Missense variants in <i>TUBA4A</i> cause myo-tubulinopathies

Tubulinopathies encompass a spectrum of disorders resulting from variants in genes encoding α- and β-tubulins, the key components of microtubules. While previous studies have linked de novo or dominantly inherited TUBA4A missense variants to neurodegenerative phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, spastic ataxia, and recently, an isolated congenital myopathy, the full phenotypic and genotypic spectrum of TUBA4A-related disorders remains incompletely characterised. In this multi-centre study, we identified one previously reported and 12 novel TUBA4A missense variants in 31 individuals from 19 unrelated families. Remarkably, individuals in 17 families presented with a myopathy without any 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 along with protein aggregation. The coexistence of neuromuscular and neurodegenerative features with protein aggregation defines a multisystem proteinopathy. These two families thus establish the first association between TUBA4A and multisystem proteinopathy. Our cohort exhibited diverse genotypes and inheritance patterns: four families demonstrated autosomal dominant transmission through heterozygous variants in TUBA4A, three probands had recessive inheritance due to homozygous variants, while the respective heterozygous carriers were asymptomatic; five probands carried de novo variants, and nine probands with heterozygous variants were classified as sporadic cases. 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 variable, ranging from normal to highly elevated. Cardiac function remained preserved across the cohort. Muscle biopsies showed heterogenous myopathic changes, including myofibre size variation, nemaline bodies, core-like regions, and internal nuclei. Immunohistochemical analysis revealed protein accumulations positive for TDP-43 (n=2), p62 (n=5), and TUBA4A (n=6). Complementary in silico and in vitro investigations suggested that the identified TUBA4A variants cause significant protein abnormalities and may differentially impact microtubule dynamics. Correlation analyses integrating clinical severity, variant location, and mechanistic readouts further demonstrated that domain specificity within TUBA4A influences both the pattern of muscle involvement and the extent of microtubule disruption. 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 TUBA4A-related disorders beyond autosomal dominant or de novo mechanisms and neurodegenerative presentations. These results underscore the importance of considering TUBA4A variants in the differential diagnosis of axial myopathies and multisystem proteinopathies, regardless of central nervous system (CNS) involvement.

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Brain
Published
2026-02-11
DOI
https://doi.org/10.1093/brain/awag059
Primary Topic
Microtubule and mitosis dynamics
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article
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article

Missense variants in TUBA4A cause myo-tubulinopathies

Chiara Folland, Ekaterina Zakharova, Hannah R. Littel, Adele D’Amico et al.
Brain
Microtubule and mitosis dynamics
article

Missense variants in TUBA4A cause myo-tubulinopathies

Chiara Folland, Ekaterina Zakharova, Hannah R. Littel, Adele D’Amico, Michael Fahey, Machteld M. Oud, Clair Habib, Laura Donker Kaat, A. Beggs, Takeshi Tokito, Ana Kosać, Zaheer M. Valivullah, A. Perrin, Thatjana Gardeitchik, Ronald van Beek, Maria Ampleeva, Yasuhiro Kimoto, Nanna Scharff Poulsen, И. А. Чекмарева, G. Sole, Seth A. Stafki, Christine C. Bruels, Dmitri Atiakshin, C. Austin-Tse, Ana Töpf, Ichizo Nishino, Clara Gontijo Camelo, G. Tasca, Gianina Ravenscroft, S. V. Kurbatov, E. Zanoteli, Brian Mangilog, Casie A. Genetti, Yoshihiko Saito, Vedrana Milić Rašić, M. O'Leary, Ksenia S. Shirokova, Peter B. Kang, Andrea Ciolfi, Mridul Johari, Lynn Pais, Takashi Okabe, Charles Van Goethem, Francesca Clementina Radio, Mireille Cossée, Joe Nemoto, Cristiane A M Moreno, Gordana Kovacevic, Masaki Nakanowatari, Nicol C Voermans, Evita Medici, Bjarne Udd, Marie-Laure Martin-Négrier, Elicia A Estrella, Erik-Jan Kamsteeg, Yasushi Oya, Nigel G Laing, Jevin M Parmar, John Vissing, Louis M Kunkel
article en

