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Original article
Functionally distinct groups of inherited PTEN mutations in autism and tumour syndromes
  1. Laura Spinelli1,2,
  2. Fiona M Black3,
  3. Jonathan N Berg3,
  4. Britta J Eickholt4,
  5. Nicholas R Leslie1,2
  1. 1Institute of Biological Chemistry, Biophysics and Bioengineering, School of Engineering and Physical Sciences, Heriot Watt University, Edinburgh, UK
  2. 2Division of Cell Signalling and Immunology, College of Life Sciences, University of Dundee, Dundee, UK
  3. 3Clinical Genetics, School of Medicine, University of Dundee, Dundee, UK
  4. 4Cluster of Excellence NeuroCure and Institute of Biochemistry, Charité—Universitätsmedizin Berlin, Berlin, Germany
  1. Correspondence to Dr Nicholas R Leslie, Institute of Biological Chemistry, Biophysics and Bioengineering, Heriot Watt University, Nasmyth Building, Riccarton Campus, Heriot Watt University, Edinburgh EH14 4AS, UK; n.r.leslie{at}, l.spinelli{at}


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.

  • Cancer: breast
  • Neurosciences
  • Cell biology

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