Relevance to Autism

TNPO3 was identified as an ASD candidate gene based on having a p-value < 0.001 following DeNovoWEST analysis of de novo variants in 16,877 ASD trios from the Simons Simplex Collection, the Autism Sequencing Consortium, the MSSNG cohort, and the SPARK cohort in Zhou et al., 2022; among the de novo variants observed in ASD cases in this analysis were four damaging de novo missense variants (defined as having a REVEL score > 0.5). Whole-exome sequencing on 67 families with ASD and abnormal head circumference from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wu et al., 2020 had previously identified a de novo missense variant in TNPO3 in an ASD proband who also presented with macrocephaly; furthermore, the authors observed an excess of TNPO3 de novo variants in 10,842 previously published cases with neurodevelopmental disorders (NDDs) deposited in denovo-db (P = 5.9E-08, Padj = 0.001, CH model; P = 1.3E-06, Padj = 0.026, denovolyzeR model; Bonferroni correction).

Molecular Function

The protein encoded by this gene is a nuclear import receptor for serine/arginine-rich (SR) proteins such as the splicing factors SFRS1 and SFRS2. Mutations in TNPO3 are responsible for autosomal dominant limb-girdle muscular dystrophy-2 (LGMDD2; OMIM 608423), an autosomal dominant myopathy characterized by proximal muscle weakness primarily affecting the lower limbs, but also affecting the upper limbs in most patients (Melia et al., 2013; Torella et al., 2013).

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