Recessive Mutations in RTN4IP1 Cause Isolated and Syndromic Optic Neuropathies

Angebault, Claire; Guichet, Pierre‐Olivier; Talmat-Amar, Yasmina; Charif, Majida; Gerber, Sylvie; Fares-Taie, Lucas; Guéguen, Naïg; Halloy, François; Moore, David; Amati‐Bonneau, Patrizia; Manes, Gae͏̈l; Hebrard, Maxime; Bocquet, Béatrice; Quilès, Mélanie; Piro-Mégy, Camille; Teigell, Marisa; Delettre, Cécile; Rossel, Mireille; Meunier, Isabelle; Preising, Markus N.; Lorenz, Birgit; Carelli, Valerio; Chinnery, Patrick F.; Yu‐Wai‐Man, Patrick; Kaplan, Josseline; Roubertie, Agathe; Barakat, Abdelhamid; Bonneau, Dominique; Reynier, Pascal; Rozet, Jean–Michel; Bomont, Pascale; Hamel, Christian; Lenaers, Guy

doi:10.1016/j.ajhg.2015.09.012

Cited by 57 publications

(62 citation statements)

References 26 publications

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“…6d , Table 1 ). Among these candidates, carbonyl reductase 4 (CBR4), an enzyme in the mitochondrial fatty acid synthesis pathway [ 24 ], reticulon 4 interacting protein 1 (RTN4IP1), enoyl coenzyme A hydratase, short chain, 1 (ECHS1), and NADH dehydrogenase (ubiquinone) 1 beta subcomplex 7 (NDUFB7)—all involved in mitochondrial oxidation [ 25 – 27 ]—as well as two mitochondrial aldehyde dehydrogenases (ALDH2 and ALDH6A1 [ 28 , 29 ]) were upregulated in transgenic muscle. In addition, mitochondrial fission factor (MFF) and microtubule-associated protein 1S (MAP1S), which control mitochondrial morphology by regulating dynamic fission and fusion process [ 30 , 31 ], were differentially expressed comparing the genotypes.…”

Section: Resultsmentioning

confidence: 99%

Overexpression of protein kinase STK25 in mice exacerbates ectopic lipid accumulation, mitochondrial dysfunction and insulin resistance in skeletal muscle

et al. 2016

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Aims/hypothesis Understanding the molecular networks controlling ectopic lipid deposition and insulin responsiveness in skeletal muscle is essential for developing new strategies to treat type 2 diabetes. We recently identified serine/threonine protein kinase 25 (STK25) as a critical regulator of liver steatosis, hepatic lipid metabolism and whole body glucose and insulin homeostasis. Here, we assessed the role of STK25 in control of ectopic fat storage and insulin responsiveness in skeletal muscle.Methods Skeletal muscle morphology was studied by histological examination, exercise performance and insulin sensitivity were assessed by treadmill running and euglycaemichyperinsulinaemic clamp, respectively, and muscle lipid metabolism was analysed by ex vivo assays in Stk25 transgenic and wild-type mice fed a high-fat diet. Lipid accumulation and mitochondrial function were also studied in rodent myoblasts overexpressing STK25. Global quantitative phosphoproteomics was performed in skeletal muscle of Stk25 transgenic and wild-type mice fed a high-fat diet to identify potential downstream mediators of STK25 action. Results We found that overexpression of STK25 in transgenic mice fed a high-fat diet increases intramyocellular lipid accumulation, impairs skeletal muscle mitochondrial function and sarcomeric ultrastructure, and induces perimysial and endomysial fibrosis, thereby reducing endurance exercise capacity and muscle insulin sensitivity. Furthermore, we observed enhanced lipid accumulation and impaired mitochondrial function in rodent myoblasts overexpressing STK25, demonstrating an autonomous action for STK25 within cells. Global phosphoproteomic analysis revealed alterations in the total abundance and phosphorylation status of different target proteins located predominantly to mitochondria and sarcomeric contractile elements in Stk25 transgenic vs wild-type muscle, respectively, providing a possible molecular mechanism for the observed phenotype. Conclusions/interpretation STK25 emerges as a new regulator of the complex interplay between lipid storage, mitochondrial energetics and insulin action in skeletal muscle, highlighting the potential of STK25 antagonists for type 2 diabetes treatment.

