Autism patient-derived SHANK2B Y29X mutation affects the development of ALDH1A1 negative dopamine neuron
Autism spectrum disorder (ASD) encompasses a range of neurodevelopmental conditions. Different mutations on a single ASD gene contribute to heterogeneity of disease phenotypes, possibly due to functional diversity of generated isoforms. SHANK2, a causative gene in ASD, demonstrates this phenomenon,...
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Published in | Molecular psychiatry |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
04.05.2024
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Abstract | Autism spectrum disorder (ASD) encompasses a range of neurodevelopmental conditions. Different mutations on a single ASD gene contribute to heterogeneity of disease phenotypes, possibly due to functional diversity of generated isoforms. SHANK2, a causative gene in ASD, demonstrates this phenomenon, but there is a scarcity of tools for studying endogenous SHANK2 proteins in an isoform-specific manner. Here, we report a point mutation on SHANK2, which is found in a patient with autism, located on exon of the SHANK2B transcript variant (NM_133266.5), hereby SHANK2B
. This mutation results in an early stop codon and an aberrant splicing event that impacts SHANK2 transcript variants distinctly. Induced pluripotent stem cells (iPSCs) carrying this mutation, from the patient or isogenic editing, fail to differentiate into functional dopamine (DA) neurons, which can be rescued by genetic correction. Available SMART-Seq single-cell data from human midbrain reveals the abundance of SHANK2B transcript in the ALDH1A1 negative DA neurons. We then show that SHANK2B
mutation primarily affects SHANK2B expression and ALDH1A1 negative DA neurons in vitro during early neuronal developmental stage. Mice knocked in with the identical mutation exhibit autistic-like behavior, decreased occupancy of ALDH1A1 negative DA neurons and decreased dopamine release in ventral tegmental area (VTA). Our study provides novel insights on a SHANK2 mutation derived from autism patient and highlights SHANK2B significance in ALDH1A1 negative DA neuron. |
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AbstractList | Autism spectrum disorder (ASD) encompasses a range of neurodevelopmental conditions. Different mutations on a single ASD gene contribute to heterogeneity of disease phenotypes, possibly due to functional diversity of generated isoforms. SHANK2, a causative gene in ASD, demonstrates this phenomenon, but there is a scarcity of tools for studying endogenous SHANK2 proteins in an isoform-specific manner. Here, we report a point mutation on SHANK2, which is found in a patient with autism, located on exon of the SHANK2B transcript variant (NM_133266.5), hereby SHANK2B
. This mutation results in an early stop codon and an aberrant splicing event that impacts SHANK2 transcript variants distinctly. Induced pluripotent stem cells (iPSCs) carrying this mutation, from the patient or isogenic editing, fail to differentiate into functional dopamine (DA) neurons, which can be rescued by genetic correction. Available SMART-Seq single-cell data from human midbrain reveals the abundance of SHANK2B transcript in the ALDH1A1 negative DA neurons. We then show that SHANK2B
mutation primarily affects SHANK2B expression and ALDH1A1 negative DA neurons in vitro during early neuronal developmental stage. Mice knocked in with the identical mutation exhibit autistic-like behavior, decreased occupancy of ALDH1A1 negative DA neurons and decreased dopamine release in ventral tegmental area (VTA). Our study provides novel insights on a SHANK2 mutation derived from autism patient and highlights SHANK2B significance in ALDH1A1 negative DA neuron. |
Author | Chen, Shuting Zhao, Yingying Chen, Qingpei Chen, Xiaoxia Chen, Jiekai Niu, Yimei Huang, Guanqun Gong, Siyi Xia, Kun Zhou, Libing Dai, Zhenzhu Zheng, Jiajun Qiu, Shenfeng Lai, Wanjing Song, Youqiang Zhang, Li So, Kwok-Fai Wang, Jie Shi, Lingling Chen, Ruhai Kang, Sai Shan, Ziyun Guo, Hui Wang, Kai Chen, Yalan Ma, Xiaokuang Hu, Yu |
