Exome sequencing identifies NMNAT1 mutations as a cause of Leber congenital amaurosis

Chiang, Pei Wen; Wang, Juan; Chen, Yang; Fu, Qin; Zhong, Jing; Chen, Yanhua; Yi, Xin; Wu, Renhua; Gan, Haixue; Shi, Yongyong; Chen, Yanling; Barnett, Christopher; Wheaton, Dianna K.; Day, Megan A; Sutherland, Joanne; Hèon, Elise; Weleber, Richard G.; Gabriel, Luis Alexandre Rassi; Cong, Peikuan; Chuang, Kuang-Hsiang; Ye, Sheng; Sallum, Juliana Maria Ferraz; Qi, Ming

doi:10.1038/ng.2370

Cited by 120 publications

(99 citation statements)

References 14 publications

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“…RPE cannot survive long-term deficiency of NAD + (37, 38), and a mutation in nicotinamide nucleotide adenylyltransferase 1 (NMNAT1), the enzyme that converts NMN into NAD + , causes severe retinal degeneration in humans (39)(40)(41). We have shown that, when oxidative stress is excessive, PARP depletes NAD + .…”

Section: Discussionmentioning

confidence: 99%

Reductive carboxylation is a major metabolic pathway in the retinal pigment epithelium

Yanagida

Knight

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

104

112

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The retinal pigment epithelium (RPE) is a monolayer of pigmented cells that requires an active metabolism to maintain outer retinal homeostasis and compensate for oxidative stress. Using 13 C metabolic flux analysis in human RPE cells, we found that RPE has an exceptionally high capacity for reductive carboxylation, a metabolic pathway that has recently garnered significant interest because of its role in cancer cell survival. The capacity for reductive carboxylation in RPE exceeds that of all other cells tested, including retina, neural tissue, glial cells, and a cancer cell line. Loss of reductive carboxylation disrupts redox balance and increases RPE sensitivity to oxidative damage, suggesting that deficiencies of reductive carboxylation may contribute to RPE cell death. Supporting reductive carboxylation by supplementation with an NAD + precursor or its substrate α-ketoglutarate or treatment with a poly(ADP ribose) polymerase inhibitor protects reductive carboxylation and RPE viability from excessive oxidative stress. The ability of these treatments to rescue RPE could be the basis for an effective strategy to treat blinding diseases caused by RPE dysfunction.reductive carboxylation | RPE | metabolism | age-related macular degeneration | oxidative stress T he retinal pigment epithelium (RPE) is a monolayer of postmitotic cells situated between the photoreceptors of the retina and the choroidal blood supply. The interaction of the RPE and photoreceptors is critical to maintaining vision. Functions of the RPE include phagocytosis of shed photoreceptor outer segments, recycling of retinoids, production and secretion of cytokines and chemokines, and mediating the exchange of nutrients and metabolites between the choroid and photoreceptors (1, 2). RPE cells provide crucial metabolic support for the retina.RPE dysfunction can lead to photoreceptor death and retinal degenerative disease, such as age-related macular degeneration (AMD), which is the leading cause of irreversible vision loss in the elderly human population (3-5). RPE cells are exposed to ongoing oxidative stress from the combined effects of light, choroidal O 2 , polyunsaturated fatty acids, and retinoids (6). The resulting impairment in RPE energy metabolism and function by oxidative stress is one likely mechanism for the pathogenesis of AMD (3, 7-11).Mitochondria support the active energy metabolism of the RPE (10-12). A recent report showed that RPE is less stable and less able to support the retina when it is forced to rely on glycolytic rather than mitochondrial metabolism (13). Another recent report supports the importance of mitochondria in RPE by showing that bolstering mitochondrial activity makes these cells more resilient to oxidative damage (14).In mitochondria, citrate can be generated from acetyl CoA and oxaloacetate as part of the TCA cycle. However, under hypoxic conditions, some cells also produce citrate via reductive carboxylation of α-ketoglutarate (αKG) through the action of NADPH-dependent isocitrate dehydrogenases (IDH) (15-17)....

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Section: Discussionmentioning

confidence: 99%

Reductive carboxylation is a major metabolic pathway in the retinal pigment epithelium

Yanagida

Knight

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

104

112

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“…It is important to note, beyond their neuronal roles, Nmnats also have obligate roles in NAD + metabolism and multiple cellular processes across species (Zhai et al, 2009;Lin et al, 2010). Very recent reports show Nmnat1 mutations cause Leber congenital amaurosis (LCA), highlighting its importance in retinal degenerative diseases in humans (Chiang et al, 2012;Falk et al, 2012;Koenekoop et al, 2012;Perrault et al, 2012).…”

Section: Wldmentioning

confidence: 99%

Molecular chaperones protect against JNK- and Nmnat-regulated axon degeneration in Drosophila

Rallis

2012

Journal of Cell Science

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SummaryAxon degeneration is observed at the early stages of many neurodegenerative conditions and this often leads to subsequent neuronal loss. We previously showed that inactivating the c-Jun N-terminal kinase (JNK) pathway leads to axon degeneration in Drosophila mushroom body (MB) neurons. To understand this process, we screened candidate suppressor genes and found that the Wallerian degeneration slow (Wld S ) protein blocked JNK axonal degeneration. Although the nicotinamide mononucleotide adenylyltransferase (Nmnat1) portion of Wld S is required, we found that its nicotinamide adenine dinucleotide (NAD + ) enzyme activity and the Wld S N-terminus (N70) are dispensable, unlike axotomy models of neurodegeneration. We suggest that Wld S -Nmnat protects against axonal degeneration through chaperone activity. Furthermore, ectopically expressed heat shock proteins (Hsp26 and Hsp70) also protected against JNK and Nmnat degeneration phenotypes. These results suggest that molecular chaperones are key in JNK-and Nmnat-regulated axonal protective functions.

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“…GUCY2D, NMNAT1, RDH12, RPGRIP1, and CRB1) (1). A 10-centimorgan region on 1p36 was identified as LCA9 locus in a Pakistani family (2) and further analysis identified NMNAT1 mutations in families with LCA, most of which had associated macular atrophy (3)(4)(5)(6). Almost all of these patients harbored compound heterozygote mutations, with the most common being a missense E257K mutation (3)(4)(5)(6).…”

Section: Leber Congenital Amaurosis (Lca)mentioning

confidence: 99%

“…A 10-centimorgan region on 1p36 was identified as LCA9 locus in a Pakistani family (2) and further analysis identified NMNAT1 mutations in families with LCA, most of which had associated macular atrophy (3)(4)(5)(6). Almost all of these patients harbored compound heterozygote mutations, with the most common being a missense E257K mutation (3)(4)(5)(6). A new study reports that individuals with a homozygous E257K mutation in one family did not have ocular abnormalities, suggesting this is a hypomorphic mutation with incomplete penetrance (7).…”

Section: Leber Congenital Amaurosis (Lca)mentioning

confidence: 99%

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Characterization of Leber Congenital Amaurosis-associated NMNAT1 Mutants

Sasaki

Margolin

Borgo

et al. 2015

Journal of Biological Chemistry

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Exome sequencing identifies NMNAT1 mutations as a cause of Leber congenital amaurosis

Cited by 120 publications

References 14 publications

Reductive carboxylation is a major metabolic pathway in the retinal pigment epithelium

Reductive carboxylation is a major metabolic pathway in the retinal pigment epithelium

Molecular chaperones protect against JNK- and Nmnat-regulated axon degeneration in Drosophila

Characterization of Leber Congenital Amaurosis-associated NMNAT1 Mutants

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