Kun Xia

Affective empathy describes the capacity to share others' emotions, yet the molecular mechanisms governing individual differences in empathic sensitivity remain poorly understood. Using a male mouse model of social transmission of depression (STD), we demonstrated that STD‑sensitive observer mice exhibit heightened neuronal excitability and upregulated major urinary protein 1 (MUP1) expression in the medial prefrontal cortex (mPFC) compared with STD‑insensitive observer mice. Mechanistically, MUP1 drives the STD‑sensitive phenotype by modulating astrocytic glutamate transporter 1 (GLT1) to augment mPFC neuronal excitability. Via virtual screening, we identified two small‑molecule compounds (C25 and C11) that bidirectionally modulate STD‑related behaviors. In summary, our work establishes MUP1 as a master modulator of STD vulnerability, deciphers mechanisms driving heterogeneous affective empathy across individuals, and unveils actionable therapeutic candidates for empathy-related psychiatric illnesses.

Autism spectrum disorder (ASD) is a genetically complex neurodevelopmental condition with a high heritability. However, genomic studies of ASD have been underrepresented in East Asian populations, and the molecular yield in ASD cohorts remains modest. Here, we present a whole-genome sequencing analysis of 3109 samples across 1033 Chinese ASD families. By examining a wide spectrum of genetic variation, we identified rare ASD-associated variants in 19.2% of affected individuals, providing a population-specific view of the genetic architecture of ASD. We identify significant enrichment of de novo variants in probands, nominate or strengthen candidate risk genes (e.g., NCL, SPPL3, ADGRB1, SLC9A3, KIF1B) through mutational burden, evolutionary constraint, recurrent missense site, and functional assays, and implicate convergent pathways including protein palmitoylation. By integrating over 40,000 ASD cases across unpublished and published global cohorts, we identify 245 ASD risk genes, including 45 with limited prior evidence and 32 with no prior association. Single-cell transcriptomic profiling of the developing human cortex reveals that ASD risk genes exhibit widespread yet heterogeneous expression across all major cell types, with peak expression in excitatory neurons, particularly intratelencephalic neurons, and enriched expression in microglia (e.g., C1QC, CARD11, SNX13, MEF2C, FOXP2, TCF12, MED13L), suggesting convergent involvement of both synaptic and neuroimmune mechanisms. Together, our findings expand the ASD genetic landscape and suggest convergent pathogenic axes involving transcriptional regulation, synaptic signaling and plasticity, and neuroimmune interactions. This work supports the development of inclusive diagnostic strategies and provides a foundation for mechanistic and intervention exploration in ASD.

Epigenetic dysregulation plays an essential role in autism spectrum disorder (ASD), but the parent-of-origin effects (POEs) of DNA methylation remain unknown. Here, we applied PacBio HiFi sequencing with haplotype-phased methylation profiling in 124 individuals (31 ASD quartets) to systematically dissect POE-dependent methylation. Comparative analysis of phased methylomes between probands and unaffected siblings identified 114 paternal- and 106 maternal-specific differential methylated cytosines (DMCs), 45 and 46 differential methylated regions (DMRs), and 2425 and 2693 methylation outliers (MOs), respectively. These POE methylation alterations were enriched in ASD-relevant gene categories but exhibited distinct genomic distributions and functional pathways between parental haplotypes. Furthermore, genome-wide parent-of-origin DMR analysis identified 443 allele-specific methylation (ASM) regions, from which we detected 34 differential expression ASMs and 62 ASM outliers, showing pronounced enrichment within PWS/AS locus and ASD-associated genes. Collectively, this study provides a comprehensive evidence of pervasive POE-dependent methylation imbalance and aberrant ASM at imprinting regions underlying ASD pathogenesis, offering insights into epigenetic mechanisms of complex neurodevelopmental disorders.

Autism spectrum disorder (ASD) is a heterogeneous condition in which genetically defined subtypes offered insights into underlying biological mechanisms and potential targeted treatments. Here, we investigate the clinical and pathogenic significance of GIGYF2 variants in ASD through an integrated approach combining clinical genetics, conditional knockout (cKO) mouse models, neurobiology, and molecular studies. Through targeted sequencing, large-scale genomic data analysis of neurodevelopmental disorder cohorts, and international collaborations, we identified ten affected individuals from eight families harboring de novo or dominantly inherited likely gene-disruptive (LGD) variants and 13 affected individuals from 13 families with de novo missense variants in GIGYF2. Clinical characterization of 16 probands with GIGYF2 variants revealed common features, including ASD, language problems, intellectual disability, and anxiety. In a Gigyf2 cKO mouse model, we observed pronounced autistic-like behaviors, cognitive deficits, and anxiety-like behaviors, mirroring phenotypes observed in affected individuals. Mechanistically, Gigyf2 deficiency disrupted synaptic homeostasis, as evidenced by altered spine density and miniature excitatory postsynaptic currents, and impaired IGF-1R/mTOR signaling, along with dysregulation of synapse-related genes such as Nrp2. Pharmacological inhibition of mTOR with rapamycin or Torin1, as well as Nrp2 knockdown rescued synaptic defects in Gigyf2 KO neurons. These findings define a novel ASD subtype associated with GIGYF2 variants and establish GIGYF2 as a key regulator of synaptic development and function, implicating GIGYF2 dysfunction in ASD pathogenesis and highlighting the IGF-1R/mTOR pathway as a potential therapeutic target for GIGYF2-related ASD subtype.

