Hereditary spastic paraplegia (HSP) is a category of neurodegenerative illnesses with significant clinical and genetic heterogeneity. Homozygous truncated variants of the ERLIN2 gene lead to HSP18 (MIM #611225). However, it is still unclear whether there is an autosomal dominant pathogenic pattern. The specific molecular mechanism needs to be investigated. We generated patient-derived iPSC models to study the mechanism of ERLIN2 heterogeneous variants leading to HSP. We identified a heterozygous missense variant p.Val71Ala of ERLIN2 in an HSP family. Based on IP-mass spectrometry, we found that the ERLIN2 heterozygous missense variant protein recruited the ubiquitin E3 ligase RNF213 to degrade IP3R1. The degradation of IP3R1 leads to the reduction of intracellular free calcium, which triggered endoplasmic reticulum (ER) stress-mediated apoptosis. Calcium homeostasis imbalance inhibited the MAPK signaling pathway that contributed to decreased cell proliferation. In summary, these results suggest that the autosomal dominant inheritance of heterozygous missense variants in ERLIN2 is a novel pathogenic mode of HSP. Furthermore, the disruption of intracellular calcium homeostasis is the pathological mechanism.
Chromatin regulators constitute a fundamental means of transcription regulation, which have been implicated in neurodevelopment and neurodevelopment disorders (NDDs). Supt16, one of candidate genes for NDDs, encodes the large subunit of facilitates chromatin transcription. However, the underlying mechanisms remain poorly understood. Here, Supt16+/- mice was generated, modeling the neurodevelopment disorder. Abnormal cognitive and social behavior was observed in the Supt16 +/- mice. Simultaneously, the number of neurocytes in the cerebral cortex and hippocampus is decreased, which might be resulted from the impairment of mouse neural stem cells (mNSCs) in the SVZ. Supt16 haploinsufficiency affects the proliferation and apoptosis of mNSCs. As the RNA-seq and chromatic immunoprecipitation sequencing assays showed, Supt16 haploinsufficiency disrupts the stemness of mNSCs by inhibiting MAPK signal pathway. Thus, this study demonstrates a critical role of Supt16 gene in the proliferation and apoptosis of mNSCs and provides a novel insight in the pathogenesis of NDDs.
Abstract The structural cuticle proteins (CPs) play important roles in the development and fitness of insects. However, knowledge about CP gene superfamily is limited in virus‐transmitting insect vectors, although its importance on transmission of plant virus has been gradually emphasized. In this study, the genome‐wide identification of CP superfamily was conducted in western flower thrips Frankliniella occidentalis that is the globally invasive pest and plant virus vector pest. The pest transmits notorious tomato spotted wilt virus (TSWV) around the world, causing large damage to a wide array of plants. One hundred and twenty‐eight F. occidentalis CP genes ( FoCP s) were annotated in this study and they were classified into 10 distinct families, including 68 CPR s, 16 CPAP1 s, 6 CPAP3 s, 2 CPCFC s, 10 Tweedle s, 4 CPF s, 16 CPLCP s, and 6 CPG s. The comprehensive analysis was performed including phylogenetic relationship, gene location and gene expression profiles during different development stages of F. occidentalis . Transcriptome analysis revealed more than 30% FoCP s were upregulated at least 1.5‐fold when F. occidentalis was infected by TSWV, indicating their potential involvement in TSWV interactions. Our study provided an overview of F. occidentalis CP superfamily. The study gave a better understand of CP's role in development and virus transmission, which provided clues for reducing viral damages through silencing CP genes in insect vectors.
The maintenance of neural stem cells (NSCs) plays a critical role in neurodevelopment and has been implicated in neurodevelopmental disorders (NDDs). However, the underlying mechanisms linking defective human neural stem cell self-renewal to NDDs remain undetermined. Our previous study found that Supt16 haploinsufficiency causes cognitive and social behavior deficits by disrupting the stemness maintenance of NSCs in mice. However, its effects and underlying mechanisms have not been elucidated in human neural stem cells (hNSCs). Here, we generated Supt16+/- induced pluripotent stem cells (iPSCs) and induced them into hNSCs. The results revealed that Supt16 heterozygous hNSCs exhibit impaired proliferation, cell cycle arrest, and increased apoptosis. As the RNA-seq analysis showed, Supt16 haploinsufficiency inhibited the PI3K/AKT/mTOR pathway, leading to rising autophagy, and further resulted in the dysregulated expression of multiple proteins related to cell proliferation and apoptotic process. Furthermore, the suppression of Supt16 heterozygous hNSC self-renewal caused by autophagy activation could be rescued by MHY1485 treatment or reproduced in rapamycin-treated hNSCs. Thus, our results showed that Supt16 was essential for hNSC self-renewal and its haploinsufficiency led to cell cycle arrest, impaired cell proliferation, and increased apoptosis of hNSCs by regulating the PI3K/AKT/mTOR/autophagy pathway. These provided a new insight to understand the causality between the Supt16 heterozygous NSCs and NDDs in humans.
Abstract Background Genodermatoses are a broad group of disorders with specific or non-specific skin-based phenotypes, most of which are monogenic disorders. However, it’s a great challenge to make a precise molecular diagnosis because of the clinical heterogeneity. The genetic and clinical heterogeneity brings great challenges for diagnosis in dermatology. The whole exome sequencing (WES) not only expedites the discovery of the genetic variations, but also contributes to genetic counselling and prenatal diagnosis. Materials and methods Followed by the initial clinical and pathological diagnosis, genetic variations were identified by WES. The pathogenicity of the copy number variations (CNVs) and single-nucleotide variants (SNVs) were evaluated according to ACMG guidelines. Candidate pathogenic SNVs were confirmed by Sanger sequencing in the proband and the family members. Results Totally 25 cases were recruited. Nine novel variations, including c.5546G > C and c.1457delC in NF1 , c.6110G > T in COL7A1 , c.2127delG in TSC1 , c.1445 C > A and c.1265G > A in TYR , Xp22.31 deletion in STS , c.908 C > T in ATP2A2 , c.1371insC in IKBKG , and nine known ones were identified in 16 cases (64%). Prenatal diagnosis was applied in 6 pregnant women by amniocentesis, two of whom carried positive findings. Conclusions Our findings highlighted the value of WES as a first-tier genetic test in determining the molecular diagnosis. We also discovered the distribution of genodermatoses in this district, which provided a novel clinical dataset for dermatologists.
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