Butler

Christensen

Duerr

Fragoso

Gaugler

Groszer

Hansen-Kiss

James

Kimmelman

Kleijer

Kwon

Liaw

Maccario

Masson

Meng

Mester

Naguib

Nelen

Ngeow

O'Roak

Odriozola

Parsons

Rodriguez-Escudero

Rubeis

Salvesen

Sasaki

Schmidt

Shen

Singh

Song

Spinelli

Steck

Tibarewal

Tolkacheva

Trotman

Vanderver

Walker

Zbuk

English

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

Crossref

Autism Research

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

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&gt;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&gt;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.</p

Wong, Chi Wai

Or, Penelope Mei Yu

Wang, Yubing

Li, Lisha

Li, Jing

Yan, Mingfei

Cao, Ye

Luk, Ho Ming

Tong, Tony Ming For

Leslie, Nick R.

Lo, Ivan Fai Man

Choy, Kwong Wai

Chan, Andrew Man Lok

Heriot Watt Pure

https://pureapps2.hw.ac.uk/ws/files/22758521/Wong_et_al_2017_Autism_Research.pdf

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

Abstract

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Heriot Watt Pure

Heriot Watt Pure