September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Mouse models of NMNAT1-Leber congenital amaurosis recapitulate key features of the human disease
Author Affiliations & Notes
  • Scott H Greenwald
    Ophthalmology, Massachusetts Eye & Ear Infirmary, Harvard Medical School, Boston, Massachusetts, United States
  • Jeremy R Charette
    The Jackson Laboratory, Bar Harbor, Maine, United States
  • Magdalena Staniszewska
    Ophthalmology, Massachusetts Eye & Ear Infirmary, Harvard Medical School, Boston, Massachusetts, United States
  • Lan Ying Shi
    The Jackson Laboratory, Bar Harbor, Maine, United States
  • Steve D.M. Brown
    Mammalian Genetics Unit, Medical Research Council (MRC), Harwell, Harwell Oxford, United Kingdom
  • Lisa Stone
    The Jackson Laboratory, Bar Harbor, Maine, United States
  • Wanda Hicks
    The Jackson Laboratory, Bar Harbor, Maine, United States
  • Michael R. Bowl
    Mammalian Genetics Unit, Medical Research Council (MRC), Harwell, Harwell Oxford, United Kingdom
  • Mark P. Krebs
    The Jackson Laboratory, Bar Harbor, Maine, United States
  • Patsy M Nishina
    The Jackson Laboratory, Bar Harbor, Maine, United States
  • Eric A Pierce
    Ophthalmology, Massachusetts Eye & Ear Infirmary, Harvard Medical School, Boston, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Scott Greenwald, None; Jeremy Charette, None; Magdalena Staniszewska, None; Lan Ying Shi, None; Steve D.M. Brown, None; Lisa Stone, None; Wanda Hicks, None; Michael Bowl, None; Mark Krebs, None; Patsy Nishina, None; Eric Pierce, None
  • Footnotes
    Support  NEI grant EY012910 (E.A.P), NEI grant 5T32 EY-007145-16 (S.H.G.), NEI grant EY016501 (P.M.N), NEI grant P30 EY003790 (Schepens Ophth. Core), NEI grant P30 EY014104 (MEEI Ophth. Core), the Foundation for Retinal Research and Gavin R. Stevens Foundation (EAP), CA34196 (The Jackson Laboratory)
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 2255. doi:
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      Scott H Greenwald, Jeremy R Charette, Magdalena Staniszewska, Lan Ying Shi, Steve D.M. Brown, Lisa Stone, Wanda Hicks, Michael R. Bowl, Mark P. Krebs, Patsy M Nishina, Eric A Pierce; Mouse models of NMNAT1-Leber congenital amaurosis recapitulate key features of the human disease. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2255.

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      © 2017 Association for Research in Vision and Ophthalmology.

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Abstract

Purpose : Availability of a reliable mammalian model of NMNAT1 -LCA would assist in determining the mechanisms through which disruptions in the nicotinamide nucleotide adenylyltransferase 1 enzyme (NMNAT1) lead to retinal cell degeneration and would provide a resource for testing treatment options and for investigating NAD+ metabolism.

Methods : Two separate N-ethyl-N-nitrosourea (ENU) generated mouse lines that harbor either a p.V9M or a p.D243G mutation in NMNAT1 were identified by Sanger sequencing. In both lines, retinal morphology was evaluated using fundus photography, optical coherence tomography (OCT), light microscopy, and transmission electron microscopy (TEM), and retinal function was assessed by electroretinography (ERG). In the mice with the p.V9M mutation, the pupillary response was recorded.

Results : Homozygous Nmnat1 mutant mice develop a recessive, rapidly progressing chorioretinal disease with onset following normal retinal development. The disease begins with pan-retinal photoreceptor degeneration and includes retinal vascular attenuation, optic atrophy, and retinal pigment epithelium loss. In homozygous Nmnat1V9M mutant mice, photoreceptor degeneration is nearly complete by four months, and by fifteen months, retinal thickness is decreased by ~57% (p = 1.6x10-26) in comparison to age-matched wildtype and heterozygous littermates. Both dark and light adapted ERGs are undetectable by four months, and in mice with very advanced stage disease, the pupillary light response is attenuated. Although disease progression is slower in homozygous Nmnat1D243G mutant mice, the retinas are 47% (p = 1.5x10-6) thinner than normal at twelve months. By that age, dark adapted ERG a- and b-waves are decreased by 83% (p=7.4x10-5) and 87% (p = 3.3x10-7), respectively, and light adapted b-waves are decreased by 71% (p = 1.7x10-4).

Conclusions : Both mouse models recapitulate key aspects of NMNAT1-LCA and confirm the pathogenicity of mutant NMNAT1. These mouse lines offer an opportunity for investigating the cellular mechanisms underlying disease pathogenesis and evaluating potential therapies for NMNAT1-LCA, as well as for conducting in situ studies on NMNAT1 function and NAD+ metabolism.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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