Autism spectrum disorders and brain volume link through a set of mTOR-related genes

Arenella, Martina; Mota, Nina Roth; Teunissen, Mariel W. A.; Brunner, Han G.; Bralten, Janita

doi:10.1101/2022.05.10.22274868

Cited by 3 publications

(6 citation statements)

References 44 publications

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“…Furthermore, according to ENIGMA consortium findings, genetic variants of PI3K‐AKT pathway genes are correlated with increased intracranial volume. Moreover, Arenella et al not only showed an association between variants in mTOR‐related genes, brain volume and ASD but also described a potential role for the genes involved in mTOR signalling (specifically genes included in both the sub‐pathways PI3K‐AKT–mTOR and RAS‐MAPK–mTOR) as mediators in the relationship between having a large brain and having ASD [57].…”

Section: Autism Spectrum Disordermentioning

confidence: 99%

Cerebellar phenotypes in germline PTEN mutation carriers

Gambini,

Ferrero,

Bulfamante

et al. 2024

Neuropathology Appl Neurobio

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PTEN hamartoma tumour syndrome (PHTS) comprises different hereditary conditions caused by germline PTEN mutations, predisposing to the development of multiple hamartomas in many body tissues and also increasing the risk of some types of cancer.Cerebellar involvement in PHTS patients has been long known due to the development of a pathognomonic cerebellar hamartoma (known as dysplastic gangliocytoma of the cerebellum or Lhermitte‐Duclos disease). Recently, a crucial role of the cerebellum has been highlighted in the pathogenesis of autism spectrum disorders, now recognised as a phenotype expressed in a variable percentage of PHTS children. In addition, rare PTEN variants are indeed identified in medulloblastoma as well, even if they are less frequent than other germline gene mutations.The importance of PTEN and its downstream signalling enzymatic pathways, PI3K/AKT/mTOR, has been studied at different levels in both human clinical settings and animal models, not only leading to a better understanding of the pathogenesis of different disorders but, most importantly, to identify potential targets for specific therapies. In particular, PTEN integrity makes an important contribution to the normal development of tissue architecture in the nervous system, including the cerebellum. Thus, in patients with PTEN germline mutations, the cerebellum is an affected organ that is increasingly recognised in different disorders, whereas, in animal models, cerebellar Pten loss causes a variety of functional and histological alterations.In this review, we summarise the range of cerebellar involvement observed in PHTS and its relationships with germline PTEN mutations, along with the phenotypes expressed by murine models with PTEN deficiency in cerebellar tissue.

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Section: Autism Spectrum Disordermentioning

confidence: 99%

Cerebellar phenotypes in germline PTEN mutation carriers

Gambini,

Ferrero,

Bulfamante

et al. 2024

Neuropathology Appl Neurobio

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“…In this issue, we see research on ASD being carried out in Arenella et al. 's study (Arenella, Mota, Teunissen, Brunner, & Bralten, 2023). The authors test whether variants in mTOR‐related genes are associated with ASD and if these genetic variants in some part help to explain the previously reported link between large brain volume and ASD.…”

mentioning

confidence: 99%

“…One of the challenges that Arenella et al. (2023) comment on is the heterogeneity in ASD. As Arenella et al.…”

mentioning

confidence: 99%

“…As Arenella et al. (2023) say in this issue, ‘Heterogeneity at the phenotypic and etiological level in ASD make it difficult to pinpoint the underlying biological mechanisms and to make steps towards better targeted (i.e. personalised) treatment options’ (Arenella et al., 2023).…”

mentioning

confidence: 99%

“…(2023) say in this issue, ‘Heterogeneity at the phenotypic and etiological level in ASD make it difficult to pinpoint the underlying biological mechanisms and to make steps towards better targeted (i.e. personalised) treatment options’ (Arenella et al., 2023). It is known that the DSM‐IV subtypes also had heterogeneity within them, but the ASD category, since it involves just one category, potentially has less specificity than a DSM‐IV subtype.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Editorial: What's in a name? Drawing on the examples of autism and schizophrenia, some reflections on diagnostic labels and their future role in child and adolescent psychiatry

Ronald

2023

Child Psychology Psychiatry

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Ten years have passed since the release of DSM‐5, which brought with it some notable changes in diagnostic labels. In this editorial, the impact of labels, and the changes in labels used in child and adolescent psychiatry, are discussed, with examples drawn from autism and schizophrenia. The diagnostic labels that children and adolescents receive feed into their treatment access and future potential but also to their self‐identities. Outside of medicine, extensive budgets and time are spent to test how consumers identify with the labels of products. Diagnoses are not commercial products, of course, but the choice of labels used in child and adolescent psychiatry should remain a priority, in light of their impact on translational science, treatment and on individuals, alongside the ever‐evolving nature of language itself.

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Causal association between mTOR-dependent circulating protein levels and autism spectrum disorder: a Mendelian randomization study

Fu,

Dong,

Chen

et al. 2024

Preprint

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Background Overactivation of the mTOR signaling pathway is a critical mechanism in the pathogenesis of autism spectrum disorder (ASD). However, the causal relationships between key molecules downstream of the mTOR signaling pathway and ASD remains unclear. This study aimed to explore the causal associations between seven mTOR-dependent circulating protein levels and ASD. Methods Instrumental variables (IVs) used as proxies for mTOR-dependent circulating protein levels were derived from the proteomics-GWAS INTERVAL study (3,301 participants) and a serum protein GWAS study in an Icelandic population (5,368 participants). Two ASD summary datasets were obtained from a meta-analysis study of ASD GWAS datasets (22,196 cases and 32,504 controls) and the FinnGen Consortium (646 cases and 301,879 controls), respectively. We applied two-sample Mendelian randomization (MR) to assess whether there is a causal association between seven mTOR-dependent circulating protein levels and ASD. Furthermore, validation analyses of positive exposures in the discovery cohort were performed to confirm the reliability of the findings. Results In this two-sample MR study, plasma PKCα level was found to be causally related to ASD in both the discovery cohort (IVW: OR = 1.15, 95% CI = 1.05–1.25, p = 0.002) and the validation cohort (IVW: OR = 1.14, 95% CI = 1.02–1.27, p = 0.017). Conclusions There was a causal association between the plasma level of PKCα and ASD, suggesting PKCα as a potential biomarker for the prevention, monitoring and treatment of ASD. However, whether PKCα can play a role in the clinical management of ASD remains to be demonstrated in future research.

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Autism spectrum disorders and brain volume link through a set of mTOR-related genes

Cited by 3 publications

References 44 publications

Cerebellar phenotypes in germline PTEN mutation carriers

Cerebellar phenotypes in germline PTEN mutation carriers

Editorial: What's in a name? Drawing on the examples of autism and schizophrenia, some reflections on diagnostic labels and their future role in child and adolescent psychiatry

Causal association between mTOR-dependent circulating protein levels and autism spectrum disorder: a Mendelian randomization study

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