Identification of a PTEN mutation with reduced protein stability, phosphatase activity, and nuclear localization in Hong Kong patients with autistic features, neurodevelopmental delays, and macrocephaly.
A Hong Kong team found a rare PTEN mutation that breaks the protein and may explain autism with big heads in a few local children.
01Research in Context
What this study did
Doctors in Hong Kong looked at 13 children who had autism, big heads, and slow development. They checked each child's DNA for changes in the PTEN gene, a gene tied to large head size and some autism cases.
Lab tests then showed if any found mutation hurt the PTEN protein's shape, stability, or job inside cells.
What they found
Three children carried a rare PTEN change called I101T. Lab work showed this version breaks down faster, works less, and drifts outside the cell nucleus where it is needed.
These results give a possible genetic reason for autism plus macrocephaly in these local patients.
How this fits with other research
Xia et al. (2020) scanned the whole genome of over 900 Han-Chinese families and found many small hints, but no single clear PTEN signal. Their wide search supersedes this small case report by showing PTEN variants are uncommon at the population level.
Liu et al. (2016) also ran a large East-Asian meta-analysis and flagged a different gene, RIT2, as the top hit. Both studies agree that many genes, not just PTEN, shape autism risk in Chinese groups.
Wang et al. (2018) used a similar case-control design in China and linked two neurexin gene tweaks to autism. Together these papers build a picture: single-gene findings matter for the families who have them, yet most families will face polygenic risk.
Why it matters
If you assess a child with autism and a noticeably large head, consider a genetics referral and mention PTEN. A positive result gives families a concrete biological explanation and may guide medical follow-up for tumor-risk syndromes. When counseling, balance this rare finding with the fact that most autism is polygenic, as shown by Xia et al. (2020) and Liu et al. (2016). Sharing both points keeps parent expectations realistic while still offering actionable information.
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02At a glance
03Original abstract
PTEN is a tumor suppressor gene inactivated in over 30% of human cancers. It encodes a lipid phosphatase that serves as a gatekeeper of the phosphoinositide 3-kinase signaling pathway. Germline mutation frequently occurs in this gene in patients diagnosed with PTEN Hamartoma Tumor Syndrome (PHTS). PHTS individuals are characterized by macrocephaly, benign growth of multiple tissues and increased tumor risk. In addition, autistic phenotypes are found in 10-20% of individuals carrying the germline PTEN mutation with macrocephaly. In this report, 13 suspected PHTS patients were screened for mutation in the PTEN gene. A missense variant (c. 302T > C) substituting the isoleucine at codon 101 to a threonine, a single nucleotide insertion (c. 327-328insC) causing a frame shift mutation and termination at codon 109, and a nonsense variant (c. 1003C > T) truncated the protein at codon 335 were identified. The I101T mutation significantly reduced PTEN protein expression levels by 2.5- to 4.0-fold. Mechanistically, I101T reduced the protein half-life of PTEN possibly due to enhanced polyubiquitination at Lysine 13. However, the I101T mutant retained almost 30% of the lipid phosphatase activity of the wild-type protein. Finally, the I101T mutant has reduced phosphorylation at a PTEN auto-dephosphorylation site at Threonine 366 and a lowered ratio of nuclear to cytosolic protein level. These partial losses of multiple PTEN biochemical functions may contribute to the tissue overgrowth and autistic features of this PHTS patient. Autism Res 2018, 11: 1098-1109. © 2018 The Authors Autism Research published by International Society for Autism Research and Wiley Periodicals, Inc. LAY SUMMARY: The genetics of autism spectrum disorders is highly complex with individual risk influenced by both genetic and environmental factors. Mutation in the human PTEN gene confers a high risk of developing autistic behavior. This report revealed that PTEN mutations occurred in 23% of a selected group of Hong Kong patients harboring autistic features with gross overgrowth symptoms. Detailed characterization of a PTEN mutation revealed reduced protein stability as one of the underlying mechanisms responsible for reduced PTEN activity.
Autism research : official journal of the International Society for Autism Research, 2018 · doi:10.1002/aur.1950