Autism‐associated PTEN missense mutation leads to enhanced nuclear localization and neurite outgrowth in an induced pluripotent stem cell line

• DOI: 10.1111/febs.15287
• Publication Date: 2020-03-09T21:34:25Z
• Authors: Chi Wai Wong; Yubing Wang; Tian Liu; Lisha Li; Stanley Kwok Kuen...; Penelope Mei‐Yu Or; Alfred Sze‐Lok Cheng; Kwong Wai Choy; Johannes Peter He...; Bo Feng; Raymond Chuen Chu...; Andrew M. Chan
• Keywords: Neurite

Germline mutation in the PTEN gene is genetic basis of hamartoma tumor syndrome with affected individuals harboring features autism spectrum disorders. Characterizing a panel 14 autism-associated missense mutations revealed reduced protein stability, catalytic activity, and subcellular distribution. Nine out (64%) mutants had expression most confined to C2 domain. Selected displayed enhanced polyubiquitination shortened half-life, but that did not appear involve sites at lysine residues codon 13 or 289. Analyzing their intrinsic lipid phosphatase activities 78% (11 14) these twofold 10-fold reduction activity toward phosphatidylinositol phosphate substrates. localization showed 64% (nine altered nuclear-to-cytosol ratios four (G44D, H123Q, E157G, D326N) showing greater nuclear localization. The E157G mutant was knocked-in an induced pluripotent stem cell line recapitulated similar targeting preference. Furthermore, iPSCs expressing were more proliferative neural progenitor stage exhibited extensive dendritic outgrowth. In summary, combination biological changes expected contribute behavioral cellular this neurodevelopmental disorder.