Autism patient-derived SHANK2B Y29X mutation affects the development of ALDH1A1 negative dopamine neuron.
Wanjing LaiYingying ZhaoYalan ChenZhenzhu DaiRuhai ChenYimei NiuXiaoxia ChenShuting ChenGuanqun HuangZiyun ShanJiajun ZhengYu HuQingpei ChenSiyi GongSai KangHui GuoXiaokuang MaYouqiang SongKun XiaJie WangLibing ZhouKowk-Fai SoKai WangShenfeng QiuLi ZhangJie-Kai ChenLingling ShiPublished in: Molecular psychiatry (2024)
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 Y29X . 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 Y29X 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.
Keyphrases
- autism spectrum disorder
- intellectual disability
- single cell
- induced pluripotent stem cells
- rna seq
- attention deficit hyperactivity disorder
- spinal cord
- genome wide
- copy number
- case report
- endothelial cells
- type diabetes
- poor prognosis
- uric acid
- big data
- adipose tissue
- dna methylation
- electronic health record
- skeletal muscle
- gene expression
- machine learning
- prefrontal cortex
- congenital heart disease
- high fat diet induced