A De Novo Missense Variant in TUBG2 in a Child with Global Developmental Delay, Microcephaly, Refractory Epilepsy and Perisylvian Polymicrogyria.
Salini ThulasirajahXueqi WangErick SellJorge DávilaDavid A DymentKristin D KernohanPublished in: Genes (2022)
Polymicrogyria is a brain malformation characterized by excessive folding of the cortex. To date, numerous causes of polymicrogyria have been identified, including variants in the genes associated with tubulinopathies. Herein, we present a child with severe intellectual disability, refractory to treatment seizures, microcephaly and MRI findings consistent with polymicrogyria, closed-lip schizencephaly, periventricular heterotopia and a dysplastic corpus callosum. Exome sequencing identified a de novo missense variant in TUBG2 , a gene not associated with human disease. The variant, NM_016437.3 c.747G>A p.(Met249Ile), is absent from available control databases and is predicated to be deleterious by in silico prediction programs. Laboratory studies show that cultured lymphoblasts derived from the patient grew significantly faster than controls. Recombinant protein was expressed (recombinant wild type and mutant TUBG2-FLAG) in 293T cells and lower levels of TUBG2 mutant compared with controls were observed. Furthermore, co-immuno-precipitation in cells transfected demonstrated that the TUBG2-GCP2 interaction is increased due to the MUT recombinant protein versus WT recombinant protein. In closing, this work provides preliminary evidence that TUBG2 may represent a novel disease gene responsible for polymicrogyria.
Keyphrases
- intellectual disability
- wild type
- autism spectrum disorder
- copy number
- endothelial cells
- cell free
- protein protein
- zika virus
- mental health
- genome wide
- amino acid
- magnetic resonance imaging
- induced apoptosis
- binding protein
- public health
- photodynamic therapy
- single molecule
- magnetic resonance
- case report
- cell cycle arrest
- oxidative stress
- weight gain
- body mass index
- big data
- cell proliferation
- cerebral ischemia
- weight loss
- blood brain barrier
- brain injury
- resting state
- deep learning
- genome wide analysis
- temporal lobe epilepsy
- combination therapy