De novo mutations in the beta-tubulin gene TUBB2A cause simplified gyral patterning and infantile-onset epilepsy

Thomas D. Cushion, Alex R. Paciorkowski, Daniela T. Pilz, Jonathan G L Mullins, Laurie E. Seltzer, Robert W. Marion, Emily Tuttle, Dalia Ghoneim, Susan L. Christian, Seo Kyung Chung, Mark I. Rees, William B. Dobyns

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

Tubulins, and microtubule polymers into which they incorporate, play critical mechanical roles in neuronal function during cell proliferation, neuronal migration, and postmigrational development: the three major overlapping events of mammalian cerebral cortex development. A number of neuronally expressed tubulin genes are associated with a spectrum of disorders affecting cerebral cortex formation. Such "tubulinopathies" include lissencephaly/pachygyria, polymicrogyria-like malformations, and simplified gyral patterns, in addition to characteristic extracortical features, such as corpus callosal, basal ganglia, and cerebellar abnormalities. Epilepsy is a common finding in these related disorders. Here we describe two unrelated individuals with infantile-onset epilepsy and abnormalities of brain morphology, harboring de novo variants that affect adjacent amino acids in a beta-tubulin gene TUBB2A. Located in a highly conserved loop, we demonstrate impaired tubulin and microtubule function resulting from each variant in vitro and by using in silico predictive modeling. We propose that the affected functional loop directly associates with the alpha-tubulin-bound guanosine triphosphate (GTP) molecule, impairing the intradimer interface and correct formation of the alpha/beta-tubulin heterodimer. This study associates mutations in TUBB2A with the spectrum of "tubulinopathy" phenotypes. As a consequence, genetic variations affecting all beta-tubulin genes expressed at high levels in the brain (TUBB2B, TUBB3, TUBB, TUBB4A, and TUBB2A) have been linked with malformations of cortical development.

Original languageEnglish (US)
Pages (from-to)634-641
Number of pages8
JournalAmerican Journal of Human Genetics
Volume94
Issue number4
DOIs
StatePublished - Apr 3 2014

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Tubulin
Epilepsy
Mutation
Genes
Lissencephaly
Microtubules
Cerebral Cortex
Malformations of Cortical Development
Corpus Callosum
Brain
Guanosine Triphosphate
Basal Ganglia
Computer Simulation
Polymers
Cell Proliferation
Phenotype
Amino Acids

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

De novo mutations in the beta-tubulin gene TUBB2A cause simplified gyral patterning and infantile-onset epilepsy. / Cushion, Thomas D.; Paciorkowski, Alex R.; Pilz, Daniela T.; Mullins, Jonathan G L; Seltzer, Laurie E.; Marion, Robert W.; Tuttle, Emily; Ghoneim, Dalia; Christian, Susan L.; Chung, Seo Kyung; Rees, Mark I.; Dobyns, William B.

In: American Journal of Human Genetics, Vol. 94, No. 4, 03.04.2014, p. 634-641.

Research output: Contribution to journalArticle

Cushion, TD, Paciorkowski, AR, Pilz, DT, Mullins, JGL, Seltzer, LE, Marion, RW, Tuttle, E, Ghoneim, D, Christian, SL, Chung, SK, Rees, MI & Dobyns, WB 2014, 'De novo mutations in the beta-tubulin gene TUBB2A cause simplified gyral patterning and infantile-onset epilepsy', American Journal of Human Genetics, vol. 94, no. 4, pp. 634-641. https://doi.org/10.1016/j.ajhg.2014.03.009
Cushion, Thomas D. ; Paciorkowski, Alex R. ; Pilz, Daniela T. ; Mullins, Jonathan G L ; Seltzer, Laurie E. ; Marion, Robert W. ; Tuttle, Emily ; Ghoneim, Dalia ; Christian, Susan L. ; Chung, Seo Kyung ; Rees, Mark I. ; Dobyns, William B. / De novo mutations in the beta-tubulin gene TUBB2A cause simplified gyral patterning and infantile-onset epilepsy. In: American Journal of Human Genetics. 2014 ; Vol. 94, No. 4. pp. 634-641.
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AU - Paciorkowski, Alex R.

AU - Pilz, Daniela T.

AU - Mullins, Jonathan G L

AU - Seltzer, Laurie E.

AU - Marion, Robert W.

AU - Tuttle, Emily

AU - Ghoneim, Dalia

AU - Christian, Susan L.

AU - Chung, Seo Kyung

AU - Rees, Mark I.

AU - Dobyns, William B.

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