De novo mutations in the beta-tubulin gene TUBB2A cause simplified gyral patterning and infantile-onset epilepsy.
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.
Neurology and Molecular Neuroscience Research Group, Institute of Life Science, College of Medicine, Swansea University, Swansea SA2 8PP, UK.
Thomas D
TD
Cushion
Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA; Departments of Pediatrics and Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14641, USA; Center for Neural Development & Disease, University of Rochester Medical Center, Rochester, NY 14642, USA.
Alex R
AR
Paciorkowski
Institute of Medical Genetics, University Hospital of Wales, Cardiff CF14 4XW, UK; Wales Epilepsy Research Network (WERN), College of Medicine, Swansea University, Swansea SA2 8PP, UK.
Daniela T
DT
Pilz
Neurology and Molecular Neuroscience Research Group, Institute of Life Science, College of Medicine, Swansea University, Swansea SA2 8PP, UK.
Jonathan G L
JG
Mullins
Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA.
Laurie E
LE
Seltzer
The Children's Hospital at Montefiore, Bronx, NY 10467-2403, USA.
Robert W
RW
Marion
Center for Neural Development & Disease, University of Rochester Medical Center, Rochester, NY 14642, USA.
Emily
E
Tuttle
Center for Neural Development & Disease, University of Rochester Medical Center, Rochester, NY 14642, USA.
Dalia
D
Ghoneim
Center for Integrative Brain Research, Seattle Children's Hospital, Seattle, WA 98101, USA.
Susan L
SL
Christian
Neurology and Molecular Neuroscience Research Group, Institute of Life Science, College of Medicine, Swansea University, Swansea SA2 8PP, UK; Wales Epilepsy Research Network (WERN), College of Medicine, Swansea University, Swansea SA2 8PP, UK.
Seo-Kyung
SK
Chung
Neurology and Molecular Neuroscience Research Group, Institute of Life Science, College of Medicine, Swansea University, Swansea SA2 8PP, UK; Wales Epilepsy Research Network (WERN), College of Medicine, Swansea University, Swansea SA2 8PP, UK. Electronic address: m.i.rees@swansea.ac.uk.
Mark I
MI
Rees
Center for Integrative Brain Research, Seattle Children's Hospital, Seattle, WA 98101, USA; Departments of Pediatrics and Neurology, University of Washington, Seattle, WA 98195, USA. Electronic address: wbd@u.washington.edu.
William B
WB
Dobyns
D000595:Amino Acid Sequence; D018891:Dentate Gyrus / Q000473:pathology*; D004827:Epilepsy / Q000235:genetics* / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D017386:Sequence Homology, Amino Acid; D014404:Tubulin / Q000737:chemistry / Q000235:genetics*
D014404:Tubulin