TUBG1 gene encodes gamma-tubulin that forms the gamma-tubulin ring complex to serve as a scaffold for formation of microtubules (PMIDs: 30016746, 21993292). Pathogenic variants in TUBG1 related to malformation of cortical development was first reported in 2013 in relation to autosomal dominant lissencephaly or pachygyria with microcephaly or dysgenesis of corpus callosum (PMID: 23603762).
Since then at least ten missense variants, including one recurrent variant, have been reported in 15 individuals in five publications (PMIDs: 23603762, 29706637, 31151415, 33728335, 33453472) with latest one from 2021. In absence of truncating variants, the mechanism of disease is dominant negative.
The gene-disease relationship is also supported by experimental evidence (PMIDs: 21993292, 23603762, 31086189). In formation of microtubules, TUBG1 interacts with TUBA1A and TUBB2A that are associated with complex brain malformation including lissencephaly. Additional mice models have shown association of TUBG1 to cortical migration abnormalities that underlies pathophysiology of lissencephaly. As experiment evidence under model and rescue category exceeded the maximum of four points, variant specific experimental evidence from mouse model (PMID: 31086189) were used to provide additional support for functional evidence under genetic evidence.
In summary, TUBG1 is definitely associated with autosomal dominant lissencephaly, supported by clinical and experimental evidence demonstrated over time. This classification has been approved by the Brain Malformations Gene Curation Expert Panel on April 26, 2022 (SOP version 8).
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