title: Two unique TUBB3 mutations cause both CFEOM3 and malformations of cortical development.
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.
authors.affiliation: Department of Ophthalmology, Boston Children's Hospital, Boston, Massachusetts.|Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.|FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Mary C
authors.initials: MC
authors.lastname: Whitman
authors.affiliation: FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts.|Department of Neurology, Boston Children's Hospital, Boston, Massachusetts.|Department of Neurology, Harvard Medical School, Boston, Massachusetts.|Howard Hughes Medical Institute, Chevy Chase, Maryland.
authors.forename: Caroline
authors.initials: C
authors.lastname: Andrews
authors.affiliation: FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts.|Department of Neurology, Boston Children's Hospital, Boston, Massachusetts.|Department of Neurology, Harvard Medical School, Boston, Massachusetts.|Howard Hughes Medical Institute, Chevy Chase, Maryland.|Program in Genomics, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Wai-Man
authors.initials: WM
authors.lastname: Chan
authors.affiliation: FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts.|Department of Neurology, Boston Children's Hospital, Boston, Massachusetts.|Department of Neurology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Max A
authors.initials: MA
authors.lastname: Tischfield
authors.affiliation: Departments of Pediatrics (Neurology), Ophthalmology and Visual Sciences, Neurology and Biomedical Engineering, University of Iowa, Iowa City, Iowa.
authors.forename: Steven F
authors.initials: SF
authors.lastname: Stasheff
authors.affiliation: Department of Medical, Oral and Biotechnological Sciences, Gabriele d'Annunzio University, Chieti, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Brancati
authors.affiliation: Department of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Xilma
authors.initials: X
authors.lastname: Ortiz-Gonzalez
authors.affiliation: Department of Biomedicine and Prevention, Tor Vergata University, Rome, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Nuovo
authors.affiliation: Department of Diagnostic Imaging, Molecular Imaging, Interventional Radiology and Radiotherapy, Tor Vergata University, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Garaci
authors.affiliation: Department of Ophthalmology, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: MacKinnon
authors.affiliation: Department of Ophthalmology, Boston Children's Hospital, Boston, Massachusetts.|Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.
authors.forename: David G
authors.initials: DG
authors.lastname: Hunter
authors.affiliation: Department of Radiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: P Ellen
authors.initials: PE
authors.lastname: Grant
authors.affiliation: Department of Ophthalmology, Boston Children's Hospital, Boston, Massachusetts.|Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.|FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts.|Department of Neurology, Boston Children's Hospital, Boston, Massachusetts.|Department of Neurology, Harvard Medical School, Boston, Massachusetts.|Howard Hughes Medical Institute, Chevy Chase, Maryland.|Program in Genomics, Boston Children's Hospital, Boston, Massachusetts.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts.|The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts.|Department of Medicine (Genetics), Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Engle
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002648:Child; D002675:Child, Preschool; D015785:Eye Diseases, Hereditary / Q000235:genetics* / Q000473:pathology*; D005260:Female; D005355:Fibrosis; D006801:Humans; D008297:Male; D054220:Malformations of Cortical Development / Q000235:genetics* / Q000473:pathology*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009886:Ophthalmoplegia; D010375:Pedigree; D010641:Phenotype; D017386:Sequence Homology, Amino Acid; D014404:Tubulin / Q000235:genetics*; D055815:Young Adult; D000093922:Congenital Cranial Dysinnervation Disorders
chemical_list: C498585:TUBB3 protein, human; D014404:Tubulin
keywords: TUBB3; congenital fibrosis of extraocular muscles; cortical development; tubulin; tubulinopathy