Relevance to Autism

A de novo missense variant with a CADD score > 25 was identified in the TLN2 gene in a Korean ASD proband in Kim et al., 2024; this gene was subsequently classified as an ASD candidate gene in males following a combined TADA analysis consisting of the Korean ASD cohort described in Kim et al., 2024 in addition to the Simons Simplex Collection and the SPARK cohort. A number of de novo variants in the TLN2 gene, including a de novo loss-of-function variant and eight de novo missense variants (four of which were predicted to be deleterious by CADD or REVEL), were previously reported in ASD probands from the Autism Sequencing Consortium, the Simons Simplex Collection, the MSSNG cohort, the SPARK cohort, and a Chinese ASD cohort (De Rubeis et al., 2014; Iossifov et al., 2014; Yuen et al., 2017; Satterstrom et al., 2020; Zhou et al., 2022; Yuan et al., 2023).

Molecular Function

This gene encodes a protein related to talin 1, a cytoskeletal protein that plays a significant role in the assembly of actin filaments and in spreading and migration of various cell types, including fibroblasts and osteoclasts. This protein has a different pattern of expression compared to talin 1 but, like talin 1, is thought to associate with unique transmembrane receptors to form novel linkages between extracellular matrices and the actin cytoskeleton. Di Paolo et al., 2002 reported that Tln2 was the predominant talin that interacted with PIP5K1C in rat brain, and this interaction induced clustering of PIP5K1C and talin at focal adhesions and increased the local production of phosphatidylinositol-4,5-bisphosphate; Morgan et al., 2004 subsequently reported that microinjection of reagents into large lamprey axons that competed with the talin-PIP kinase interaction resulted in a dramatic decrease of synaptic actin and an impairment of clathrin-mediated synaptic vesicle endocytosis.

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