Abstract

Tubulinopathies encompass a spectrum of disorders resulting from variants in genes encoding α- and β-tubulins, the key components of microtubules. While previous studies have linked de novo or dominantly inherited TUBA4A missense variants to neurodegenerative phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, spastic ataxia, and recently, an isolated congenital myopathy, the full phenotypic and genotypic spectrum of TUBA4A-related disorders remains incompletely characterised. In this multi-centre study, we identified one previously reported and 12 novel TUBA4A missense variants in 31 individuals from 19 unrelated families. Remarkably, individuals in 17 families presented with a myopathy without any 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 along with protein aggregation. The coexistence of neuromuscular and neurodegenerative features with protein aggregation defines a multisystem proteinopathy. These two families thus establish the first association between TUBA4A and multisystem proteinopathy. Our cohort exhibited diverse genotypes and inheritance patterns: four families demonstrated autosomal dominant transmission through heterozygous variants in TUBA4A, three probands had recessive inheritance due to homozygous variants, while the respective heterozygous carriers were asymptomatic; five probands carried de novo variants, and nine probands with heterozygous variants were classified as sporadic cases. 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 variable, ranging from normal to highly elevated. Cardiac function remained preserved across the cohort. Muscle biopsies showed heterogenous myopathic changes, including myofibre size variation, nemaline bodies, core-like regions, and internal nuclei. Immunohistochemical analysis revealed protein accumulations positive for TDP-43 (n=2), p62 (n=5), and TUBA4A (n=6). Complementary in silico and in vitro investigations suggested that the identified TUBA4A variants cause significant protein abnormalities and may differentially impact microtubule dynamics. Correlation analyses integrating clinical severity, variant location, and mechanistic readouts further demonstrated that domain specificity within TUBA4A influences both the pattern of muscle involvement and the extent of microtubule disruption. 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 TUBA4A-related disorders beyond autosomal dominant or de novo mechanisms and neurodegenerative presentations. These results underscore the importance of considering TUBA4A variants in the differential diagnosis of axial myopathies and multisystem proteinopathies, regardless of central nervous system (CNS) involvement.

Brain
Broad Institute (US), University of Miyazaki (JP), University of Copenhagen (DK), Boston Children's Hospital (US), Centre National de la Recherche Scientifique (FR), Radboud University Nijmegen (NL), Université de Bordeaux (FR), Inserm (FR), Yamaguchi University (JP), Université de Montpellier (FR), Harry Perkins Institute of Medical Research (AU), Voronezh State Medical Academy named after N.N. Burdenko (RU), Erasmus MC (NL), Copenhagen University Hospital (DK), Radboud University Medical Center (NL), Russian New University (RU), University of Belgrade (RS), Physiologie et Médecine Expérimentale du Coeur et des Muscles (FR), National Center of Neurology and Psychiatry (JP), Bordeaux Population Health (FR), Radboud Institute for Molecular Life Sciences (NL), Akebono Clinic (JP), Hôpital Pellegrin (FR), Shimonoseki City Hospital (JP), Institut de Génétique Moléculaire de Montpellier (FR), Bambino Gesù Children's Hospital (IT), Research Centre for Medical Genetics (RU), Ministry of Health (MN), NIHR Newcastle Biomedical Research Centre (GB), University of Minnesota Medical Center (US), Institute of Public Health of Serbia (RS), Shioda General Hospital (JP), University Children's Hospital, Belgrade (RS), Institut Universitaire de Recherche Clinique (FR), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (BR), National Medical Research Center of Cardiology (RU), Institute of Child and Mother Health (BD), Austin Health (AU), Folkhälsans Forskningscentrum (FI), Monash University (AU)
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