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

L. Guo, B.P.H. Engelen, I.M.G.M. Hemel, I.F.M. de Coo, M. Vreeburg, S.C.E.H. Sallevelt, D.M.E.I. Hellebrekers, E.H. Jacobs, F. Sadeghi-Niaraki, F.H.J. van Tienen, H.J.M. Smeets*, M. Gerards

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

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.
Original languageEnglish
Pages (from-to)1789-1795
Number of pages7
JournalEuropean Journal of Human Genetics
Volume29
Issue number12
Early online date23 Aug 2021
DOIs
Publication statusPublished - Dec 2021

Keywords

  • PROTEIN
  • LRPPRC
  • POLYADENYLATION

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