Functionally distinct groups of inherited PTEN mutations in autism and tumour syndromes
L Spinelli, FM Black, JN Berg, BJ Eickholt… - Journal of Medical …, 2015 - jmg.bmj.com
Journal of Medical Genetics, 2015•jmg.bmj.com
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 …
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 …
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.
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