Molecular and phenotypic abnormalities in individuals with germline heterozygous PTEN mutations and autism

T W Frazier, R Embacher, A K Tilot, K Koenig, J Mester, C Eng, T W Frazier, R Embacher, A K Tilot, K Koenig, J Mester, C Eng

Abstract

PTEN is a tumor suppressor associated with an inherited cancer syndrome and an important regulator of ongoing neural connectivity and plasticity. The present study examined molecular and phenotypic characteristics of individuals with germline heterozygous PTEN mutations and autism spectrum disorder (ASD) (PTEN-ASD), with the aim of identifying pathophysiologic markers that specifically associate with PTEN-ASD and that may serve as targets for future treatment trials. PTEN-ASD patients (n=17) were compared with idiopathic (non-PTEN) ASD patients with (macro-ASD, n=16) and without macrocephaly (normo-ASD, n=38) and healthy controls (n=14). Group differences were evaluated for PTEN pathway protein expression levels, global and regional structural brain volumes and cortical thickness measures, neurocognition and adaptive behavior. RNA expression patterns and brain characteristics of a murine model of Pten mislocalization were used to further evaluate abnormalities observed in human PTEN-ASD patients. PTEN-ASD had a high proportion of missense mutations and showed reduced PTEN protein levels. Compared with the other groups, prominent white-matter and cognitive abnormalities were specifically associated with PTEN-ASD patients, with strong reductions in processing speed and working memory. White-matter abnormalities mediated the relationship between PTEN protein reductions and reduced cognitive ability. The Pten(m3m4) murine model had differential expression of genes related to myelination and increased corpus callosum. Processing speed and working memory deficits and white-matter abnormalities may serve as useful features that signal clinicians that PTEN is etiologic and prompting referral to genetic professionals for gene testing, genetic counseling and cancer risk management; and could reveal treatment targets in trials of treatments for PTEN-ASD.

Conflict of interest statement

Conflict of Interest

No other disclosures were reported.

Figures

Figure 1
Figure 1
Mediational models displaying the direct relationships between PTEN protein score and full scale IQ and indirect relationships via white matter characteristics. Direct relationships are shown in blue. Indirect relationships are shown in red. *p<.05. pten score was not significantly related to total cortical thickness precluding mediation.>

Figure 2

Mouse model myelination-related gene expression…

Figure 2

Mouse model myelination-related gene expression network and white matter evaluation. (A) Ingenuity Pathway…

Figure 2
Mouse model myelination-related gene expression network and white matter evaluation. (A) Ingenuity Pathway Analysis network of myelination-related gene expression is upregulated in Ptenm3m4/m3m4 cortex at six weeks of age. The color of the molecule indicates the expression change from wild-type, with red and green indicating up- and down-regulation, respectively. Color intensity reflects the extent of change. The function of each differentially expressed gene is represented by the shape of the molecule, and listed in the legend below. (B) Representative images of MBP (scale bar = 250 µm) and NeuN (scale bar = 500 µm) immunofluorescence staining in Ptenm3m4/m3m4 and Wt cortex at six weeks of age. (C) Quantification of corpus callosum and cortical thickness measured from staining shown in (B).
Figure 2
Figure 2
Mouse model myelination-related gene expression network and white matter evaluation. (A) Ingenuity Pathway Analysis network of myelination-related gene expression is upregulated in Ptenm3m4/m3m4 cortex at six weeks of age. The color of the molecule indicates the expression change from wild-type, with red and green indicating up- and down-regulation, respectively. Color intensity reflects the extent of change. The function of each differentially expressed gene is represented by the shape of the molecule, and listed in the legend below. (B) Representative images of MBP (scale bar = 250 µm) and NeuN (scale bar = 500 µm) immunofluorescence staining in Ptenm3m4/m3m4 and Wt cortex at six weeks of age. (C) Quantification of corpus callosum and cortical thickness measured from staining shown in (B).

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