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, Cecile; Rossel, Mireille; Meunier, Isabelle; Preising, Markus N.; Lorenz, Birgit; Carelli, Valério; 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.2015.10.015

Cited by 9 publications

(34 citation statements)

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“…The most enriched GO term from commonly down‐regulated genes in the PDX TA and DIA was mitochondrion ( Figure D). Many of the genes annotating to this category play a role in oxidative phosphorylation including Bcs1l , Rtn4lp1 (Nogo‐interacting mitochondrial protein), and Lace1 ( Figure E) . There were additional repressed genes that annotated to cytosol or membrane that play roles in energy metabolism, including Tfrc (transferrin receptor protein 1), which is a critical regulator iron uptake and Irs1 , which encodes an adapter protein and signal transducer for insulin‐mediated activation of the insulin‐like growth factor 1 receptor.…”

Section: Resultsmentioning

confidence: 99%

Distinct cachexia profiles in response to human pancreatic tumours in mouse limb and respiratory muscle

Nosacka

Delitto

et al. 2020

J cachexia sarcopenia muscle

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Background Cancer cachexia is a life‐threatening metabolic syndrome that causes significant loss of skeletal muscle mass and significantly increases mortality in cancer patients. Currently, there is an urgent need for better understanding of the molecular pathophysiology of this disease so that effective therapies can be developed. The majority of pre‐clinical studies evaluating skeletal muscle's response to cancer have focused on one or two pre‐clinical models, and almost all have focused specifically on limb muscles. In the current study, we reveal key differences in the histology and transcriptomic signatures of a limb muscle and a respiratory muscle in orthotopic pancreatic cancer patient‐derived xenograft (PDX) mice. Methods To create four cohorts of PDX mice evaluated in this study, tumours resected from four pancreatic ductal adenocarcinoma patients were portioned and attached to the pancreas of immunodeficient NSG mice. Results Body weight, muscle mass, and fat mass were significantly decreased in each PDX line. Histological assessment of cryosections taken from the tibialis anterior (TA) and diaphragm (DIA) revealed differential effects of tumour burden on their morphology. Subsequent genome‐wide microarray analysis on TA and DIA also revealed key differences between their transcriptomes in response to cancer. Genes up‐regulated in the DIA were enriched for extracellular matrix protein‐encoding genes and genes related to the inflammatory response, while down‐regulated genes were enriched for mitochondria related protein‐encoding genes. Conversely, the TA showed up‐regulation of canonical atrophy‐associated pathways such as ubiquitin‐mediated protein degradation and apoptosis, and down‐regulation of genes encoding extracellular matrix proteins. Conclusions These data suggest that distinct biological processes may account for wasting in different skeletal muscles in response to the same tumour burden. Further investigation into these differences will be critical for the future development of effective clinical strategies to counter cancer cachexia.

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Section: Resultsmentioning

confidence: 99%

Distinct cachexia profiles in response to human pancreatic tumours in mouse limb and respiratory muscle

Nosacka

Delitto

et al. 2020

J cachexia sarcopenia muscle

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“…9 The Iranian mutation was absent in ethically and geographically matched 450 exomes. With Sanger sequencing using primers, which are described elsewhere, 3 we confirmed the identified mutations and tested the carrier status of the unaffected relatives when their DNA was available. This study was approved by the institutional review boards of Angers University Hospital in Angers, France; Neurological Institute "Besta" in Milan, Italy; Technical University of Munich in Munich, Germany; and King's College in London, England.…”

Section: Genetic Investigationsmentioning

confidence: 99%

“…Biochemical measurement of individual oxidative phosphorylation complex activities was performed by standard spectrophotometric assays 11 in muscle homogenate and digitonin-treated skin fibroblasts. Assessments of RTN4IP1 abundance and the mitochondrial network structure of RTN4IP1-mutated and control fibroblast cell lines were performed according to the process described in Angebault et al 3 Quadruple immunofluorescence analysis and assessment of the assembly of the respiratory chain complexes of muscle biopsy specimens were performed according to the process described in Rocha et al 12 Blue native polyacrylamide gel electrophoresis on skeletal muscle samples was performed as described in Alston et al 13…”

