title: A novel syndrome caused by the E410K amino acid substitution in the neuronal β-tubulin isotype 3.
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.
authors: Department of Neurology, Boston Children’s Hospital, Boston, MA 02115, USA.
authors: Sheena
authors: S
authors: Chew
authors: Ravikumar
authors: R
authors: Balasubramanian
authors: Wai-Man
authors: WM
authors: Chan
authors: Peter B
authors: PB
authors: Kang
authors: Caroline
authors: C
authors: Andrews
authors: Bryn D
authors: BD
authors: Webb
authors: Sarah E
authors: SE
authors: MacKinnon
authors: Darren T
authors: DT
authors: Oystreck
authors: Jessica
authors: J
authors: Rankin
authors: Thomas O
authors: TO
authors: Crawford
authors: Michael
authors: M
authors: Geraghty
authors: Scott L
authors: SL
authors: Pomeroy
authors: William F
authors: WF
authors: Crowley
authors: Ethylin Wang
authors: EW
authors: Jabs
authors: David G
authors: DG
authors: Hunter
authors: Patricia E
authors: PE
authors: Grant
authors: Elizabeth C
authors: EC
authors: Engle
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics*; D002648:Child; D005260:Female; D006801:Humans; D017436:Kallmann Syndrome / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D020331:Mobius Syndrome / Q000175:diagnosis / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D009474:Neurons / Q000502:physiology*; D010375:Pedigree; D014404:Tubulin / Q000235:genetics*; D014839:Vomiting / Q000175:diagnosis / Q000235:genetics*; D055815:Young Adult
chemical_list: C498585:TUBB3 protein, human; D014404:Tubulin
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