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Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA – sequence: 13 givenname: Qingpei surname: Chen fullname: Chen, Qingpei organization: Guangdong-Hongkong-Macau CNS Regeneration Institute of Jinan University, Key Laboratory of CNS Regeneration (Jinan University)-Ministry of Education, Guangdong Key Laboratory of Non-human Primate Research, Guangzhou, 510632, China – sequence: 14 givenname: Siyi surname: Gong fullname: Gong, Siyi organization: Guangdong-Hongkong-Macau CNS Regeneration Institute of Jinan University, Key Laboratory of CNS Regeneration (Jinan University)-Ministry of Education, Guangdong Key Laboratory of Non-human Primate Research, Guangzhou, 510632, China – sequence: 15 givenname: Sai surname: Kang fullname: Kang, Sai organization: Guangdong-Hongkong-Macau CNS Regeneration Institute of Jinan University, Key Laboratory of CNS Regeneration (Jinan University)-Ministry of Education, Guangdong Key Laboratory of Non-human Primate Research, Guangzhou, 510632, China – sequence: 16 givenname: Hui surname: Guo fullname: Guo, Hui organization: Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, 410008, China – sequence: 17 givenname: Xiaokuang orcidid: 0000-0001-7900-6779 surname: Ma fullname: Ma, Xiaokuang organization: Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, 850004, USA – sequence: 18 givenname: Youqiang surname: Song fullname: Song, Youqiang organization: School of Biomedical Sciences, University of Hong Kong, Hong Kong SAR, China – sequence: 19 givenname: Kun orcidid: 0000-0001-8090-6002 surname: Xia fullname: Xia, Kun organization: Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, 410008, China – sequence: 20 givenname: Jie surname: Wang fullname: Wang, Jie organization: Center for Cell Lineage and Development, CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Joint School of Life Sciences, Guangzhou Medical University, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China – sequence: 21 givenname: Libing surname: Zhou fullname: Zhou, Libing organization: Guangdong-Hongkong-Macau CNS Regeneration Institute of Jinan University, Key Laboratory of CNS Regeneration (Jinan University)-Ministry of Education, Guangdong Key Laboratory of Non-human Primate Research, Guangzhou, 510632, China – sequence: 22 givenname: Kwok-Fai orcidid: 0000-0003-4039-4246 surname: So fullname: So, Kwok-Fai organization: Guangdong-Hongkong-Macau CNS Regeneration Institute of Jinan University, Key Laboratory of CNS Regeneration (Jinan University)-Ministry of Education, Guangdong Key Laboratory of Non-human Primate Research, Guangzhou, 510632, China – sequence: 23 givenname: Kai orcidid: 0000-0002-5585-982X surname: Wang fullname: Wang, Kai organization: Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA – sequence: 24 givenname: Shenfeng orcidid: 0000-0002-0730-1602 surname: Qiu fullname: Qiu, Shenfeng organization: Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, 850004, USA – sequence: 25 givenname: Li orcidid: 0000-0003-1489-0879 surname: Zhang fullname: Zhang, Li email: zhangli@jnu.edu.cn organization: Guangdong-Hongkong-Macau CNS Regeneration Institute of Jinan University, Key Laboratory of CNS Regeneration (Jinan University)-Ministry of Education, Guangdong Key Laboratory of Non-human Primate Research, Guangzhou, 510632, China. zhangli@jnu.edu.cn – sequence: 26 givenname: Jiekai orcidid: 0000-0001-5168-7074 surname: Chen fullname: Chen, Jiekai email: chen_jiekai@gibh.ac.cn, chen_jiekai@gibh.ac.cn organization: Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, 999077, China. chen_jiekai@gibh.ac.cn – sequence: 27 givenname: Lingling orcidid: 0000-0003-4225-209X surname: Shi fullname: Shi, Lingling email: tlingshi@jnu.edu.cn, tlingshi@jnu.edu.cn, tlingshi@jnu.edu.cn, tlingshi@jnu.edu.cn organization: Department of Neurology, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, China. tlingshi@jnu.edu.cn |
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Snippet | Autism spectrum disorder (ASD) encompasses a range of neurodevelopmental conditions. Different mutations on a single ASD gene contribute to heterogeneity of... |
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Title | Autism patient-derived SHANK2B Y29X mutation affects the development of ALDH1A1 negative dopamine neuron |
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