Modeling non-syndromic autism and the impact of TRPC6 disrup

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Modeling non-syndromic autism and the impact of TRPC6 disrup

Postby marciogama » Thu Nov 13, 2014 8:13 pm


This research has received a lot of attention in the Brazilian press.

Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons

K Griesi-Oliveira, A Acab, A R Gupta, D Y Sunaga, T Chailangkarn, X Nicol, Y Nunez, M F Walker, J D Murdoch, S J Sanders, T V Fernandez, W Ji, R P Lifton, E Vadasz, A Dietrich, D Pradhan, H Song, G-l Ming, X Gu, G Haddad, M C N Marchetto, N Spitzer, M R Passos-Bueno, M W State and A R Muotri

An increasing number of genetic variants have been implicated in autism spectrum disorders (ASDs), and the functional study of such variants will be critical for the elucidation of autism pathophysiology. Here, we report a de novo balanced translocation disruption of TRPC6, a cation channel, in a non-syndromic autistic individual. Using multiple models, such as dental pulp cells, induced pluripotent stem cell (iPSC)-derived neuronal cells and mouse models, we demonstrate that TRPC6 reduction or haploinsufficiency leads to altered neuronal development, morphology and function. The observed neuronal phenotypes could then be rescued by TRPC6 complementation and by treatment with insulin-like growth factor-1 or hyperforin, a TRPC6-specific agonist, suggesting that ASD individuals with alterations in this pathway may benefit from these drugs. We also demonstrate that methyl CpG binding protein-2 (MeCP2) levels affect TRPC6 expression. Mutations in MeCP2 cause Rett syndrome, revealing common pathways among ASDs. Genetic sequencing of TRPC6 in 1041 ASD individuals and 2872 controls revealed significantly more nonsynonymous mutations in the ASD population, and identified loss-of-function mutations with incomplete penetrance in two patients. Taken together, these findings suggest that TRPC6 is a novel predisposing gene for ASD that may act in a multiple-hit model. This is the first study to use iPSC-derived human neurons to model non-syndromic ASD and illustrate the potential of modeling genetically complex sporadic diseases using such cells. ... 4141a.html

Hyperforin - "Hyperforin is a phytochemical produced by some of the members of the plant genus Hypericum, notably Hypericum perforatum (St John's wort)" (Wikipedia)

More info: ... _in_autism ... tory.shtml (bad translation)

Best regards,

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