Transcriptome-based network analysis related to M2-like tumor-associated macrophage infiltration identified VARS1 as a potential target for improving melanoma immunotherapy efficacy.

RATIONALE: The M2-like tumor-associated macrophages (TAMs) are independent prognostic factors in melanoma. METHODS: We performed weighted gene co-expression network analysis (WGCNA) to identify the module most correlated with M2-like TAMs. The Cancer Genome Atlas (TCGA) patients were classified into two clusters that differed based on prognosis and biological function, with consensus clustering. A prognostic model was established based on the differentially expressed genes (DEGs) of the two clusters. We investigated the difference in immune cell infiltration and immune response-related gene expression between the high and low risk score groups. RESULTS: The risk score was defined as an independent prognostic value in melanoma. VARS1 was a hub gene in the M2-like macrophage-associated WGCNA module that the DepMap portal demonstrated was necessary for melanoma growth. Overexpressing VARS1 in vitro increased melanoma cell migration and invasion, while downregulating VARS1 had the opposite result. VARS1 overexpression promoted M2 macrophage polarization and increased TGF-ß1 concentrations in tumor cell supernatant in vitro. VARS1 expression was inversely correlated with immune-related signaling pathways and the expression of several immune checkpoint genes. In addition, the VARS1 expression level helped predict the response to anti-PD-1 immunotherapy. Pan-cancer analysis demonstrated that VARS1 expression negatively correlated with CD8 T cell infiltration and the immune response-related pathways in most cancers. CONCLUSION: We established an M2-like TAM-related prognostic model for melanoma and explored the role of VARS1 in melanoma progression, M2 macrophage polarization, and the development of immunotherapy resistance.

VARS1 mutations associated with neurodevelopmental disorder are located on a short amino acid stretch of the anticodon-binding domain.

Majority of 37 human aminoacyl tRNA synthetases have been incriminated in diverse, mostly recessive, genetic diseases. In accordance with this, we uncovered a novel homozygous valyl-tRNA synthetase 1 (VARS1) gene variant, leading to p.T1068M mutation. As in the previously reported VARS1 mutations, the affected individual harboring p.T1068M was experiencing a neurodevelopmental disorder with intractable seizures, psychomotor retardation, and microcephaly. To link this phenotypic outcome with the observed genotype, we structurally modeled human VARS1 and interpreted p.T1068M within the spatial distribution of previously reported VARS1 variants. As a result, we uncovered that p.T1068M is clustered with three other pathogenic mutations in a 15 amino acid long stretch of the VARS1 anticodon-binding domain. While forming a helix-turn-helix motif within the anticodon-binding domain, this stretch harbors one-fourth of the reported VARS1 mutations. Here, we propose that these clustered mutations can destabilize the interactions between the anticodon-binding and the tRNA synthetase domains and thus hindering the optimal enzymatic activity of VARS1. We expect that the depiction of this mutation cluster will pave the way for the development of drugs, capable of alleviating the functional impact of these mutations.

A case of neurodevelopmental disorder of microcephaly-epilepsy-cortical atrophy caused by VARS1 gene mutation and molecular genetic analysis / 中华神经科杂志

Objective:To investigate the clinical characteristics and genotypes of neurodevelopmental disorders of microcephaly-epilepsy-cortical atrophy caused by VARS1 gene mutation.Methods:The clinical data of a child with VARS1 gene mutation who visited Anhui Children′s Hospital in December 2021 were reviewed and followed up. Using "VARS1" "VARS" "VALYL-tRNA synthetase" "Valyl-tRNA synthetase" as the search terms, the Chinese data bases (China National Knowledge Infrastructure database, Wanfang database) and PubMed database (the database establishment until 2022). Articles related to genetic diseases were searched and clinical phenotypes and genotypes were summarized.Results:This case was a 3-month-old girl. After birth, she suffered from repeated convulsions and feeding difficulties, and gradually developed microcephaly, hypotonia, and overall developmental delay. Brain imaging showed cortical atrophy, corpus callosum dysplasia, and craniosynostosis. The results of whole exome sequencing indicated a new homozygous gene mutation in VARS1: gene mutation in exon 27 of chromosome 6 c.3203C>T(p.Thr1068 Met), which was from the patient 's parents. She took phenobarbital, levetiracetam, and sodium valproate for anti-epileptic treatment regularly, and then convulsed as a seizure every few days. A total of 19 patients were reported in 5 literatures that met the search criteria, all of whom presented with neurodevelopmental disorders. A total of 20 VARS1 gene mutation sites have been found so far. Conclusions:Neurodevelopmental disorders of microcephaly-epilepsy-cortical atrophy should be considered for children with neurodevelopmental disorders such as microcephaly, epilepsy, developmental delay, and cortical atrophy. Gene sequencing plays an important role in the diagnosis of the disease.