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Lack of association of rare functional variants in TSC1/TSC2 genes with autism spectrum disorder

BACKGROUND: Autism spectrum disorder (ASD) is reported in 30 to 60% of patients with tuberous sclerosis complex (TSC) but shared genetic mechanisms that exist between TSC-associated ASD and idiopathic ASD have yet to be determined. Through the small G-protein Rheb, the TSC proteins, hamartin and tub...

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Autores principales: Bahl, Samira, Chiang, Colby, Beauchamp, Roberta L, Neale, Benjamin M, Daly, Mark J, Gusella, James F, Talkowski, Michael E, Ramesh, Vijaya
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3610211/
https://www.ncbi.nlm.nih.gov/pubmed/23514105
http://dx.doi.org/10.1186/2040-2392-4-5
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author Bahl, Samira
Chiang, Colby
Beauchamp, Roberta L
Neale, Benjamin M
Daly, Mark J
Gusella, James F
Talkowski, Michael E
Ramesh, Vijaya
author_facet Bahl, Samira
Chiang, Colby
Beauchamp, Roberta L
Neale, Benjamin M
Daly, Mark J
Gusella, James F
Talkowski, Michael E
Ramesh, Vijaya
author_sort Bahl, Samira
collection PubMed
description BACKGROUND: Autism spectrum disorder (ASD) is reported in 30 to 60% of patients with tuberous sclerosis complex (TSC) but shared genetic mechanisms that exist between TSC-associated ASD and idiopathic ASD have yet to be determined. Through the small G-protein Rheb, the TSC proteins, hamartin and tuberin, negatively regulate mammalian target of rapamycin complex 1 (mTORC1) signaling. It is well established that mTORC1 plays a pivotal role in neuronal translation and connectivity, so dysregulation of mTORC1 signaling could be a common feature in many ASDs. Pam, an E3 ubiquitin ligase, binds to TSC proteins and regulates mTORC1 signaling in the CNS, and the FBXO45-Pam ubiquitin ligase complex plays an essential role in neurodevelopment by regulating synapse formation and growth. Since mounting evidence has established autism as a disorder of the synapses, we tested whether rare genetic variants in TSC1, TSC2, MYCBP2, RHEB and FBXO45, genes that regulate mTORC1 signaling and/or play a role in synapse development and function, contribute to the pathogenesis of idiopathic ASD. METHODS: Exons and splice junctions of TSC1, TSC2, MYCBP2, RHEB and FBXO45 were resequenced for 300 ASD trios from the Simons Simplex Collection (SSC) using a pooled PCR amplification and next-generation sequencing strategy, targeted to the discovery of deleterious coding variation. These detected, potentially functional, variants were confirmed by Sanger sequencing of the individual samples comprising the pools in which they were identified. RESULTS: We identified a total of 23 missense variants in MYCBP2, TSC1 and TSC2. These variants exhibited a near equal distribution between the proband and parental pools, with no statistical excess in ASD cases (P > 0.05). All proband variants were inherited. No putative deleterious variants were confirmed in RHEB and FBXO45. Three intronic variants, identified as potential splice defects in MYCBP2 did not show aberrant splicing upon RNA assay. Overall, we did not find an over-representation of ASD causal variants in the genes studied to support them as contributors to autism susceptibility. CONCLUSIONS: We did not observe an enrichment of rare functional variants in TSC1 and TSC2 genes in our sample set of 300 trios.
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spelling pubmed-36102112013-03-29 Lack of association of rare functional variants in TSC1/TSC2 genes with autism spectrum disorder Bahl, Samira Chiang, Colby Beauchamp, Roberta L Neale, Benjamin M Daly, Mark J Gusella, James F Talkowski, Michael E Ramesh, Vijaya Mol Autism Research BACKGROUND: Autism spectrum disorder (ASD) is reported in 30 to 60% of patients with tuberous sclerosis complex (TSC) but shared genetic mechanisms that exist between TSC-associated ASD and idiopathic ASD have yet to be determined. Through the small G-protein Rheb, the TSC proteins, hamartin and tuberin, negatively regulate mammalian target of rapamycin complex 1 (mTORC1) signaling. It is well established that mTORC1 plays a pivotal role in neuronal translation and connectivity, so dysregulation of mTORC1 signaling could be a common feature in many ASDs. Pam, an E3 ubiquitin ligase, binds to TSC proteins and regulates mTORC1 signaling in the CNS, and the FBXO45-Pam ubiquitin ligase complex plays an essential role in neurodevelopment by regulating synapse formation and growth. Since mounting evidence has established autism as a disorder of the synapses, we tested whether rare genetic variants in TSC1, TSC2, MYCBP2, RHEB and FBXO45, genes that regulate mTORC1 signaling and/or play a role in synapse development and function, contribute to the pathogenesis of idiopathic ASD. METHODS: Exons and splice junctions of TSC1, TSC2, MYCBP2, RHEB and FBXO45 were resequenced for 300 ASD trios from the Simons Simplex Collection (SSC) using a pooled PCR amplification and next-generation sequencing strategy, targeted to the discovery of deleterious coding variation. These detected, potentially functional, variants were confirmed by Sanger sequencing of the individual samples comprising the pools in which they were identified. RESULTS: We identified a total of 23 missense variants in MYCBP2, TSC1 and TSC2. These variants exhibited a near equal distribution between the proband and parental pools, with no statistical excess in ASD cases (P > 0.05). All proband variants were inherited. No putative deleterious variants were confirmed in RHEB and FBXO45. Three intronic variants, identified as potential splice defects in MYCBP2 did not show aberrant splicing upon RNA assay. Overall, we did not find an over-representation of ASD causal variants in the genes studied to support them as contributors to autism susceptibility. CONCLUSIONS: We did not observe an enrichment of rare functional variants in TSC1 and TSC2 genes in our sample set of 300 trios. BioMed Central 2013-03-20 /pmc/articles/PMC3610211/ /pubmed/23514105 http://dx.doi.org/10.1186/2040-2392-4-5 Text en Copyright ©2013 Bahl et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Bahl, Samira
Chiang, Colby
Beauchamp, Roberta L
Neale, Benjamin M
Daly, Mark J
Gusella, James F
Talkowski, Michael E
Ramesh, Vijaya
Lack of association of rare functional variants in TSC1/TSC2 genes with autism spectrum disorder
title Lack of association of rare functional variants in TSC1/TSC2 genes with autism spectrum disorder
title_full Lack of association of rare functional variants in TSC1/TSC2 genes with autism spectrum disorder
title_fullStr Lack of association of rare functional variants in TSC1/TSC2 genes with autism spectrum disorder
title_full_unstemmed Lack of association of rare functional variants in TSC1/TSC2 genes with autism spectrum disorder
title_short Lack of association of rare functional variants in TSC1/TSC2 genes with autism spectrum disorder
title_sort lack of association of rare functional variants in tsc1/tsc2 genes with autism spectrum disorder
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3610211/
https://www.ncbi.nlm.nih.gov/pubmed/23514105
http://dx.doi.org/10.1186/2040-2392-4-5
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