Individuals with germline PTEN tumor-suppressor variants have PTEN hamartoma tumor syndrome (PHTS). Clinically, PHTS has variable presentations; there are distinct subsets of PHTS-affected individuals, such as those diagnosed with autism spectrum disorder (ASD) or cancer. It remains unclear why mutations in one gene can lead to such seemingly disparate phenotypes. Therefore, we sought to determine whether it is possible to predict a given PHTS-affected individual's a priori risk of ASD, cancer, or the co-occurrence of both phenotypes. By integrating network proximity analysis performed on the human interactome, molecular simulations, and residue-interaction networks, we demonstrate the role of conformational dynamics in the structural communication and long-range allosteric regulation of germline PTEN variants associated with ASD or cancer. We show that the PTEN interactome shares significant overlap with the ASD and cancer interactomes, providing network-based evidence that PTEN is a crucial player in the biology of both disorders. Importantly, this finding suggests that a germline PTEN variant might perturb the ASD or cancer networks differently, thus favoring one disease outcome at any one time. Furthermore, protein-dynamic structural-network analysis reveals small-world structural communication mediated by highly conserved functional residues and potential allosteric regulation of PTEN. We identified a salient structural-communication pathway that extends across the inter-domain interface for cancer-only mutations. In contrast, the structural-communication pathway is predominantly restricted to the phosphatase domain for ASD-only mutations. Our integrative approach supports the prediction and potential modulation of the relevant conformational states that influence structural communication and long-range perturbations associated with mutational effects that lead to PTEN-ASD or PTEN-cancer phenotypes.

Individuals with germline mutations in the tumor suppressor gene phosphatase and tensin homolog (PTEN), irrespective of clinical presentation, are diagnosed with PTEN hamartoma tumor syndrome (PHTS). PHTS confers a high risk of breast, thyroid, and other cancers or autism spectrum disorder (ASD) with macrocephaly. It remains unclear why mutations in one gene can lead to seemingly disparate phenotypes. Thus, we sought to identify differences in ASD vs. cancer-associated germline PTEN missense mutations by investigating putative structural effects induced by each mutation. We utilized a theoretical computational approach combining in silico structural analysis and molecular dynamics (MD) to interrogate 17 selected mutations from our patient population: six mutations were observed in patients with ASD (only), six mutations in patients with PHTS-associated cancer (only), four mutations shared across both phenotypes, and one mutation with both ASD and cancer. We demonstrate structural stability changes where all six cancer-associated mutations showed a global decrease in structural stability and increased dynamics across the domain interface with a proclivity to unfold, mediating a closed (inactive) active site. In contrast, five of the six ASD-associated mutations showed localized destabilization that contribute to the partial opening of the active site. Our results lend insight into distinctive structural effects of germline PTEN mutations associated with PTEN-ASD vs. those associated with PTEN-cancer, potentially aiding in identification of the shared and separate molecular features that contribute to autism or cancer, thus, providing a deeper understanding of genotype-phenotype relationships for germline PTEN mutations.

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There is a strong genetic association between germline PTEN mutation and autism spectrum disorder (ASD), making Pten-mutant models exemplary for the study of ASD pathophysiology. We developed the Ptenm3m4 mouse, where Pten is largely restricted from the nucleus, which recapitulates patient-like, autism-related phenotypes: behavioral changes, macrocephaly, and white matter abnormalities. This study aimed to investigate the contribution of oligodendrocyte (OL) lineage differentiation and functional changes in myelination to the white matter phenotype. OL lineage differentiation and myelination in Ptenm3m4 mice was studied using immunohistochemical and electron microscopic analyses. We also used primary oligodendrocyte progenitor cells (OPCs) to determine the effect of the Ptenm3m4 mutation on OPC proliferation, migration and maturation. Finally, we assessed the myelinating competency of mutant OLs via co-culture with wildtype dorsal root ganglia (DRG) neurons. The in vivo analyses of Ptenm3m4/m3m4 murine brains showed deficits in proteolipid protein (Plp) trafficking in myelinating OLs. Despite the increased expression of myelin proteins in the brain, myelin deposition was observed to be abnormal, often occurring adjacent to, rather than around axons. Mutant primary OPCs showed enhanced proliferation and migration. Furthermore, mutant OPCs matured precociously, exhibiting aberrant myelination in vitro. Mutant OPCs, when co-cultured with wildtype DRG neurons, showed an inability to properly ensheath axons. Our findings provide evidence that the Ptenm3m4 mutation disrupts the differentiation and myelination programs of developing OLs. OL dysfunction in the Ptenm3m4 model explains the leukodystrophy phenotype, a feature commonly associated with autism, and highlights the growing importance of glial dysfunction in autism pathogenesis.

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Ataxia telangiectasia (AT) is a developmental disorder in which many organ systems are affected. The children are recognized by a progressive cerebellar deterioration. The gene for AT has now been localized to a region of chromosome 11q22-23 of no more than 3Mb in size and its product appears to be involved directly or indirectly in some form of DNA recombination. Patients and their cells are unusually sensitive to ionizing radiation and various radiometric drugs. Observations on the progressive nature of the disorder, with loss of selected cells or failure to develop normally, might be compatible with the pathological effect of an inability to correctly regulate apoptosis in some cell lineages. While this is an intriguing speculation there is, at present, no evidence for such a defect in AT.

Germline mutations in PTEN account for~10% of cases of autism spectrum disorder (ASD) with coincident macrocephaly. To explore the importance of nuclear PTEN in the development of ASD and macrocephaly, we previously generated a mouse model with predominantly cytoplasmic localization of Pten (Pten m3m4/m3m4).Cytoplasmic predominant Pten localization results in a phenotype of extreme macrocephaly and autistic-like traits. Transcriptomic analysis of the Pten m3m4/m3m4 cortex found upregulated gene pathways related to myeloid cell activation, myeloid cell migration, and phagocytosis. These transcriptomic findings were used to direct in vitro assays on Pten wild-type and Pten m3m4/m3m4 microglia. We found increased Iba1 and C1q expression with enhanced phagocytic capacity in Pten m3m4/m3m4 microglia, indicating microglial activation. Moreover, through a series of neuron-microglia co-culture experiments, we found Pten m3m4/m3m4 microglia are more efficient at synaptic pruning compared with wild-type controls. In addition, we found evidence for neuron-microglia cross-talk, where Pten m3m4/m3m4 neurons elicit enhanced pruning from innately activated microglia. Subsequent in vivo studies validated our in vitro findings. We observed a concurrent decline in the expression of Pten and synaptic markers in the Pten m3m4/m3m4 cortex. At~3 weeks of age, with a 50% drop in Pten expression compared with wild-type levels, we observed enhanced activation of microglia in the Pten m3m4/m3m4 brain. Collectively, our data provide evidence that dysregulated Pten in microglia has an etiological role in microglial activation, phagocytosis, and synaptic pruning, creating avenues for future studies on the importance of PTEN in maintaining microglia homeostasis.