当前位置: X-MOL 学术Eur. J. Hum. Genet. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Pathogenic SLIRP variants as a novel cause of autosomal recessive mitochondrial encephalomyopathy with complex I and IV deficiency
European Journal of Human Genetics ( IF 5.2 ) Pub Date : 2021-08-23 , DOI: 10.1038/s41431-021-00947-1
Le Guo 1, 2 , Bob P H Engelen 3 , Irene M G M Hemel 3 , Irenaeus F M de Coo 1, 2 , Maaike Vreeburg 4 , Suzanne C E H Sallevelt 4 , Debby M E I Hellebrekers 4 , Ed H Jacobs 5 , Farah Sadeghi-Niaraki 5 , Florence H J van Tienen 1, 2 , Hubert J M Smeets 1, 2, 6 , Mike Gerards 3
Affiliation  

In a Dutch non-consanguineous patient having mitochondrial encephalomyopathy with complex I and complex IV deficiency, whole exome sequencing revealed two compound heterozygous variants in SLIRP. SLIRP gene encodes a stem-loop RNA-binding protein that regulates mitochondrial RNA expression and oxidative phosphorylation (OXPHOS). A frameshift and a deep-intronic splicing variant reduced the amount of functional wild-type SLIRP RNA to 5%. Consequently, in patient fibroblasts, MT-ND1, MT-ND6, and MT-CO1 expression was reduced. Lentiviral transduction of wild-type SLIRP cDNA in patient fibroblasts increased MT-ND1, MT-ND6, and MT-CO1 expression (2.5–7.2-fold), whereas mutant cDNAs did not. A fourfold decrease of citrate synthase versus total protein ratio in patient fibroblasts indicated that the resulting reduced mitochondrial mass caused the OXPHOS deficiency. Transduction with wild-type SLIRP cDNA led to a 2.4-fold increase of this ratio and partly restored OXPHOS activity. This confirmed causality of the SLIRP variants. In conclusion, we report SLIRP variants as a novel cause of mitochondrial encephalomyopathy with OXPHOS deficiency.



中文翻译:

致病性 SLIRP 变异作为常染色体隐性线粒体脑肌病伴 I 和 IV 缺陷的新病因

在一名患有线粒体脑肌病并伴有复合体 I 和复合体 IV 缺陷的荷兰非近亲血缘患者中,全外显子组测序揭示了SLIRP中的两种复合杂合变异。SLIRP基因编码一种调节线粒体 RNA 表达和氧化磷酸化 (OXPHOS) 的茎环 RNA 结合蛋白。移码和深内含子剪接变体将功能性野生型SLIRP RNA 的数量减少到 5%。因此,在患者成纤维细胞中,MT - ND1MT - ND6MT - CO1表达减少。野生型SLIRP的慢病毒转导患者成纤维细胞中的 cDNA 增加了MT - ND1MT - ND6MT - CO1表达(2.5-7.2 倍),而突变体 cDNA 则没有。患者成纤维细胞中柠檬酸合酶与总蛋白比率的四倍降低表明由此产生的线粒体质量减少导致了 OXPHOS 缺乏。用野生型SLIRP cDNA 转导导致该比率增加 2.4 倍并部分恢复 OXPHOS 活性。这证实了SLIRP变体的因果关系。总之,我们将SLIRP变异报告为 OXPHOS 缺乏的线粒体脑肌病的新原因。

更新日期:2021-08-23
down
wechat
bug