A novel syndrome caused by the E410K amino acid substitution in the neuronal β-tubulin isotype 3

Sheena Chew, Ravikumar Balasubramanian, Wai Man Chan, Peter B. Kang, Caroline Andrews, Bryn D. Webb, Sarah E. MacKinnon, Darren T. Oystreck, Jessica Rankin, Thomas O. Crawford, Michael Geraghty, Scott L. Pomeroy, William F. Crowley, Ethylin Wang Jabs, David G. Hunter, Patricia E. Grant, Elizabeth C. Engle

Research output: Contribution to journalArticle

Abstract

Missense mutations in TUBB3, the gene that encodes the neuronal-specific protein β-tubulin isotype 3, can cause isolated or syndromic congenital fibrosis of the extraocular muscles, a form of complex congenital strabismus characterized by cranial nerve misguidance. One of the eight TUBB3 mutations reported to cause congenital fibrosis of the extraocular muscles, c.1228G>A results in a TUBB3 E410K amino acid substitution that directly alters a kinesin motor protein binding site. We report the detailed phenotypes of eight unrelated individuals who harbour this de novo mutation, and thus define the 'TUBB3 E410K syndrome'. Individuals harbouring this mutation were previously reported to have congenital fibrosis of the extraocular muscles, facial weakness, developmental delay and possible peripheral neuropathy. We now confirm by electrophysiology that a progressive sensorimotor polyneuropathy does indeed segregate with the mutation, and expand the TUBB3 E410K phenotype to include Kallmann syndrome (hypogonadotropic hypogonadism and anosmia), stereotyped midface hypoplasia, intellectual disabilities and, in some cases, vocal cord paralysis, tracheomalacia and cyclic vomiting. Neuroimaging reveals a thin corpus callosum and anterior commissure, and hypoplastic to absent olfactory sulci, olfactory bulbs and oculomotor and facial nerves, which support underlying abnormalities in axon guidance and maintenance. Thus, the E410K substitution defines a new genetic aetiology for Moebius syndrome, Kallmann syndrome and cyclic vomiting. Moreover, the c.1228G>A mutation was absent in DNA from ∼600 individuals who had either Kallmann syndrome or isolated or syndromic ocular and/or facial dysmotility disorders, but who did not have the combined features of the TUBB3 E410K syndrome, highlighting the specificity of this phenotype-genotype correlation. The definition of the TUBB3 E410K syndrome will allow clinicians to identify affected individuals and predict the mutation based on clinical features alone.

Original languageEnglish (US)
Pages (from-to)522-535
Number of pages14
JournalBrain
Volume136
Issue number2
DOIs
StatePublished - Feb 2013

Keywords

  • CFEOM
  • Kallmann syndrome
  • TUBB3
  • cyclic vomiting
  • peripheral neuropathy

ASJC Scopus subject areas

  • Clinical Neurology

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  • Cite this

    Chew, S., Balasubramanian, R., Chan, W. M., Kang, P. B., Andrews, C., Webb, B. D., MacKinnon, S. E., Oystreck, D. T., Rankin, J., Crawford, T. O., Geraghty, M., Pomeroy, S. L., Crowley, W. F., Jabs, E. W., Hunter, D. G., Grant, P. E., & Engle, E. C. (2013). A novel syndrome caused by the E410K amino acid substitution in the neuronal β-tubulin isotype 3. Brain, 136(2), 522-535. https://doi.org/10.1093/brain/aws345