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

Chi Wai Wong, Penelope Mei Yu Or, Yubing Wang, Lisha Li, Jing Li, Mingfei Yan, Ye Cao, Ho Ming Luk, Tony Ming For Tong, Nick R. Leslie, Ivan Fai Man Lo, Kwong Wai Choy, Andrew Man Lok Chan

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)
52 Downloads (Pure)

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.

Original languageEnglish
JournalAutism Research
Early online date2 Apr 2018
DOIs
Publication statusE-pub ahead of print - 2 Apr 2018

Keywords

  • Autism spectrum disorders
  • Hong Kong
  • Macrocephaly
  • PTEN
  • PTEN hamartoma tumor syndrome

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology
  • Genetics(clinical)

Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this