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


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 alpha and beta 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.

Type Journal
ISBN 1476-5438 (Electronic) 1018-4813 (Linking)
Authors Jurgens, J. A.; Barry, B. J.; Lemire, G.; Chan, W. M.; Whitman, M. C.; Shaaban, S.; Robson, C. D.; MacKinnon, S.; England, E. M.; McMillan, H. J.; Kelly, C.; Pratt, B. M.; Care4Rare Canada, Consortium; O'Donnell-Luria, A.; MacArthur, D. G.; Boycott, K. M.; Hunter, D. G.; Engle, E. C.
Responsible Garvan Author Prof Daniel MacArthur
Published Date 2021-05-30
Published Volume 29
Published Issue 5
Published Pages 816-826
Status Published in-print
DOI 10.1038/s41431-020-00804-7
URL link to publisher's version