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

Guo, Le; Engelen, Bob P H; Hemel, Irene M.G.M.; Coo, I.F.M. de; Vreeburg, Maaike; Sallevelt, Suzanne C E H; Hellebrekers, Debby M.E.I.; Jacobs, Ed; Sadeghi-Niaraki, Farah; Tienen, F.H.J. van; Smeets, Hubert J.M.; Gerards, Mike

doi:10.1038/s41431-021-00947-1

Cited by 9 publications

(8 citation statements)

References 27 publications

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“…SLIRP variants also cause a respiratory deficiency that leads to mitochondrial encephalomyopathy 14 . SLIRP knockdown results in increased turnover of LRPPRC [13][14][15] , and in vivo co-stabilisation has been shown 13,16 , suggesting that the two entities might have interdependent functions. However, there are no structures available for LRPPRC, SLIRP or any complexes containing them, and thus although mitoribosomal models have been determined 17,18 , the molecular mechanisms of mRNA binding and association with interacting partners remained unknown.…”

mentioning

confidence: 99%

“…It has been further reported to interact with a small 11-kDa protein cofactor SLIRP (SRA stem-loop-interacting RNA-binding protein) that plays roles in LRPPRC stability and maintaining steady-state mRNA levels 13 . SLIRP silencing results in destabilization of respiratory complexes and loss of enzymatic activity, implicating a role in mRNA homeostasis 14 , whereas SLIRP variants also cause a respiratory deficiency that leads to mitochondrial encephalomyopathy 15 In addition, SLIRP knockdown results in increased turnover of LRPPRC 13,15,16 , and in vivo co-stabilisation has been shown 13,17 , suggesting that the two entities might have interdependent functions. However, there are no structures available for LRPPRC, SLIRP or any complexes containing them, and thus although mitoribosomal models have been determined 18,19 , the molecular mechanisms of mRNA binding and association with interacting partners remained unknown.…”

mentioning

confidence: 99%

“…It has been further reported to interact with a small 11-kDa protein cofactor SLIRP (SRA stem-loop-interacting RNA-binding protein) that plays roles in LRPPRC stability and maintaining steady-state mRNA levels 13 . SLIRP variants also cause a respiratory deficiency that leads to mitochondrial encephalomyopathy 14 . SLIRP knockdown results in increased turnover of LRPPRC [13][14][15] , and in vivo co-stabilisation has been shown 13,16 , suggesting that the two entities might have interdependent functions.…”

mentioning

confidence: 99%

“…SLIRP silencing results in the destabilization of respiratory complexes, loss of enzymatic activity, and reduction in mRNA levels, implicating a role in mRNA homeostasis 17 . SLIRP variants cause a respiratory deficiency that leads to mitochondrial encephalomyopathy 18 . In addition, SLIRP knockdown results in increased turnover of LRPPRC 16, 18, 19 , and in vivo co-stabilisation suggests that the two entities have interdependent functions 16, 20 .…”

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confidence: 99%

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Structural basis of LRPPRC-SLIRP-dependent translation by the mitoribosome

Singh

Itoh

Huynen

et al. 2022

Preprint

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In mammalian mitochondria, mRNAs are co-transcriptionally stabilized by LRPPRC. Here we show that LRPPRC forms a stable complex with SLIRP and mitoribosome to act as a carrier of genetic information, thus linking the gene expression system. The structure of translating human mitoribosome in complex with LRPPRC-SLIRP and mRNA shows how the mRNA is delivered for translation along a corridor formed by LRPPRC with proteins of the mitoribosomal small subunit mS31-mS39.

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confidence: 99%

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confidence: 99%

“…It has been further reported to interact with a small 11-kDa protein cofactor SLIRP (SRA stem-loop-interacting RNA-binding protein) that plays roles in LRPPRC stability and maintaining steady-state mRNA levels 13 . SLIRP variants also cause a respiratory deficiency that leads to mitochondrial encephalomyopathy 14 . SLIRP knockdown results in increased turnover of LRPPRC [13][14][15] , and in vivo co-stabilisation has been shown 13,16 , suggesting that the two entities might have interdependent functions.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

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Structural basis of LRPPRC-SLIRP-dependent translation by the mitoribosome

Singh

Itoh

Huynen

et al. 2022

Preprint

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“…In contrast to common malformations, the genetic basis of rare disease continues to be elucidated with more and more causal genes identified annually [2][3][4]. Guo and colleagues identify variants in SLIRP as a novel cause of mitochondrial disease [5]. In this issue, variants in IMPDH2 are associated with dystonia in a large family [6]; IMPDH2 acts in the dopamine synthesis pathway previously implicated in the aetiology of dystonia.…”

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Genomics elucidates both common and rare disease aetiology

McNeill

2021

Eur J Hum Genet

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Welcome to the final issue of European Journal of Human Genetics for 2021. We close the year with a range of interesting and informative papers. Birth defects (congenital anomalies) affect many thousands of neonates every year; yet the aetiology of many of them remains unresolved. Schreiner et al review what is known about the genomic basis of congenital diaphragmatic hernia (CDH) [1]. Around 10% of cases of CDH are associated with a copy number variant. Implicated pathways include NRF2 and vitamin A homeostasis. In contrast to common malformations, the genetic basis of rare disease continues to be elucidated with more and more causal genes identified annually [2][3][4]. Guo and colleagues identify variants in SLIRP as a novel cause of mitochondrial disease [5]. In this issue, variants in IMPDH2 are associated with dystonia in a large family [6]; IMPDH2 acts in the dopamine synthesis pathway previously implicated in the aetiology of dystonia. Of course, even with modern technology there remain patients for whom a molecular genetic diagnosis remains elusive. Pham et al demonstrate that variants in DLK4 are not responsible for Silver-Russell-Syndrome [7].Kawasaki disease is a paediatric vasculitis with a risk of coronary artery involvement. In this month's EJHG Hoggart et al identify a potential genetic risk factor for coronary artery involvement in Kawasaki disease [8]. For many genetic diseases, little is known about population epidemiology. In a study of malignant hyperthermia gene variants in Iceland, it was estimated that 1/ 1450 Icelanders carry an actionable variant in a malignant hyperthermia gene [9]. Keratoconus (defined as noninflammatory corneal ectasia) is of uncertain aetiology. Fransen et al identify a shared genetic link between keratoconus and the connective tissue disease Ehlers-Danlos syndrome [10]. Male factor infertility is frequently of unknown aetiology. Arafat and colleagues identify variants in GCNA in association with low sperm count and impared sperm motility [11].Not all (rare) disease is monogenic (that is explained by variants in a single gene). In an Indian study, 14 families with clinical phenotypes associated with causal variants in more than one mendelian disease gene are reported [12]. The clinical consequences were described as blended phenotypes, a mild phenotype from gene A being obscured by a severe phenotype from gene B or 2 distinct phenotypes in the same patient. Undoubtedly such multilocus variation has the potential to contribute to phenotype variability in genetic diseases. Sharing information on pathogenic gene variants is crucial to help clinical reporting. The updated LOVD3 platform provides one mechanism for doing so [13].All genomics research must be ethically approved and adhere to conditions set by the relevant committees. But do research ethics committees have sufficient understanding to review and grant permission for ethically robust genomics research? A study of Australian research ethics committees highlights a potential need for extra training for committee ...

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