalandgeneticspectrumofryr1relatedcongenitalmyopathieswithcoresandminicoresanitalianpopulationstudy AT alicedonati expandingtheclinicalpathologicalandgeneticspectrumofryr1relatedcongenitalmyopathieswithcoresandminicoresanitalianpopulationstudy AT vincenzonigro expandingtheclinicalpathologicalandgeneticspectrumofryr1relatedcongenitalmyopathieswithcoresandminicoresanitalianpopulationstudy AT antonellapini expandingtheclinicalpathologicalandgeneticspectrumofryr1relatedcongenitalmyopathieswithcoresandminicoresanitalianpopulationstudy AT melaniagiannotta expandingtheclinicalpathologicalandgeneticspectrumofryr1relatedcongenitalmyopathieswithcoresandminicoresanitalianpopulationstudy AT claudiadosi expandingtheclinicalpathologicalandgeneticspectrumofryr1relatedcongenitalmyopathieswithcoresandminicoresanitalianpopulationstudy AT enzoricci expandingtheclinicalpathologicalandgeneticspectrumofryr1relatedcongenitalmyopathieswithcoresandminicoresanitalianpopulationstudy AT eugeniomercuri expandingtheclinicalpathologicalandgeneticspectrumofryr1relatedcongenitalmyopathieswithcoresandminicoresanitalianpopulationstudy AT giovanniminervini expandingtheclinicalpathologicalandgeneticspectrumofryr1relatedcongenitalmyopathieswithcoresandminicoresanitalianpopulationstudy AT silviotosatto expandingtheclinicalpathologicalandgeneticspectrumofryr1relatedcongenitalmyopathieswithcoresandminicoresanitalianpopulationstudy AT filipposantorelli expandingtheclinicalpathologicalandgeneticspectrumofryr1relatedcongenitalmyopathieswithcoresandminicoresanitalianpopulationstudy AT claudiobruno expandingtheclinicalpathologicalandgeneticspectrumofryr1relatedcongenitalmyopathieswithcoresandminicoresanitalianpopulationstudy AT elenapegoraro expandingtheclinicalpathologicalandgeneticspectrumofryr1relatedcongenitalmyopathieswithcoresandminicoresanitalianpopulationstudy |