Neurodevelopmental disorders (NDDs) are frequently associated with dysregulation of epigenetic mechanisms. Recent studies have implicated variants in components of the Male-Specific Lethal (MSL) complex, including MSL2, in NDD pathogenesis. However, the pathogenic mechanisms underlying MSL2-related neurodevelopmental disorders remain poorly defined. Here, we elucidate the role of MSL2 in neurodevelopment and NDDs through comprehensive analysis of conditional knockout mice and multi-omics profiling. Aggregation of published and unpublished genomic data and case series revealed that pathogenic variants in MSL complex components, including MSL2, presented with shared phenotypes. Using a nervous system-specific Msl2 conditional knockout mouse model, we demonstrate that Msl2 deficiency leads to impaired social novelty recognition, learning deficits, and spatial memory impairments. These behavioral abnormalities are characterized by disrupted neocortical lamination, compromised proliferation capacity and differentiative ability of neural progenitor cells, and reduced neuronal migration. Mechanistically, Msl2-deficient brains exhibit significantly reduced levels of histone H4 lysine 16 acetylation (H4K16ac), particularly at promoter regions. Integrated RNA-seq, ChIP-seq, and ATAC-seq analyses revealed widespread transcriptional downregulation and loss of chromatin accessibility at NDD-related genes. Variants in the MSL2 DNA-binding domain disrupted its ability to target key regulatory genes including FMR1, confirming direct epigenetic regulation. Together, these findings demonstrate that MSL2 promotes neurodevelopment primarily by maintaining chromatin accessibility through H4K16ac deposition, and its disruption underlies the molecular and behavioral hallmarks of NDDs.

Myopia represents a refractive anomaly characterized by impaired vision resulting from a misfocused image in front of the fovea. Although numerous genes linked to high myopia (HM) have been identified, the exact etiology and pathogenesis mechanisms of HM remain predominantly obscure. In a prior investigation, a mutation in the P4HA2 gene was identified in association with HM. To illuminate the potential mechanisms of action of P4HA2 in HM, we established a P4HA2 ‐knockout mouse line ( P4ha2 ^−/− ) and a P4HA2‐knockout HEK293 cell line for this study. P4ha2 ^−/− mice exhibited compromised visual acuity and altered light transmission pathways as evidenced by multiple biometric assessments. Furthermore, we observed a time‐dependent disruption in the arrangement of collagen fibrils in the sclera and cornea of the P4ha2 ^−/− mice, attributed to diminished thermal stability due to decreased collagen hydroxylation. Our findings also revealed elevated fibronectin levels and reduced Collagen I expression in the sclera and cornea of the P4ha2 ^−/− mice, as well as in P4HA2‐knockout HEK293 cells, suggesting an imbalance in extracellular matrix (ECM) components that could further perturb light transmission pathways, which induced HM‐associated refractive error. In summary, P4HA2 contributes significantly to the pathogenesis and progressive deterioration of refractive error by accelerating collagen degeneration via reduced collagen hydroxylation.

Neurodevelopmental Disorders (NDDs) represent chronic cerebral dysfunctions arising from gene-environment interactions, encompassing conditions such Autism Spectrum Disorders (ASD) and attention-deficit/hyperactivity disorders (ADHD). Emerging evidence identifies Maternal immune activation (MIA) as a critical environmental risk factor for NDDs. Gestational infections, inflammatory responses, or immune dysregulation elevate maternal-fetal inflammatory mediators, which disrupt neurodevelopmental trajectories via placental-fetal signaling cascades. Preclinical models (rodents, non-human primates) demonstrate that MIA induces characteristic NDD phenotypes—including social deficits and cognitive impairments—through microglial hyperactivation, aberrant synaptic pruning, oxidative stress, and mitochondrial dysfunction. Concurrently, gut microbiota dysbiosis and Th17/Treg immune imbalance exacerbate neuroinflammatory processes. Novel therapeutic strategies targeting inflammatory pathways microglial modulation, or microbial homeostasis restoration show translational promise. Future investigations must unravel MIA’s molecular underpinnings and multifactorial interactions to enable early-risk stratification and precision interventions for NDDs.