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Am J Med Genet A. 2016 Feb;170A(2):297-305. doi: 10.1002/ajmg.a.37362. Epub 2015 Dec 6.

Two unique TUBB3 mutations cause both CFEOM3 and malformations of cortical development.

Whitman MC1,2,3, Andrews C3,4,5,6, Chan WM3,4,5,6,7, Tischfield MA3,4,5, Stasheff SF8, Brancati F9, Ortiz-Gonzalez X10, Nuovo S11, Garaci F12, MacKinnon SE1, Hunter DG1,2, Grant PE13, Engle EC1,2,3,4,5,6,7,14,15,16.

Author information

1
Department of Ophthalmology, Boston Children's Hospital, Boston, Massachusetts.
2
Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.
3
FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts.
4
Department of Neurology, Boston Children's Hospital, Boston, Massachusetts.
5
Department of Neurology, Harvard Medical School, Boston, Massachusetts.
6
Howard Hughes Medical Institute, Chevy Chase, Maryland.
7
Program in Genomics, Boston Children's Hospital, Boston, Massachusetts.
8
Departments of Pediatrics (Neurology), Ophthalmology and Visual Sciences, Neurology and Biomedical Engineering, University of Iowa, Iowa City, Iowa.
9
Department of Medical, Oral and Biotechnological Sciences, Gabriele d'Annunzio University, Chieti, Italy.
10
Department of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
11
Department of Biomedicine and Prevention, Tor Vergata University, Rome, Italy.
12
Department of Diagnostic Imaging, Molecular Imaging, Interventional Radiology and Radiotherapy, Tor Vergata University, Rome, Italy.
13
Department of Radiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
14
Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
15
The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts.
16
Department of Medicine (Genetics), Boston Children's Hospital, Boston, Massachusetts.

Abstract

One set of missense mutations in the neuron specific beta tubulin isotype 3 (TUBB3) has been reported to cause malformations of cortical development (MCD), while a second set has been reported to cause isolated or syndromic Congenital Fibrosis of the Extraocular Muscles type 3 (CFEOM3). Because TUBB3 mutations reported to cause CFEOM had not been associated with cortical malformations, while mutations reported to cause MCD had not been associated with CFEOM or other forms of paralytic strabismus, it was hypothesized that each set of mutations might alter microtubule function differently. Here, however, we report two novel de novo heterozygous TUBB3 amino acid substitutions, G71R and G98S, in four patients with both MCD and syndromic CFEOM3. These patients present with moderately severe CFEOM3, nystagmus, torticollis, and developmental delay, and have intellectual and social disabilities. Neuroimaging reveals defective cortical gyration, as well as hypoplasia or agenesis of the corpus callosum and anterior commissure, malformations of hippocampi, thalami, basal ganglia and cerebella, and brainstem and cranial nerve hypoplasia. These new TUBB3 substitutions meld the two previously distinct TUBB3-associated phenotypes, and implicate similar microtubule dysfunction underlying both.

KEYWORDS:

TUBB3; congenital fibrosis of extraocular muscles; cortical development; tubulin; tubulinopathy

PMID:
26639658
PMCID:
PMC4770801
DOI:
10.1002/ajmg.a.37362
[Indexed for MEDLINE]
Free PMC Article

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