Functionally distinct groups of inherited PTEN mutations in autism and tumour syndromes

J Med Genet. 2015 Feb;52(2):128-34. doi: 10.1136/jmedgenet-2014-102803. Epub 2014 Dec 19.


Background: Germline mutations in the phosphatase PTEN are associated with diverse human pathologies, including tumour susceptibility, developmental abnormalities and autism, but any genotype-phenotype relationships are poorly understood.

Methods: We have studied the functional consequences of seven PTEN mutations identified in patients diagnosed with autism and macrocephaly and five mutations from severe tumour bearing sufferers of PTEN hamartoma tumour syndrome (PHTS).

Results: All seven autism-associated PTEN mutants investigated retained the ability to suppress cellular AKT signalling, although five were highly unstable. Observed effects on AKT also correlated with the ability to suppress soma size and the length and density of dendritic spines in primary neurons. Conversely, all five PTEN mutations from severe cases of PHTS appeared to directly and strongly disrupt the ability to inhibit AKT signalling.

Conclusions: Our work implies that alleles causing incomplete loss of PTEN function are more commonly linked to autism than to severe PHTS cases.

Keywords: Cancer: breast; Cell biology; Neurosciences.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autistic Disorder / enzymology
  • Autistic Disorder / genetics*
  • Biocatalysis
  • Cells, Cultured
  • Genetic Predisposition to Disease*
  • Hamartoma Syndrome, Multiple / enzymology
  • Hamartoma Syndrome, Multiple / genetics*
  • Humans
  • Inheritance Patterns / genetics*
  • Mutation, Missense / genetics*
  • Neurons / metabolism
  • PTEN Phosphohydrolase / chemistry
  • PTEN Phosphohydrolase / genetics*
  • Protein Stability


  • PTEN Phosphohydrolase
  • PTEN protein, human