ASH1L haploinsufficiency results in autistic-like phenotypes in mice and links Eph receptor gene to autism spectrum disorder

Yan, Yuze; Tian, Miaomiao; Li, Meng; Zhou, Gang; Chen, Qinan; Xu, Mingrui; Hu, Yi; Luo, Wenhan; Guo, Xiu‐Xian; Zhang, Cheng; Xie, Haiyang; Wu, Qing-Feng; Xiong, Wei; Liu, Shiguo; Guan, Ji‐Song

doi:10.1016/j.neuron.2021.12.035

Cited by 31 publications

(13 citation statements)

References 73 publications

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Section: Discussionmentioning

confidence: 99%

“…Ash1l has been identified as a risk gene for mental developmental disorders (Cheon et al, 2022; Liu et al, 2020; Yan et al, 2022). Its haploinsufficiency blocks activity‐dependent synapse elimination and increases spine density on cortical neurons and dorsal striatal medium spiny neurons; meanwhile, the expression of voltage‐gated potassium channels, which negatively regulate neuronal excitability, is also decreased in auditory cortex (Yan et al, 2022). In DRG neurons, Ash1l haploinsufficiency resulted in 668 genes up‐regulated and predominantly implicated in processes associated with neuronal excitability, neurite outgrowth and vesicular transportation and release (Figure 8j).…”

Section: Discussionmentioning

confidence: 99%

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Ash1L ameliorates psoriasis via limiting neuronal activity‐dependent release of miR‐let‐7b

Du,

Yang,

Tong

et al. 2023

British J Pharmacology

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Background and PurposePsoriasis is a common autoimmune skin disease which significantly diminishes patients’ quality of life. Primary afferents of the somatosensory system and cutaneous immune system interaction essentially mediates the pathogenesis of psoriasis. This study aims to elucidate the molecular mechanism for how primary sensory neurons regulate psoriasis formation.Experimental ApproachSkin and total RNA was extracted from WT and Ash1l+/‐ (ASH1 like histone lysine methyltransferase) mice in both naïve and IMQ (Imiquimod)‐induced psoriasis model conditions. Immunohistochemistry, qRT‐PCR and FACS were then performed. Microfluidic chamber coculture was used to investigate the interaction between somatosensory sensory neurons and bone marrow dendritic cells (BMDCs) ex vivo. Whole‐cell patch clamp recordings was used to evaluate neuronal excitability after Ash1L haploinsufficiency in primary sensory neurons.Key ResultsThe haploinsufficiency of ASH1L, a histone methyltransferase, in primary sensory neurons causes both neurite hyperinnervation and increased neuronal excitability, which promote miR‐let‐7b release from primary afferents in the skin in a neuronal activity‐dependent manner. With a “GUUGUGU” core sequence, miR‐let‐7b functions as an endogenous ligand of Toll‐like receptor 7 (TLR7) and stimulates the activation of dermal DCs and interleukin (IL)‐23/IL‐17 axis, ultimately exacerbating the symptoms of psoriasis. Thus, by limiting miR‐let‐7b release from primary afferents, ASH1L prevents dermal DCs activation and ameliorates psoriasis.Conclusion and ImplicationsSomatosensory neuron ASH1L modulates cutaneous immune by limiting neuronal activity‐dependent release of miR‐let‐7b, which can directly activate dermal DCs via TLR7 and ultimately lead to aggravated psoriatic lesion.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Ash1L ameliorates psoriasis via limiting neuronal activity‐dependent release of miR‐let‐7b

Du,

Yang,

Tong

et al. 2023

British J Pharmacology

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“…Additional filters were also performed to restrict target genes to brain expressed genes and haploinsufficient genes (since haploinsufficiency of ASD ( Katayama et al, 2016 ; Yan et al, 2022 ) and epilepsy ( Chénier et al, 2014 ; Carvill et al, 2021 ) related genes has been demonstrated as a risk factor). For the first filter, genes were considered brain expressed as expressed in any GTEx v7 brain tissue (N = 18,036 genes).…”

Section: Methodsmentioning

confidence: 99%

Analysis of common genetic variation across targets of microRNAs dysregulated both in ASD and epilepsy reveals negative correlation

Stella

Díaz‐Caneja²,

Penzol³

et al. 2023

Front. Genet.

