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PLPPR4 haploinsufficiency causes neurodevelopmental disorders by disrupting synaptic plasticity via mTOR signalling
Phospholipid phosphatase related 4 (PLPPR4), a neuron‐specific membrane protein located at the postsynaptic density of glutamatergic synapses, is a putative regulator of neuronal plasticity. However, PLPPR4 dysfunction has not been linked to genetic disorders. In this study, we report three unrelate...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10623522/ https://www.ncbi.nlm.nih.gov/pubmed/37550884 http://dx.doi.org/10.1111/jcmm.17899 |
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author | Li, Huanzheng Zhang, Qian Wan, Ru Zhou, Lili Xu, Xueqin Xu, Chenyang Yu, Yuan Xu, Yunzhi Xiang, Yanbao Tang, Shaohua |
author_facet | Li, Huanzheng Zhang, Qian Wan, Ru Zhou, Lili Xu, Xueqin Xu, Chenyang Yu, Yuan Xu, Yunzhi Xiang, Yanbao Tang, Shaohua |
author_sort | Li, Huanzheng |
collection | PubMed |
description | Phospholipid phosphatase related 4 (PLPPR4), a neuron‐specific membrane protein located at the postsynaptic density of glutamatergic synapses, is a putative regulator of neuronal plasticity. However, PLPPR4 dysfunction has not been linked to genetic disorders. In this study, we report three unrelated patients with intellectual disability (ID) or autism spectrum disorder (ASD) who harbour a de novo heterozygous copy number loss of PLPPR4 in 1p21.2p21.3, a heterozygous nonsense mutation in PLPPR4 (NM_014839, c.4C > T, p.Gln2*) and a homozygous splice mutation in PLPPR4 (NM_014839: c.408 + 2 T > C), respectively. Bionano single‐molecule optical mapping confirmed PLPPR4 deletion contains no additional pathogenic genes. Our results suggested that the loss of function of PLPPR4 is associated with neurodevelopmental disorders. To test the pathogenesis of PLPPR4, peripheral blood mononuclear cells obtained from the patient with heterozygous deletion of PLPPR4 were induced to specific iPSCs (CHWi001‐A) and then differentiated into neurons. The neurons carrying the deletion of PLPPR4 displayed the reduced density of dendritic protrusions, shorter neurites and reduced axon length, suggesting the causal role of PLPPR4 in neurodevelopmental disorders. As the mTOR signalling pathway was essential for regulating the axon maturation and function, we found that mTOR signalling was inhibited with a higher level of p‐AKT, p‐mTOR and p‐ERK1/2, decreased p‐PI3K in PLPPR4‐iPSCs neurons. Additionally, we found silencing PLPPR4 disturbed the mTOR signalling pathway. Our results suggested PLPPR4 modulates neurodevelopment by affecting the plasticity of neurons via the mTOR signalling pathway. |
format | Online Article Text |
id | pubmed-10623522 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-106235222023-11-04 PLPPR4 haploinsufficiency causes neurodevelopmental disorders by disrupting synaptic plasticity via mTOR signalling Li, Huanzheng Zhang, Qian Wan, Ru Zhou, Lili Xu, Xueqin Xu, Chenyang Yu, Yuan Xu, Yunzhi Xiang, Yanbao Tang, Shaohua J Cell Mol Med Original Articles Phospholipid phosphatase related 4 (PLPPR4), a neuron‐specific membrane protein located at the postsynaptic density of glutamatergic synapses, is a putative regulator of neuronal plasticity. However, PLPPR4 dysfunction has not been linked to genetic disorders. In this study, we report three unrelated patients with intellectual disability (ID) or autism spectrum disorder (ASD) who harbour a de novo heterozygous copy number loss of PLPPR4 in 1p21.2p21.3, a heterozygous nonsense mutation in PLPPR4 (NM_014839, c.4C > T, p.Gln2*) and a homozygous splice mutation in PLPPR4 (NM_014839: c.408 + 2 T > C), respectively. Bionano single‐molecule optical mapping confirmed PLPPR4 deletion contains no additional pathogenic genes. Our results suggested that the loss of function of PLPPR4 is associated with neurodevelopmental disorders. To test the pathogenesis of PLPPR4, peripheral blood mononuclear cells obtained from the patient with heterozygous deletion of PLPPR4 were induced to specific iPSCs (CHWi001‐A) and then differentiated into neurons. The neurons carrying the deletion of PLPPR4 displayed the reduced density of dendritic protrusions, shorter neurites and reduced axon length, suggesting the causal role of PLPPR4 in neurodevelopmental disorders. As the mTOR signalling pathway was essential for regulating the axon maturation and function, we found that mTOR signalling was inhibited with a higher level of p‐AKT, p‐mTOR and p‐ERK1/2, decreased p‐PI3K in PLPPR4‐iPSCs neurons. Additionally, we found silencing PLPPR4 disturbed the mTOR signalling pathway. Our results suggested PLPPR4 modulates neurodevelopment by affecting the plasticity of neurons via the mTOR signalling pathway. John Wiley and Sons Inc. 2023-08-07 /pmc/articles/PMC10623522/ /pubmed/37550884 http://dx.doi.org/10.1111/jcmm.17899 Text en © 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles Li, Huanzheng Zhang, Qian Wan, Ru Zhou, Lili Xu, Xueqin Xu, Chenyang Yu, Yuan Xu, Yunzhi Xiang, Yanbao Tang, Shaohua PLPPR4 haploinsufficiency causes neurodevelopmental disorders by disrupting synaptic plasticity via mTOR signalling |
title |
PLPPR4 haploinsufficiency causes neurodevelopmental disorders by disrupting synaptic plasticity via mTOR signalling |
title_full |
PLPPR4 haploinsufficiency causes neurodevelopmental disorders by disrupting synaptic plasticity via mTOR signalling |
title_fullStr |
PLPPR4 haploinsufficiency causes neurodevelopmental disorders by disrupting synaptic plasticity via mTOR signalling |
title_full_unstemmed |
PLPPR4 haploinsufficiency causes neurodevelopmental disorders by disrupting synaptic plasticity via mTOR signalling |
title_short |
PLPPR4 haploinsufficiency causes neurodevelopmental disorders by disrupting synaptic plasticity via mTOR signalling |
title_sort | plppr4 haploinsufficiency causes neurodevelopmental disorders by disrupting synaptic plasticity via mtor signalling |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10623522/ https://www.ncbi.nlm.nih.gov/pubmed/37550884 http://dx.doi.org/10.1111/jcmm.17899 |
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