Section: Biochemical and Cellular Studies Of Fibroblasts And Muscle Bmentioning

confidence: 99%

“…1,2 Recently, the first mutations in the RTN4IP1 (OMIM 610502) were described in individuals with isolated recessive optic atrophy-10 (OPA10) in 3 families with a founder effect as well as in 2 sisters from an unrelated family, who were affected with a syndromic form associating the optic atrophy with cerebellar ataxia, mild intellectual disability, and seizures. 3 The RTN4IP1 gene encodes a mitochondrial targeted protein 4 with a quinone oxidoreductase activity, involving 2 domains-an aminoterminal region with an alcohol dehydrogenase GroES-like signature (ADH_N) and a carboxy-terminal domain including a zinc-binding motif (ADH_Zinc). Mutations in this gene were not reported to affect mitochondrial network morphologic features, as is frequently the case in cells from individuals with dominant optic atrophy, 5,6 but result in a mild deficit in mitochondrial complexes I and IV enzymatic activities.…”

mentioning

confidence: 99%

“…Mutations in this gene were not reported to affect mitochondrial network morphologic features, as is frequently the case in cells from individuals with dominant optic atrophy, 5,6 but result in a mild deficit in mitochondrial complexes I and IV enzymatic activities. 3 Together, these data led us to consider RTN4IP1 sequence integrity in cohorts of individuals with inherited optic atrophy and complex I deficiency by using either targeted or wholeexome sequencing. In this article, we report on the identification of 11 novel families with RTN4IP1 mutations and describe their association with various neurologic phenotypes.…”

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Neurologic Phenotypes Associated With Mutations in RTN4IP1 (OPA10) in Children and Young Adults

et al. 2018

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IMPORTANCE Neurologic disorders with isolated symptoms or complex syndromes are relatively frequent among mitochondrial inherited diseases. Recessive RTN4IP1 gene mutations have been shown to cause isolated and syndromic optic neuropathies. OBJECTIVE To define the spectrum of clinical phenotypes associated with mutations in RTN4IP1 encoding a mitochondrial quinone oxidoreductase. DESIGN, SETTING, AND PARTICIPANTS This study involved 12 individuals from 11 families with severe central nervous system diseases and optic atrophy. Targeted and whole-exome sequencing were performed-at Hospital Angers (France),

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Exome sequencing identifies novel missense and deletion variants in RTN4IP1 associated with optic atrophy, global developmental delay, epilepsy, ataxia, and choreoathetosis

D’Gama

England

Madden

et al. 2020

American J of Med Genetics Pt A

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Inherited optic neuropathies (IONs) are neurodegenerative disorders characterized by optic atrophy with or without extraocular manifestations. Optic atrophy‐10 (OPA10) is an autosomal recessive ION recently reported to be caused by mutations in RTN4IP1, which encodes reticulon 4 interacting protein 1 (RTN4IP1), a mitochondrial ubiquinol oxydo‐reductase. Here we report novel compound heterozygous mutations in RTN4IP1 in a male proband with developmental delay, epilepsy, optic atrophy, ataxia, and choreoathetosis. Workup was notable for transiently elevated lactate and lactate‐to‐pyruvate ratio, brain magnetic resonance imaging with optic atrophy and T2 signal abnormalities, and a nondiagnostic initial genetic workup, including chromosomal microarray and mitochondrial panel testing. Exome sequencing identified a paternally inherited missense variant (c.263T>G, p.Val88Gly) predicted to be deleterious and a maternally inherited deletion encompassing RTN4IP1. To our knowledge, this is the first report of a non‐single nucleotide pathogenic variant associated with OPA10. This case highlights the expanding phenotypic spectrum of OPA10, the association between “syndromic” cases and severe RTN4IP1 mutations, and the importance of nonbiased genetic testing, such as ES, to analyze multiple genes and variants types, in patients suspected of having genetic disease.

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Recessive Mutations in RTN4IP1 Cause Isolated and Syndromic Optic Neuropathies

Cited by 9 publications

References 0 publications

Distinct cachexia profiles in response to human pancreatic tumours in mouse limb and respiratory muscle

Distinct cachexia profiles in response to human pancreatic tumours in mouse limb and respiratory muscle

Neurologic Phenotypes Associated With Mutations in RTN4IP1 (OPA10) in Children and Young Adults

Exome sequencing identifies novel missense and deletion variants in RTN4IP1 associated with optic atrophy, global developmental delay, epilepsy, ataxia, and choreoathetosis

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