A pathogenic role for germline PTEN variants which accumulate into the nucleus

Area of Science:

• Molecular Biology
• Genetics
• Cell Biology

Background:

• The PTEN gene is a crucial regulator with both cytoplasmic and nuclear functions.
• Mutations in PTEN are linked to PTEN hamartoma tumor syndrome (PHTS) and autism spectrum disorders (ASD).
• Functional characterization of PTEN variants is essential for understanding disease mechanisms.

Purpose of the Study:

• To functionally characterize the PTEN Q17E missense variant found in PHTS and ASD patients.
• To investigate the role of the PTEN N-terminus in nuclear localization and protein activity.
• To explore the pathogenicity of PTEN N-terminal variants.

Main Methods:

• Functional characterization of the PTEN Q17E variant using S. cerevisiae and mammalian cell models.
• Assessment of PIP3-catalytic activity and protein stability.
• Analysis of PTEN N-terminal variants and their nuclear localization.

Main Results:

• The PTEN Q17E variant showed partially reduced PIP3-catalytic activity but normal cellular stability.
• PTEN Q17E accumulated in the nucleus via its N-terminal nuclear localization sequence.
• Germline PTEN N-terminal variants can cause nuclear accumulation and impaired PIP3-catalytic activity.

Conclusions:

• PTEN N-terminal mutations frequently lead to nuclear PTEN accumulation.
• Nuclear retention of PTEN, coupled with impaired activity, contributes to pathogenicity in PHTS and ASD.
• These findings may inform precision therapies for PTEN pathway disorders.