Characterization of Leber Congenital Amaurosis-associated NMNAT1 Mutants

BackgroundLeber congenital amaurosis (LCA) is a severe visual impairment responsible for infantile blindness, representing ~5% of all inherited retinal dystrophies. LCA encompasses a group of heterogeneous disorders, with 24 genes currently implicated in pathogenesis. Such clinical and genetic heterogeneity poses great challenges for treatment, with personalized therapies anticipated to be the best treatment candidates. Unraveling the individual genetic etiology of disease is a prerequisite for personalized therapies, and could identify potential treatment candidates, inform patient management, and discriminate syndromic forms of disease.MethodsWe have genetically analyzed 45 affected and 82 unaffected individuals from 34 unrelated LCA pedigrees using predominantly next‐generation sequencing and Array CGH technology.ResultsWe present the molecular findings for an Australian LCA cohort, sourced from the Australian Inherited Retinal Disease Registry & DNA Bank. CEP290 and GUCY2D mutations, each represent 19% of unrelated LCA cases, followed by NMNAT1 (12%). Genetic subtypes were consistent with other reports, and were resolved in 90% of this cohort.ConclusionThe high resolution rate achieved, equivalent to recent findings using whole exome/genome sequencing, reflects the progression from hypothesis (LCA Panel) to non‐hypothesis (RD Panel) testing and, coupled with Array CGH analysis, is a highly effective first‐tier test for LCA.

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“…The c.769G>A variant, occurring in >70% of LCA9 cases (Sasaki et al. ), was detailed previously (Chiang et al. ; Falk et al.…”

Section: Resultsmentioning

confidence: 99%

The genetic profile of Leber congenital amaurosis in an Australian cohort

Thompson

Roach

McLaren

et al. 2017

Molec Gen & Gen Med

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“…Although LCA mutations are widely distributed across the NMNAT1 gene, most NMNAT1 mutant proteins characterized exhibit several common features. NAD + synthase activity is reduced by most mutations in vitro , yet patient fibroblasts exhibit normal basal NAD + levels, suggesting that enzyme deficiency is not a primary cause of disease [10,38]. Importantly, ectopic expression of several LCA9 NMNAT1 mutants is sufficient to protect cultured neurons from Wallerian degeneration, indicating that LCA9-causing mutations do not disrupt the qualitative neuroprotective properties of NMNAT proteins [38].…”

Section: Molecular Functions Of Nmnat Necessary For Neuronal Maintenamentioning

confidence: 99%

“…NAD + synthase activity is reduced by most mutations in vitro , yet patient fibroblasts exhibit normal basal NAD + levels, suggesting that enzyme deficiency is not a primary cause of disease [10,38]. Importantly, ectopic expression of several LCA9 NMNAT1 mutants is sufficient to protect cultured neurons from Wallerian degeneration, indicating that LCA9-causing mutations do not disrupt the qualitative neuroprotective properties of NMNAT proteins [38]. However in vitro , NMNAT1 mutant proteins are more susceptible to stress-induced unfolding compared to wild type protein, which may amplified in vivo to cause disease [38].…”

Section: Molecular Functions Of Nmnat Necessary For Neuronal Maintenamentioning

confidence: 99%

“…Importantly, ectopic expression of several LCA9 NMNAT1 mutants is sufficient to protect cultured neurons from Wallerian degeneration, indicating that LCA9-causing mutations do not disrupt the qualitative neuroprotective properties of NMNAT proteins [38]. However in vitro , NMNAT1 mutant proteins are more susceptible to stress-induced unfolding compared to wild type protein, which may amplified in vivo to cause disease [38]. Interestingly, Drosophila photoreceptors are also particularly vulnerable to loss of Nmnat, but Nmnat’s enzyme activity is completely dispensable for maintenance of retinal health and function in this model [34].…”

Section: Molecular Functions Of Nmnat Necessary For Neuronal Maintenamentioning

confidence: 99%

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NMNAT: It’s an NAD + synthase… It’s a chaperone… It’s a neuroprotector

Brazill

Zhu

et al. 2017

Current Opinion in Genetics & Development

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Nicotinamide mononucleotide adenylyl transferases (NMNATs) are a family of highly conserved proteins indispensable for cellular homeostasis. NMNATs are classically known for their enzymatic function of catalyzing NAD+ synthesis, but also have gained a reputation as essential neuronal maintenance factors. NMNAT deficiency has been associated with various human diseases with pronounced consequences on neural tissues, underscoring the importance of the neuronal maintenance and protective roles of these proteins. New mechanistic studies have challenged the role of NMNAT-catalyzed NAD+ production in delaying Wallerian degeneration and specified new mechanisms of NMNAT’s chaperone function critical for neuronal health. Progress in understanding the regulation of NMNAT has uncovered a neuronal stress response with great therapeutic promise for treating various neurodegenerative conditions.

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“…This hypothesis is supported by past studies demonstrating that LCA, the leading cause of childhood blindness from retinal disease, can be caused by mutations in nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) (Chiang et al, 2012; Falk et al, 2012; Koenekoop et al, 2012; Perrault et al, 2012), an enzyme involved in NAD + biosynthesis. The various mutant forms of NMNAT1 associated with LCA exhibit reduced NAD + biosynthetic capacity and/or impaired protein folding (Falk et al, 2012; Koenekoop et al, 2012; Sasaki et al, 2015) with both factors contributing to disease pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

NAMPT-Mediated NAD+ Biosynthesis Is Essential for Vision In Mice

et al. 2016

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SUMMARY Photoreceptor death is the endpoint of many blinding diseases. Identifying unifying pathogenic mechanisms in these diseases may offer global approaches for facilitating photoreceptor survival. We found that rod or cone photoreceptor-specific deletion of nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme in the major NAD+ biosynthetic pathway beginning with nicotinamide, caused retinal degeneration. In both cases, we could rescue vision with nicotinamide mononucleotide (NMN). Significantly, retinal NAD+ deficiency was an early feature of multiple mouse models of retinal dysfunction, including light-induced degeneration, streptozotocin-induced diabetic retinopathy, and age-associated dysfunction. Mechanistically, NAD+ deficiency caused metabolic dysfunction and consequent photoreceptor death. We further demonstrate that the NAD+-dependent mitochondrial deacylases SIRT3/SIRT5 play important roles in retinal homeostasis and that NAD+ deficiency causes SIRT3 dysfunction. These findings demonstrate that NAD+ biosynthesis is essential for vision, provide a foundation for future work to further clarify the mechanisms involved, and identify a unifying therapeutic target for diverse blinding diseases.

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Characterization of Leber Congenital Amaurosis-associated NMNAT1 Mutants

Abstract: Background: Leber congenital amaurosis 9 (LCA9) is a severe retinal degeneration condition caused by mutations in the NAD ϩ biosynthetic enzyme NMNAT1.

Cited by 34 publications

References 28 publications

The genetic profile of Leber congenital amaurosis in an Australian cohort

The genetic profile of Leber congenital amaurosis in an Australian cohort

NMNAT: It’s an NAD + synthase… It’s a chaperone… It’s a neuroprotector

NAMPT-Mediated NAD+ Biosynthesis Is Essential for Vision In Mice

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