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Distinguishing between PTEN clinical phenotypes through mutation analysis.

Stephanie Portelli1,2,3, Lucy Barr1,2,3, Alex G C de Sá1,2,3,4

  • 1Structural Biology and Bioinformatics, Department of Biochemistry, University of Melbourne, Melbourne, Victoria, Australia.

Computational and Structural Biotechnology Journal
|June 18, 2021
PubMed
Summary

Germline mutations in Phosphate and tensin homolog on chromosome ten (PTEN) cause diverse PTEN hamartoma tumor syndromes. Molecular changes in PTEN protein structure and function predict specific clinical outcomes, aiding in variant interpretation.

Keywords:
Genotype-phenotype correlationsMachine learningMutation analysisPHTSPTEN

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Area of Science:

  • Genetics
  • Molecular Biology
  • Oncology

Background:

  • Germline mutations in Phosphate and tensin homolog on chromosome ten (PTEN) are linked to PTEN hamartoma tumor syndrome.
  • This syndrome presents diverse clinical phenotypes, including macrocephaly, autism spectrum disorder (ASD), Cowden syndrome, and cancer predisposition.
  • The molecular basis for these varied phenotypic outcomes remains unclear.

Purpose of the Study:

  • To investigate the molecular consequences of PTEN mutations on protein structure and function.
  • To correlate these molecular changes with distinct clinical phenotypes.
  • To improve the interpretation of PTEN variants of unknown significance.

Main Methods:

  • Analysis of molecular consequences of PTEN mutations, including changes in phosphatase activity, protein stability, and intramolecular interactions.
  • Saturation mutagenesis to assess the impact of numerous PTEN variants.
  • Correlation of molecular data with observed clinical phenotypes.

Main Results:

  • Molecular changes in PTEN protein activity, stability, and interactions accurately distinguish between different disease phenotypes.
  • Cancer-associated PTEN variants induce the most significant molecular alterations.
  • Autism spectrum disorder (ASD)-associated variants show milder changes, while non-pathogenic variants have neutral effects.
  • Over half of variants of unknown significance could be linked to disease phenotypes.
  • More than half of Cowden syndrome mutations are likely associated with cancer development.

Conclusions:

  • Understanding the molecular impact of PTEN mutations is crucial for predicting clinical outcomes.
  • This approach can differentiate between PTEN variants causing diverse syndromes like ASD and Cowden syndrome.
  • The findings enhance the clinical interpretation of PTEN variants, including those of unknown significance and Cowden syndrome-related mutations.