Missense variants in TUBA4A cause myo-tubulinopathies

Mridul Johari; Chiara Folland; Yoshihiko Saito; Machteld M Oud; Jevin M Parmar; Ana Töpf; Sergei Kurbatov; Maria Ampleeva; Ekaterina Y Zakharova; Irina A Chekmareva; Ksenia S Shirokova; Dmitrii Atiakshin; Thatjana Gardeitchik; Erik-Jan Kamsteeg; Evita Medici; Laura Donker Kaat; Christine C Bruels; Seth A Stafki; Elicia A Estrella; Hannah R Littel; Louis M Kunkel; Peter B Kang; Ikeoluwa Osei-Owusu; Lynn Pais; Melaine O'Leary; Christina Austin-Tse; Anne O'Donnell-Luria; Brian Mangilog; Francesca Clementina Radio; Adele D'Amico; Andrea Ciolfi; Marco Tartaglia; Aurélien Perrin; Charles Van Goethem; Guilhem Sole; Marie-Laure Martin-Négrier; Mireille Cossée; Casie A Genetti; Zaheer M Valivullah; Vedrana Milic; Gordana Kovacevic; Ana Kosac; Cristiane A M Moreno; Clara Gontijo Camelo; Edmar Zanoteli; Michael C Fahey; Alan H Beggs; John Vissing; Volker Straub; Marco Savarese; Giorgio Tasca; Nicol Voermans; Nigel G Laing; Bjarne Udd; Ichizo Nishino; Gianina Ravenscroft

doi:10.1101/2025.06.26.25330266

Prépublication

Missense variants in TUBA4A cause myo-tubulinopathies

Mridul Johari, Chiara Folland, Yoshihiko Saito, Machteld M Oud, Jevin M Parmar, Ana Töpf, Sergei Kurbatov, Maria Ampleeva, Ekaterina Y Zakharova, Irina A Chekmareva, …

medRxiv : the preprint server for health sciences

28/06/2025

DOI: https://doi.org/10.1101/2025.06.26.25330266

PMID: 40666348

Résumé

tubulin

autophagy

protein aggregate myopathy

tubulinopathy

genotype-phenotype correlation

Tubulinopathies encompass a wide spectrum of disorders resulting from variants in genes encoding α- and β-tubulins, the key components of microtubules. While previous studies have linked or dominantly inherited missense variants to neurodegenerative phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, hereditary spastic ataxia, and more recently, an isolated report of congenital myopathy, the full phenotypic and genotypic spectrum of -related disorders remains incompletely characterised. In this multi-centre study, we identified 13 novel missense variants in 31 individuals from 19 unrelated families. Remarkably, affected individuals in 17 families presented with a primary axial myopathy without any identified CNS involvement or history of such disease. In the remaining two families, we observed probands with cerebellar ataxia and epilepsy accompanying proximal and axial muscle weakness, establishing the first documented association between variants and multisystem proteinopathy. Our cohort exhibited diverse genotypes and associated inheritance patterns: four families demonstrated autosomal dominant transmission through heterozygous variants in , three probands had homozygous variants, where the biallelic genotype was found to be associated with the disease, and the heterozygous carriers were asymptomatic; five probands carried variants, and nine probands with heterozygous variants were classified as "isolated-sporadic cases" where parental samples were unavailable. Clinical phenotypes ranged from mild to severe myopathy, predominantly affecting the axial and paraspinal muscles. We observed a range of disease onset, from congenital to late adulthood. Creatine kinase levels were also variable, ranging from normal to highly elevated. Cardiac function remained preserved across the cohort. Muscle biopsies revealed a range of pathologies, including myofibre size variation, myofibre atrophy, nemaline bodies, core-like regions, internal nuclei, and endomysial fibrosis. Immunohistochemical staining showed evidence of proteinopathy, with autophagic features and TUBA4A accumulation in patient myofibres. Complementary and investigations suggested that the identified substitutions cause significant protein abnormalities and may differentially impact microtubule dynamics. Our findings establish myo-tubulinopathies as distinct clinical entities, encompassing both primary myopathies and multisystem proteinopathies with muscle involvement. This study broadens the phenotypic and genotypic spectrum of -related disorders beyond autosomal dominant or mechanisms and neurodegenerative presentations. These results underscore the importance of considering variants in the differential diagnosis of axial myopathies and multisystem proteinopathies, regardless of central nervous system (CNS) involvement.

