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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
A novel syndrome caused by the E410K amino acid substitution in the neuronal β-tubulin isotype 3
Brain, Volume 136, No. 2, Year 2013
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Description
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. © 2013 The Author.
Authors & Co-Authors
Chew, Sheena
United States, Boston
Boston Children's Hospital
United States, Boston
Harvard Medical School
United States, Chevy Chase
Howard Hughes Medical Institute
Chan, Waiman
United States, Boston
Boston Children's Hospital
United States, Chevy Chase
Howard Hughes Medical Institute
Kang, Peter B.
United States, Boston
Boston Children's Hospital
United States, Boston
Harvard Medical School
Andrews, Caroline V.
United States, Boston
Boston Children's Hospital
United States, Boston
Harvard Medical School
United States, Chevy Chase
Howard Hughes Medical Institute
Webb, Bryn D.
United States, New York
Icahn School of Medicine at Mount Sinai
MacKinnon, Sarah E.
United States, Boston
Boston Children's Hospital
Oystreck, Darren T.
United States, Boston
Boston Children's Hospital
Geraghty, Michael T.
Canada, Ottawa
University of Ottawa
Pomeroy, Scott L.
United States, Boston
Boston Children's Hospital
United States, Boston
Harvard Medical School
United States, Cambridge
Massachusetts Institute of Technology
Jabs, Ethylin Wang
United States, New York
Icahn School of Medicine at Mount Sinai
Hunter, David G.
United States, Boston
Boston Children's Hospital
Grant, Patricia Ellen
United States, Boston
Boston Children's Hospital
Engle, Elizabeth C.
United States, Boston
Boston Children's Hospital
United States, Boston
Harvard Medical School
United States, Chevy Chase
Howard Hughes Medical Institute
United States, Cambridge
Massachusetts Institute of Technology
Statistics
Citations: 96
Authors: 13
Affiliations: 8
Identifiers
Doi:
10.1093/brain/aws345
ISSN:
00068950
Research Areas
Cancer
Genetics And Genomics