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Novel variants in TUBA1A cause congenital fibrosis of the extraocular muscles with or without malformations of cortical brain development

European Journal of Human Genetics volume 29, pages 816–826 (2021)Cite this article

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Abstract

Variants in multiple tubulin genes have been implicated in neurodevelopmental disorders, including malformations of cortical development (MCD) and congenital fibrosis of the extraocular muscles (CFEOM). Distinct missense variants in the beta-tubulin encoding genes TUBB3 and TUBB2B cause MCD, CFEOM, or both, suggesting substitution-specific mechanisms. Variants in the alpha tubulin-encoding gene TUBA1A have been associated with MCD, but not with CFEOM. Using exome sequencing (ES) and genome sequencing (GS), we identified 3 unrelated probands with CFEOM who harbored novel heterozygous TUBA1A missense variants c.1216C>G, p.(His406Asp); c.467G>A, p.(Arg156His); and c.1193T>G, p.(Met398Arg). MRI revealed small oculomotor-innervated muscles and asymmetrical caudate heads and lateral ventricles with or without corpus callosal thinning. Two of the three probands had MCD. Mutated amino acid residues localize either to the longitudinal interface at which α and β tubulins heterodimerize (Met398, His406) or to the lateral interface at which tubulin protofilaments interact (Arg156), and His406 interacts with the motor domain of kinesin-1. This series of individuals supports TUBA1A variants as a cause of CFEOM and expands our knowledge of tubulinopathies.

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Fig. 1: TUBA1A variants are associated with CFEOM.
Fig. 2: Brain MRI demonstrates features of classic tubulinopathies with or without MCD.
Fig. 3: Structural modeling of tubulinopathy variants.

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Acknowledgements

We thank the participants and their family members, Dr. Monkol Lek and Mr. Ben Weisburd for their efforts in reprocessing and upload of sequence data for analysis at the Broad Institute, and Dr. Dan Doherty of the University of Washington for connecting the Bostonian and Canadian researchers.

Funding

This project was supported by NEI R01EY027421 and NHLBI X01HL132377 (ECE), the Broad Institute of MIT and Harvard Center for Mendelian Genomics (NHGRI/NEI/NHLBI UM1HG008900), the Ocular Genomics Institute Genomics Core (Massachusetts Eye and Ear Infirmary/Harvard Medical School, NEI 2P30EY014104), NHGRI R01HG009141, the Care4Rare Canada Consortium funded by Genome Canada and the Ontario Genomics Institute (OGI-147), the Canadian Institutes of Health Research, Ontario Research Fund, Genome Alberta, Genome British Columbia, Genome Quebec, and Children’s Hospital of Eastern Ontario Foundation. JJ was supported by T32GM007748-42, 5T32NS007473-19, and 5T32EY007145-16. MW was supported by NEI 5K08EY027850 and BCH Ophthalmology Foundation Faculty Discovery Award. MW, SM, and DH receive research support from Children’s Hospital Ophthalmology Foundation, Inc., Boston, MA. KMB is a Tier 1 Canada Research Chair in Rare Disease Precision Health. ECE is a Howard Hughes Medical Institute Investigator.

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Authors and Affiliations

  1. F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, USA

    Julie A. Jurgens, Wai-Man Chan, Mary C. Whitman, Sherin Shaaban, Brandon M. Pratt & Elizabeth C. Engle

  2. Department of Neurology, Boston Children’s Hospital, Boston, MA, USA

    Julie A. Jurgens, Brenda J. Barry, Wai-Man Chan, Sherin Shaaban, Brandon M. Pratt & Elizabeth C. Engle

  3. Department of Neurology, Harvard Medical School, Boston, MA, USA

    Julie A. Jurgens, Wai-Man Chan, Sherin Shaaban, Brandon M. Pratt & Elizabeth C. Engle

  4. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Julie A. Jurgens, Wai-Man Chan & Elizabeth C. Engle

  5. Howard Hughes Medical Institute, Chevy Chase, MD, USA

    Brenda J. Barry, Wai-Man Chan & Elizabeth C. Engle

  6. Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada

    Gabrielle Lemire & Kym M. Boycott

  7. Department of Ophthalmology, Boston Children’s Hospital, Boston, MA, USA

    Mary C. Whitman, Sarah MacKinnon, David G. Hunter & Elizabeth C. Engle

  8. Department of Ophthalmology, Harvard Medical School, Boston, MA, USA

    Mary C. Whitman, Sarah MacKinnon, David G. Hunter & Elizabeth C. Engle

  9. Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA

    Sherin Shaaban

  10. Division of Neuroradiology, Department of Radiology, Boston Children’s Hospital, Boston, MA, USA

    Caroline D. Robson

  11. Department of Radiology, Harvard Medical School, Boston, MA, USA

    Caroline D. Robson

  12. Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Eleina M. England, Anne O’Donnell-Luria & Daniel G. MacArthur

  13. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA

    Eleina M. England, Anne O’Donnell-Luria & Daniel G. MacArthur

  14. Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, USA

    Eleina M. England & Anne O’Donnell-Luria

  15. Division of Neurology, Department of Pediatrics, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada

    Hugh J. McMillan

  16. Pediatric Ophthalmology and Physician Informatics, MultiCare Health System, Tacoma, WA, USA

    Christopher Kelly

  17. Centre for Population Genomics, Garvan Institute of Medical Research and UNSW, Sydney, NSW, Australia

    Daniel G. MacArthur

  18. Murdoch Children’s Research Institute, Parkville, VIC, Australia

    Daniel G. MacArthur

  19. Department of Genetics, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada

    Kym M. Boycott

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Correspondence to Elizabeth C. Engle.

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Jurgens, J.A., Barry, B.J., Lemire, G. et al. Novel variants in TUBA1A cause congenital fibrosis of the extraocular muscles with or without malformations of cortical brain development. Eur J Hum Genet 29, 816–826 (2021). https://doi.org/10.1038/s41431-020-00804-7

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