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Détails

Titre: Missense variants in TUBA4A cause myo-tubulinopathies
Créateurs - sans rôle: Mridul Johari - Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, WA, Australia
Chiara Folland - Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, WA, Australia
Yoshihiko Saito - Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan
Machteld M Oud - Radboud University Medical Center
Jevin M Parmar - Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, WA, Australia
Ana Töpf - John Walton Muscular Dystrophy Research Centre, NIHR Newcastle Biomedical Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
Sergei Kurbatov - Research Institute of Experimental Biology and Medicine, Voronezh State Medical University named after N.N. Burdenko, Voronezh, Russian Federation
Maria Ampleeva - Independent Clinical Bioinformatics Laboratory, Moscow, Russia
Ekaterina Y Zakharova - Research Centre for Medical Genetics
Irina A Chekmareva - Federal State Budgetary Institution "National Medical Research Center of Surgery named after A. Vishnevsky", Ministry of Health of the Russian Federation, Moscow, Russia
Ksenia S Shirokova - Research Institute of Experimental Biology and Medicine, Voronezh State Medical University named after N.N. Burdenko, Voronezh, Russian Federation
Dmitrii Atiakshin - RUDN University, Moscow, Russian Federation
Thatjana Gardeitchik - Radboud University Medical Center
Erik-Jan Kamsteeg - Dept Human Genetics, Radboudumc, Nijmegen, The Netherlands
Evita Medici - Dept Neurology, Erasmus University Medical Center Rotterdam, The Netherlands
Laura Donker Kaat - Dept Clinical Genetics, Erasmus University Medical Center Rotterdam, The Netherlands
Christine C Bruels - Greg Marzolf Jr. Muscular Dystrophy Center, Department of Neurology, University of Minnesota Medical School
Seth A Stafki - Greg Marzolf Jr. Muscular Dystrophy Center, Department of Neurology, University of Minnesota Medical School
Elicia A Estrella - Division of Genetics & Genomics, Boston Children's Hospital and Harvard Medical School
Hannah R Littel - Greg Marzolf Jr. Muscular Dystrophy Center, Department of Neurology, University of Minnesota Medical School
Louis M Kunkel - Division of Genetics & Genomics, Boston Children's Hospital and Harvard Medical School
Peter B Kang - University of Minnesota Medical School
Ikeoluwa Osei-Owusu - Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Lynn Pais - Broad Institute
Melaine O'Leary - Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Christina Austin-Tse - Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Anne O'Donnell-Luria - Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Brian Mangilog - Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Francesca Clementina Radio - Molecular Genetics and Functional Genomics, Bambino Gesù Children's Hospital, IRCCS, 00146, Rome, Italy
Adele D'Amico - Neuromuscular and neurodegenerative disorders, Bambino Gesù Children's Hospital, IRCCS, 00146, Rome, Italy
Andrea Ciolfi - Bambino Gesù Children's Hospital
Marco Tartaglia - Molecular Genetics and Functional Genomics, Bambino Gesù Children's Hospital, IRCCS, 00146, Rome, Italy
Aurélien Perrin - Centre Hospitalier Universitaire de Montpellier
Charles Van Goethem - Centre Hospitalier Universitaire de Montpellier
Guilhem Sole - Neurology and Neuromuscular Diseases Department, Neuromuscular Reference Centre AOC, FILNEMUS, EURO-NMD, Pellegrin Hospital, Bordeaux University Hospitals, Bordeaux, France
Marie-Laure Martin-Négrier - Pathology Department, University Hospital of Bordeaux, France. Univ. Bordeaux, CNRS UMR5293, Bordeaux, France
Mireille Cossée - Centre Hospitalier Universitaire de Montpellier
Casie A Genetti - Boston Children's Hospital
Zaheer M Valivullah - Center for Mendelian Genomics, Broad Institute Harvard, Cambridge, MA 02142, USA
Vedrana Milic - Clinic for Neurology and Psychiatry for Children and Youth,Belgrade,Serbia
Gordana Kovacevic - Mother and Child Health Care Institute,Belgrade,Serbia
Ana Kosac - Clinic for Neurology and Psychiatry for Children and Youth, Belgrade, Serbia
Cristiane A M Moreno - Department of Neurology, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo. Brazil
Clara Gontijo Camelo - Department of Neurology, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo. Brazil
Edmar Zanoteli - Universidade de São Paulo
Michael C Fahey - Monash University
Alan H Beggs - Boston Children's Hospital
John Vissing - University of Copenhagen
Volker Straub - John Walton Muscular Dystrophy Research Centre, NIHR Newcastle Biomedical Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
Marco Savarese - Folkhälsan Research Center, Helsinki, Finland
Giorgio Tasca - John Walton Muscular Dystrophy Research Centre, NIHR Newcastle Biomedical Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
Nicol Voermans - Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Amalia Children's Hospital, Radboud University Medical Centre, Nijmegen, The Netherlands
Nigel G Laing - Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, WA, Australia
Bjarne Udd - Folkhälsan Research Center, Helsinki, Finland
Ichizo Nishino - Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan
Gianina Ravenscroft - Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, WA, Australia
Détails de publication: medRxiv : the preprint server for health sciences
Éditeur: United States
Note de subvention: P50 HD105351 / NICHD NIH HHS UM1 HG008900 / NHGRI NIH HHS U01 HG011755 / NHGRI NIH HHS R01 HG009141 / NHGRI NIH HHS
Identifiants: 99148700009311
Unité académique: Physiologie et Médecine Expérimentale du coeur et des muscles - PhyMedExp
Langue: English
Type de ressource: Preprint