Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004352 (autism)
 32,579 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report on a mother and son with Cowden syndrome and a PTEN mutation. The boy also exhibits autistic behavior and mental retardation, while his mother has a normal intelligence and social interaction pattern. We review the scanty literature data on the association of Cowden syndrome and autism and emphasize that the association of progressive macrocephaly and pervasive developmental disorder seems to be an indication for screening for PTEN mutations.
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PMID:PTEN mutation in a family with Cowden syndrome and autism. 1149 68

The genetic aetiology of autism remains elusive. Occasionally, individuals with Cowden syndrome (a cancer syndrome) and other related hamartoma disorders such as Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and Proteus-like conditions, are characterised by germline PTEN mutations, and may have neurobehavioural features resembling autism as well as overgrowth and macrocephaly. Therefore, we undertook PTEN gene mutation analysis in 18 subjects mainly prospectively ascertained with autism spectrum disorder and macrocephaly. Of these 18 autistic subjects (13 males and five females; ages 3.1-18.4 years) with a head circumference range from 2.5 to 8.0 standard deviations above the mean, three males (17%) carried germline PTEN mutations. These three probands had previously undescribed PTEN mutations: H93R (exon 4), D252G (exon 7), and F241S (exon 7). They had the larger head circumference measurements amongst all our study subjects. The three residues altered in our patients were highly evolutionarily conserved. We suggest that PTEN gene testing be considered for patients with autistic behaviour and extreme macrocephaly. The gene findings may impact on recurrence risks as well as medical management for the patient.
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PMID:Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. 1580 58

In a comprehensive set of experiments in this issue of Neuron, Kwon et al. demonstrate that conditional inactivation of Pten leads to behavioral abnormalities and neuropathological changes. Pten mutants displayed reduced social interaction and heightened responses to sensory stimuli. Additionally, neuronal hypertrophy, as well as macrocephaly was observed. Based on rare human mutations in PTEN and the PI3K pathway, the authors suggest they have produced a potential animal model of autism with macrocephaly.
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PMID:Pten and the brain: sizing up social interaction. 1667 93

CNS deletion of Pten in the mouse has revealed its roles in controlling cell size and number, thus providing compelling etiology for macrocephaly and Lhermitte-Duclos disease. PTEN mutations in individuals with autism spectrum disorders (ASD) have also been reported, although a causal link between PTEN and ASD remains unclear. In the present study, we deleted Pten in limited differentiated neuronal populations in the cerebral cortex and hippocampus of mice. Resulting mutant mice showed abnormal social interaction and exaggerated responses to sensory stimuli. We observed macrocephaly and neuronal hypertrophy, including hypertrophic and ectopic dendrites and axonal tracts with increased synapses. This abnormal morphology was associated with activation of the Akt/mTor/S6k pathway and inactivation of Gsk3beta. Thus, our data suggest that abnormal activation of the PI3K/AKT pathway in specific neuronal populations can underlie macrocephaly and behavioral abnormalities reminiscent of certain features of human ASD.
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PMID:Pten regulates neuronal arborization and social interaction in mice. 1667 86

The tumor suppressor PTEN (phosphatase and tensin homolog) plays a critical role in the development and maintenance of the mammalian nervous system. Effects of inherited mutation of PTEN are highly variable and include macrocephaly, Lhermitte-Duclos disease (LDD) caused by a hamartomatous enlargement of the cerebellum, ataxia, seizures and autism, in addition to cancer predisposition. In the mouse, selective inactivation of Pten in post-mitotic granule neurons of the cerebellum and dentate gyrus showed that Pten was required for proper regulation of neuronal nuclear and soma size. Hypertrophy of Pten-deficient neurons required the activity of the serine-threonine kinase mTor. mTor is a master regulator of cell and organ growth which can trigger a cascade of downstream signaling pathways involving, in part, components of the translational machinery, including S6k1 and its substrate the ribosomal protein S6. Deletion of S6k1 in mice results in decreased size. Therefore, to determine the relative contribution of S6k1 to Pten-deficient neuronal hypertrophy in vivo, we crossed Pten brain-conditional knockouts with S6k1 null mice. Double mutant mice show no reversion or improvement in their Pten-related size and neurological defects including enlarged cerebella and dentate gyri with increased size of neuronal nuclei and somata, ataxia, and premature death. The hypertrophic Pten/S6k1-deficient neurons contained high levels of phosphorylated S6, similar to Pten-deficient neurons, suggesting that the mTor/S6k/S6 branch of the pathway was still active. Thus, we conclude that S6k1 is not required to cause hypertrophy of Pten-deficient neurons. This study reveals a cell type-dependent role for S6k1 in PI3K-dependent hypertrophy.
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PMID:S6k1 is not required for Pten-deficient neuronal hypertrophy. 1677 79

