Relevance to Autism

Goodman et al., 2021 identified 15 individuals with de novo coding variants in the TNPO2 gene who presented with global developmental delay, dysmorphic features, ophthalmologic abnormalities, and neurological features; behavioral deficits, including autism spectrum disorder or autistic features, were observed in 10 of 14 individuals in this study. Furthermore, functional studies in Drosophila in this study found that proband-associated variants were capable of causing more or less severe developmental phenotypes compared to wild-type TNPO2 when ectopically expressed, consistent with either loss-of-function or gain-of-function effects; one of the variants experimentally shown to result in loss-of-function effects was detected in an individual with autism spectrum disorder. De novo missense variants in the TNPO2 gene had previously been identified in ASD probands from the SPARK cohort (Feliciano et al., 2019) and the Autism Sequencing Consortium (Satterstrom et al., 2020).

Molecular Function

Probably functions in nuclear protein import as nuclear transport receptor. Serves as receptor for nuclear localization signals (NLS) in cargo substrates. Is thought to mediate docking of the importin/substrate complex to the nuclear pore complex (NPC) through binding to nucleoporin and the complex is subsequently translocated through the pore by an energy requiring, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to the importin, the importin/substrate complex dissociates and importin is re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran. The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus.

External Links

References