Pathogenic SLIRP variants as a novel cause of autosomal recessive mitochondrial encephalomyopathy with complex I and IV deficiency

• Published in: European journal of human genetics : EJHG Vol. 29; no. 12; pp. 1789 - 1795
• Main Authors: Guo, Le, Engelen, Bob P H, Hemel, Irene M G M, de Coo, Irenaeus F M, Vreeburg, Maaike, Sallevelt, Suzanne C E H, Hellebrekers, Debby M E I, Jacobs, Ed H, Sadeghi-Niaraki, Farah, van Tienen, Florence H J, Smeets, Hubert J M, Gerards, Mike
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.12.2021; Springer International Publishing
• Subjects: Citrate synthase; Electron transport chain; Fibroblasts; Mitochondria; Oxidative phosphorylation; Phosphorylation; Ribonucleic acid; RNA; RNA-binding protein
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/s41431-021-00947-1

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.