Recently, Butler et al. [2005; J Med Genet 42:318-321] reported the presence of heterozygous germline mutations in the PTEN tumor suppressor gene in three children with autism and macrocephaly. Here, we report the presence of PTEN mutations in two additional unrelated children with macrocephaly and autism. Our findings extend those of Butler et al. and suggest that PTEN gene sequencing should be included in the genetic evaluation of this subset of autistic individuals.
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PMID:Increasing knowledge of PTEN germline mutations: Two additional patients with autism and macrocephaly. 1728 65

Mutations in the PTEN gene are associated with a broad spectrum of disorders, including Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and Lhermitte-Duclos disease. In addition, PTEN mutations have been described in a few patients with autism spectrum disorders (ASDs) and macrocephaly. In this study, we screened the PTEN gene for mutations and deletions in 88 patients with ASDs and macrocephaly (defined as >or=2 SD above the mean). Mutation analysis was performed by direct sequencing of all exons and flanking regions, as well as the promoter region. Dosage analysis of PTEN was carried out using multiplex ligation-dependent probe amplification (MLPA). No partial or whole gene deletions were observed. We identified a de novo missense mutation (D326N) in a highly conserved amino acid in a 5-year-old boy with autism, mental retardation, language delay, extreme macrocephaly (+9.6 SD) and polydactyly of both feet. Polydactyly has previously been described in two patients with Lhermitte-Duclos disease and CS and is thus likely to be a rare sign of PTEN mutations. Our findings suggest that PTEN mutations are a relatively infrequent cause of ASDs with macrocephaly. Screening of PTEN mutations is warranted in patients with autism and pronounced macrocephaly, even in the absence of other features of PTEN-related tumor syndromes.
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PMID:Mutation screening of the PTEN gene in patients with autism spectrum disorders and macrocephaly. 1742 95

Improving clinical tests are allowing us to more precisely classify autism spectrum disorders and diagnose them at earlier ages. This raises the possibility of earlier and potentially more effective therapeutic interventions. To fully capitalize on this opportunity, however, will require better understanding of the neurobiological changes underlying this devastating group of developmental disorders. It is becoming clear that the normal trajectory of neurodevelopment is altered in autism, with aberrations in brain growth, neuronal patterning and cortical connectivity. Changes to the structure and function of synapses and dendrites have also been strongly implicated in the pathology of autism by morphological, genetic and animal modeling studies. Finally, environmental factors are likely to interact with the underlying genetic profile, and foster the clinical heterogeneity seen in autism spectrum disorders. In this review we attempt to link the molecular pathways altered in autism to the neurodevelopmental and clinical changes that characterize the disease. We focus on signaling molecules such as neurotrophin, Reelin, PTEN and hepatocyte growth factor, neurotransmitters such as serotonin and glutamate, and synaptic proteins such as neurexin, SHANK and neuroligin. We also discuss evidence implicating oxidative stress, neuroglial activation and neuroimmunity in autism.
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PMID:The neurobiology of autism. 1791 29

The functions ascribed to PTEN have become more diverse since its discovery as a putative phosphatase mutated in many human tumors. Although it can dephosphorylate lipids and proteins, it also has functions independent of phosphatase activity in normal and pathological states. In addition, control of PTEN function is very complex. It is positively and negatively regulated at the transcriptional level, as well as post-translationally by phosphorylation, ubiquitylation, oxidation and acetylation. Although most of its tumor suppressor activity is likely to be caused by lipid dephosphorylation at the plasma membrane, PTEN also resides in the cytoplasm and nucleus, and its subcellular distribution is under strict control. Deregulation of PTEN function is implicated in other human diseases in addition to cancer, including diabetes and autism.
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PMID:New insights into PTEN. 1803 82

The tumor suppressor PTEN dephosphorylates phospholipids generated through the activity of PI3K. PTEN thus antagonizes PI3K activity and regulates a multitude of cellular processes such as angiogenesis, motility, invasiveness, survival and proliferation, all of which can initiate and sustain the malignant phenotype. Although PTEN's lipid phosphatase activity is key to its tumor suppressive functions, it also dephosphorylates protein substrates and interacts with other key regulatory molecules, salient among them the tumor suppressor p53. Given the critical roles of PTEN in cellular homeostasis, it is not surprising that both PTEN expression levels and PTEN protein activities are tightly controlled by a complex conglomeration of molecules that regulate post-translational modifications, subcellular localization, transcriptional activation and transcriptional repression. As one of the most commonly altered molecules in human disease, PTEN plays an important role in a myriad of signaling cascades, and plays a central role in normal brain development and brain tumor pathogenesis. As such it influences prognosis of human cancer, predicts response to therapy, constitutes the lynchpin of genetic syndromes, and may underlie neurocognitive abnormalities such as autism spectrum disorders and Alzheimer's disease. Thus, targeting PTEN and its signaling affiliates sows the seeds for combating not only cancer but also neurocognitive disorders.
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PMID:PTEN in brain tumors. 1841 62


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