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Section: Resultsmentioning

confidence: 99%

Overexpression of protein kinase STK25 in mice exacerbates ectopic lipid accumulation, mitochondrial dysfunction and insulin resistance in skeletal muscle

et al. 2016

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“…In contrast, autosomal recessive non-syndromic optic neuropathies are uncommon. They have been ascribed to biallelic mutations in TMEM126A (OMIM#612988; OPA7 ) , encoding a mitochondrial protein of unknown function, and ACO2 (OMIM#100850; OPA9 ) , encoding the mitochondrial aconitase, and RTN4IP1 (OMIM#610502, OPA10 ),29 encoding the mitochondrial reticulon 4-interacting protein. Interestingly, in addition to non-syndromic optic neuropathies, biallelic ACO2 mutations have been shown to cause syndromic optic neuropathy with encephalopathy and cerebellar atrophy30 31 and SLC25A46 (OMIM#610826) mutations have been reported to cause a wide spectrum of optic atrophy plus phenotypes, including neurodegenerative diseases with cerebellar dysfunction, peripheral neuropathy, progressive myoclonic ataxia and lethal congenital pontocerebellar hypoplasia, and Leigh syndrome with optic atrophy 32–36.…”

Section: Discussionmentioning

confidence: 99%

Compound heterozygosity for severe and hypomorphicNDUFS2mutations cause non-syndromic LHON-like optic neuropathy

et al. 2016

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BackgroundNon-syndromic hereditary optic neuropathy (HON) has been ascribed to mutations in mitochondrial fusion/fission dynamics genes, nuclear and mitochondrial DNA-encoded respiratory enzyme genes or nuclear genes of poorly known mitochondrial function. However, the disease causing gene remains unknown in many families. The objective of the present study was to identify the molecular cause of non-syndromic LHON-like disease in siblings born to non-consanguineous parents of French origin.MethodsWe used a combination of genetic analysis (gene mapping and whole-exome sequencing) in a multiplex family of non-syndromic HON and of functional analyses in patient-derived cultured skin fibroblasts and the yeast Yarrowia lipolytica.ResultsWe identified compound heterozygote NDUFS2 disease-causing mutations (p.Tyr53Cys; p.Tyr308Cys). Studies using patient-derived cultured skin fibroblasts revealed mildly decreased NDUFS2 and complex I abundance but apparently normal respiratory chain activity. In the yeast Y. lipolytica ortholog NUCM, the mutations resulted in absence of complex I and moderate reduction in nicotinamide adenine dinucleotide-ubiquinone oxidoreductase activity, respectively.ConclusionsBiallelism for NDUFS2 mutations causing severe complex I deficiency has been previously reported to cause Leigh syndrome with optic neuropathy. Our results are consistent with the view that compound heterozygosity for severe and hypomorphic NDUFS2 mutations can cause non-syndromic HON. This observation suggests a direct correlation between the severity of NDUFS2 mutations and that of the disease and further support that there exist a genetic overlap between non-syndromic and syndromic HON due to defective mitochondrial function.

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“…Bright field images were taken on a SPOT camera mounted on a Zeiss Axioplan 2 imaging microscope. TEM analysis has been performed in 72 hpf embryos, using protocol previously described (63).…”

Section: Number 12 December 2019mentioning

confidence: 99%

Sonic Hedgehog repression underlies gigaxonin mutation–induced motor deficits in giant axonal neuropathy

Arribat¹,

Mysiak²,

Lescouzères³

et al. 2019

Journal of Clinical Investigation

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Recessive Mutations in RTN4IP1 Cause Isolated and Syndromic Optic Neuropathies

Cited by 57 publications

References 26 publications

Overexpression of protein kinase STK25 in mice exacerbates ectopic lipid accumulation, mitochondrial dysfunction and insulin resistance in skeletal muscle

Overexpression of protein kinase STK25 in mice exacerbates ectopic lipid accumulation, mitochondrial dysfunction and insulin resistance in skeletal muscle

Compound heterozygosity for severe and hypomorphicNDUFS2mutations cause non-syndromic LHON-like optic neuropathy

Sonic Hedgehog repression underlies gigaxonin mutation–induced motor deficits in giant axonal neuropathy

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