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Genetic overlap involving rare disrupting mutations may contribute to high comorbidity rates between autism spectrum disorders and epilepsy. Despite their polygenic nature, genome-wide association studies have not reported a significant contribution of common genetic variation to comorbidity between both conditions. Analysis of common genetic variation affecting specific shared pathways such as miRNA dysregulation could help to elucidate the polygenic mechanisms underlying comorbidity between autism spectrum disorders and epilepsy. We evaluated here the role of common predisposing variation to autism spectrum disorders and epilepsy across target genes of 14 miRNAs selected through bibliographic research as being dysregulated in both disorders. We considered 4,581 target genes from various in silico sources. We described negative genetic correlation between autism spectrum disorders and epilepsy across variants located within target genes of the 14 miRNAs selected (p = 0.0228). Moreover, polygenic transmission disequilibrium test on an independent cohort of autism spectrum disorders trios (N = 233) revealed an under-transmission of autism spectrum disorders predisposing alleles within miRNAs’ target genes across autism spectrum disorders trios without comorbid epilepsy, thus reinforcing the negative relationship at the common genetic variation between both traits. Our study provides evidence of a negative relationship between autism spectrum disorders and epilepsy at the common genetic variation level that becomes more evident when focusing on the miRNA regulatory networks, which contrasts with observed clinical comorbidity and results from rare variation studies. Our findings may help to conceptualize the genetic heterogeneity and the comorbidity with epilepsy in autism spectrum disorders.

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“…25) had 2 molecular results (G6PD [OMIM 305900] and COL4A3 [OMIM 120070]) (Table 3). [51][52][53][54][55][56][57][58][59][60] Sequence analysis uncovered 33 of 47 of all at-risk genotypes (…”

Section: Positive Gs Findingsmentioning

confidence: 99%

At-Risk Genomic Findings for Pediatric-Onset Disorders From Genome Sequencing vs Medically Actionable Gene Panel in Proactive Screening of Newborns and Children

et al. 2023

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ImportanceAlthough the clinical utility of genome sequencing for critically ill children is well recognized, its utility for proactive pediatric screening is not well explored.ObjectiveTo evaluate molecular findings from screening ostensibly healthy children with genome sequencing compared with a gene panel for medically actionable pediatric conditions.Design, Setting, and ParticipantsThis case series study was conducted among consecutive, apparently healthy children undergoing proactive genetic screening for pediatric disorders by genome sequencing (n = 562) or an exome-based panel of 268 genes (n = 606) from March 1, 2018, through July 31, 2022.ExposuresGenetic screening for pediatric-onset disorders using genome sequencing or an exome-based panel of 268 genes.Main Outcomes and MeasuresMolecular findings indicative of genetic disease risk.ResultsOf 562 apparently healthy children (286 girls [50.9%]; median age, 29 days [IQR, 9-117 days]) undergoing screening by genome sequencing, 46 (8.2%; 95% CI, 5.9%-10.5%) were found to be at risk for pediatric-onset disease, including 22 children (3.9%) at risk for high-penetrance disorders. Sequence analysis uncovered molecular diagnoses among 32 individuals (5.7%), while copy number variant analysis uncovered molecular diagnoses among 14 individuals (2.5%), including 4 individuals (0.7%) with chromosome scale abnormalities. Overall, there were 47 molecular diagnoses, with 1 individual receiving 2 diagnoses; of the 47 potential diagnoses, 22 (46.8%) were associated with high-penetrance conditions. Pathogenic variants in medically actionable pediatric genes were found in 6 individuals (1.1%), constituting 12.8% (6 of 47) of all diagnoses. At least 1 pharmacogenomic variant was reported for 89.0% (500 of 562) of the cohort. In contrast, of 606 children (293 girls [48.3%]; median age, 26 days [IQR, 10-67 days]) undergoing gene panel screening, only 13 (2.1%; 95% CI, 1.0%-3.3%) resulted in potential childhood-onset diagnoses, a significantly lower rate than those screened by genome sequencing (P &lt; .001).Conclusions and RelevanceIn this case series study, genome sequencing as a proactive screening approach for children, due to its unrestrictive gene content and technical advantages in comparison with an exome-based gene panel for medically actionable childhood conditions, uncovered a wide range of heterogeneous high-penetrance pediatric conditions that could guide early interventions and medical management.

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ASH1L haploinsufficiency results in autistic-like phenotypes in mice and links Eph receptor gene to autism spectrum disorder

Cited by 31 publications

References 73 publications

Ash1L ameliorates psoriasis via limiting neuronal activity‐dependent release of miR‐let‐7b

Ash1L ameliorates psoriasis via limiting neuronal activity‐dependent release of miR‐let‐7b

Analysis of common genetic variation across targets of microRNAs dysregulated both in ASD and epilepsy reveals negative correlation

At-Risk Genomic Findings for Pediatric-Onset Disorders From Genome Sequencing vs Medically Actionable Gene Panel in Proactive Screening of Newborns and Children

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