Relevance to Autism

Recurrent mutations in the PTEN gene have been identified in multiple individuals with ASD as described below. Deleterious variants in PTEN have been identified in individuals presenting with ASD and macrocephaly in multiple studies (PMIDs 15805158, 18759867, 19265751, 20533527). Two de novo deleterious events in the PTEN gene were identified in exome sequencing studies in simplex ASD cases in 2012: a missense variant (p.Thr167Asn) that was classified as "severe" in O'Roak et al. Nature 2012 (PMID 22495309); and a frameshift variant (p.Cys136MetfsX44) in O'Roak et al. Science 2012 (PMID 23160955). A detailed examination of ASD cases with heterozygous PTEN mutations in Frazier et al., 2015 found that these cases had a high proportion of missense variants, showed reduced PTEN protein levels, and exhibited prominent white-matter and cognitive abnormalities compared to other groups (PMID 25288137). An additional de novo loss-of-function variant in the PTEN gene was subsequently identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report furthermore identified PTEN as a gene meeting high statistical significance with a 0.01 < FDR 0.05, meaning that this gene had a 95% chance of being a true autism gene. This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). 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 PTEN as a gene reaching exome-wide significance (P < 2.5E-06). PTEN has also been designated as a syndromic ASD gene, as mutations in the PTEN gene are causative for Cowden syndrome, a disorder in which a subpopulation of individuals with the syndrome develop autism (PMID 11496368).

Molecular Function

The protein encoded this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It contains a tensin like domain as well as a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases.

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References

Model Summary

Pten mutant larvae showed an increase in PKB expression and overgrowth of head imaginal tissue.

References