RESUMO
The diagnostic gap for rare neurodegenerative diseases is still considerable, despite continuous advances in gene identification. Many novel Mendelian genes have only been identified in a few families worldwide. Here we report the identification of an autosomal-dominant gene for hereditary spastic paraplegia (HSP) in 10 families that are of diverse geographic origin and whose affected members all carry unique truncating changes in a circumscript region of UBAP1 (ubiquitin-associated protein 1). HSP is a neurodegenerative disease characterized by progressive lower-limb spasticity and weakness, as well as frequent bladder dysfunction. At least 40% of affected persons are currently undiagnosed after exome sequencing. We identified pathological truncating variants in UBAP1 in affected persons from Iran, USA, Germany, Canada, Spain, and Bulgarian Roma. The genetic support ranges from linkage in the largest family (LOD = 8.3) to three confirmed de novo mutations. We show that mRNA in the fibroblasts of affected individuals escapes nonsense-mediated decay and thus leads to the expression of truncated proteins; in addition, concentrations of the full-length protein are reduced in comparison to those in controls. This suggests either a dominant-negative effect or haploinsufficiency. UBAP1 links endosomal trafficking to the ubiquitination machinery pathways that have been previously implicated in HSPs, and UBAP1 provides a bridge toward a more unified pathophysiology.
Assuntos
Proteínas de Transporte/genética , Mutação , Paraplegia Espástica Hereditária/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Criança , Pré-Escolar , Bases de Dados Factuais , Modelos Animais de Doenças , Endossomos/metabolismo , Saúde da Família , Feminino , Fibroblastos/metabolismo , Genes Dominantes , Ligação Genética , Predisposição Genética para Doença , Genômica , Células HEK293 , Haploinsuficiência , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Isoformas de Proteínas , Adulto Jovem , Peixe-ZebraRESUMO
The emerging Coronavirus Disease 2019 (COVID-19) pandemic has posed a serious threat to the public health worldwide, demanding urgent vaccine provide. According to the virus feature as an RNA virus, a high rate of mutations imposes some vaccine design difficulties. Bioinformatics tools have been widely used to make advantage of conserved regions as well as immunogenicity. In this study, we aimed at immunoinformatic evaluation of SARS-CoV-2 proteins conservancy and immunogenicity to design a preventive vaccine candidate. Spike, Membrane and Nucleocapsid amino acid sequences were obtained, and four possible fusion proteins were assessed and compared in terms of structural features and immunogenicity, and population coverage. MHC-I and MHC-II T-cell epitopes, the linear and conformational B-cell epitopes were evaluated. Among the predicted models, the truncated form of Spike in fusion with M and N protein applying AAY linker has high rate of MHC-I and MCH-II epitopes with high antigenicity and acceptable population coverage of 82.95% in Iran and 92.51% in Europe. The in silico study provided truncated Spike-M-N SARS-CoV-2 as a potential preventive vaccine candidate for further in vivo evaluation.