RESUMO
AIMS: Colony stimulating factor 1 receptor (CSF1R)-related leukoencephalopathy is a rapidly progressing neurodegenerative disease caused by CSF1R gene mutations. This study aimed to identify and investigate the effect of a novel intronic mutation (c.1754-3C>G) of CSF1R on splicing. METHODS: A novel intronic mutation was identified using whole-exome sequencing. To investigate the impact of this mutation, we employed various bioinformatics tools to analyze the transcription of the CSF1R gene and the three-dimensional structure of its encoded protein. Furthermore, reverse transcription polymerase chain reaction (RT-PCR) was performed to validate the findings. RESULTS: A novel mutation (c.1754-3C>G) in CSF1R was identified, which results in exon 13 skipping due to the disruption of the 3' splice site consensus sequence NYAG/G. This exon skipping event was further validated in the peripheral blood of the mutation carrier through RT-PCR and Sanger sequencing. Protein structure prediction indicated a disruption in the tyrosine kinase domain, with the truncated protein showing significant structural alterations. CONCLUSIONS: Our findings underscore the importance of intronic mis-splicing mutations in the diagnosis and management of CSF1R-related leukoencephalopathy.
Assuntos
Íntrons , Leucoencefalopatias , Mutação , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos , Humanos , Leucoencefalopatias/genética , Mutação/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Íntrons/genética , Feminino , Masculino , Adulto , Splicing de RNA/genética , Receptor de Fator Estimulador de Colônias de MacrófagosRESUMO
Appropriately manipulating macrophage M1/M2 phenotypic transition is a promising therapeutic strategy for tissue repair after myocardial infarction (MI). Here we showed that gene ablation of hypoxia-induced mitogenic factor (HIMF) in mice (Himf-/- and HIMFflox/flox;Lyz2-Cre) attenuated M1 macrophage-dominated inflammatory response and promoted M2 macrophage accumulation in infarcted hearts. This in turn reduced myocardial infarct size and improved cardiac function after MI. Correspondingly, expression of HIMF in macrophages induced expression of pro-inflammatory cytokines; the culturing medium of HIMF-overexpressing macrophages impaired the cardiac fibroblast viability and function. Furthermore, macrophage HIMF was found to up-regulate C/EBP-homologous protein (CHOP) expression, which exaggerated the release of pro-inflammatory cytokines via activating signal transducer of activator of transcription 1 (STAT1) and 3 (STAT3) signaling. Together these data suggested that HIMF promotes M1-type and prohibits M2-type macrophage polarization by activating the CHOP-STAT1/STAT3 signaling pathway to negatively regulate myocardial repair. HIMF might thus constitute a novel target to treat MI.