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

The FEBS Journal
Chi Wai WongAndrew M Chan

Abstract

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

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Methods Mentioned

BETA
ubiquitination
sumoylation
phosphatase assay
nuclear
transgenic
nuclear translocation

Software Mentioned

imagej
metamorph imaging

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