Relevance to Autism

A compound heterozygous mutation in the TRIP12 gene was identified in an ASD proband from a nonconsanguineous family that showed evidence of distant shared ancestry as identified by homozygosity analysis (Chahrour et al., 2012). Two de novo LoF variants and two de novo missense variants in the TRIP12 gene were identified in ASD probands from independent simplex cohorts (PMID 22542183, 25418537). Transmission and de novo association (TADA) analysis of ASD cases and controls from the Autism Sequencing Consortium and the Simons Simplex Collection in Sanders et al., 2015 identified TRIP12 as an ASD candidate gene with a false discovery rate (FDR) 0.01. A third de novo LoF variant in the TRIP12 gene was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016. A patient with intellectual disability and a de novo frameshift variant in TRIP12 that was first reported in Lelieveld et al., 2016 was subsequently reported to have a diagnosis of ASD in Bramswig et al., 2016. Two previously unreported patients that were diagnosed with ASD and intellectual disability were also found to have de novo LoF variants in the TRIP12 gene in Bramswig et al., 2016. Variants in the TRIP12 gene have also been observed in patients with intellectual disability without autism (Lelieveld et al., 2016; Bramswig et al., 2016). An additional de novo LoF variant in TRIP12 was identified in an ASD proband from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017. Zhang et al., 2017 described nine novel patients with TRIP12 variants (five deletions, four SNVs), all of whom presented with developmental delay/intellectual disability; autistic behaviors (6/8 patients), speech delay (8/8 patients), motor delay (7/8 patients), obesity (4/7 patients), narrow palpebral fissures (4/7 patients), and downturned corners of the mouth (4/8 cases) were also frequently observed. Two additional de novo LoF variants in TRIP12 were identified in ASD probands from a cohort of 262 Japanese trios in Takata et al., 2018; TADA-Denovo analysis demonstrated that this gene was significantly enriched for damaging de novo mutations in the Japanese ASD cohort, as well as in a combined dataset consisting of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium in addition to the Japanese ASD cohort. A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified TRIP12 as a gene reaching exome-wide significance (P < 2.5E-06).

Molecular Function

The protein encoded by this gene is an E3 ubiquitin-protein ligase involved in the degradation of the p19ARF/ARF isoform of CDKN2A, a tumor suppressor. The encoded protein also plays a role in the DNA damage response by regulating the stability of USP7, which regulates tumor suppressor p53.

External Links

References

Model Summary

Both ctrip mutants showed no change in habituation.

References