title: Mouse Models of NMNAT1-Leber Congenital Amaurosis (LCA9) Recapitulate Key Features of the Human Disease.
abstract: The nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) enzyme is essential for regenerating the nuclear pool of NAD(+) in all nucleated cells in the body, and mounting evidence also suggests that it has a separate role in neuroprotection. Recently, mutations in the NMNAT1 gene were associated with Leber congenital amaurosis, a severe retinal degenerative disease that causes blindness during infancy. Availability of a reliable mammalian model of NMNAT1-Leber congenital amaurosis would assist in determining the mechanisms through which disruptions in NMNAT1 lead to retinal cell degeneration and would provide a resource for testing treatment options. To this end, we identified two separate N-ethyl-N-nitrosourea-generated mouse lines that harbor either a p.V9M or a p.D243G mutation. Both mouse models recapitulate key aspects of the human disease and confirm the pathogenicity of mutant NMNAT1. Homozygous Nmnat1 mutant mice develop a rapidly progressing chorioretinal disease that begins with photoreceptor degeneration and includes attenuation of the retinal vasculature, optic atrophy, and retinal pigment epithelium loss. Retinal function deteriorates in both mouse lines, and, in the more rapidly progressing homozygous Nmnat1(V9M) mutant mice, the electroretinogram becomes undetectable and the pupillary light response weakens. These mouse models offer an opportunity for investigating the cellular mechanisms underlying disease pathogenesis, evaluating potential therapies for NMNAT1-Leber congenital amaurosis, and conducting in situ studies on NMNAT1 function and NAD(+) metabolism.
authors.affiliation: Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye & Ear Infirmary, Harvard Medical School, Boston, Massachusetts.
authors.forename: Scott H
authors.initials: SH
authors.lastname: Greenwald
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine.
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Charette
authors.affiliation: Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye & Ear Infirmary, Harvard Medical School, Boston, Massachusetts.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Staniszewska
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine.
authors.forename: Lan Ying
authors.initials: LY
authors.lastname: Shi
authors.affiliation: Mammalian Genetics Unit, Medical Research Council (MRC), Harwell Campus, Oxfordshire, United Kingdom.
authors.forename: Steve D M
authors.initials: SDM
authors.lastname: Brown
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine.
authors.forename: Lisa
authors.initials: L
authors.lastname: Stone
authors.affiliation: Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye & Ear Infirmary, Harvard Medical School, Boston, Massachusetts.
authors.forename: Qin
authors.initials: Q
authors.lastname: Liu
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine.
authors.forename: Wanda L
authors.initials: WL
authors.lastname: Hicks
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine.
authors.forename: Gayle B
authors.initials: GB
authors.lastname: Collin
authors.affiliation: Mammalian Genetics Unit, Medical Research Council (MRC), Harwell Campus, Oxfordshire, United Kingdom.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Bowl
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Krebs
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine.
authors.forename: Patsy M
authors.initials: PM
authors.lastname: Nishina
authors.affiliation: Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye & Ear Infirmary, Harvard Medical School, Boston, Massachusetts. Electronic address: eric_pierce@meei.harvard.edu.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Pierce
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005838:Genotype; D006801:Humans; D057130:Leber Congenital Amaurosis / Q000235:genetics* / Q000503:physiopathology*; D051379:Mice; D008817:Mice, Mutant Strains; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000235:genetics*; D016133:Polymerase Chain Reaction
chemical_list: D009612:Nicotinamide-Nucleotide Adenylyltransferase; C510972:Nmnat1 protein, mouse