Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration  

Oleh:

Koenekoop, Robert K ; Hui, Wang ; Majewski, Jacek ; Xia, Wang ; Lopez, Irma

Jenis: Article from Journal - ilmiah internasional
Dalam koleksi: Nature Genetics vol. 44 no. 09 (Sep. 2012), page 1035–1039.

Ketersediaan

Perpustakaan FK Nomor Panggil: N12.K Non-tandon: tidak ada Tandon: 1

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Isi artikel

Leber congenital amaurosis (LCA) is a blinding retinal disease that presents within the first year after birth. Using exome sequencing, we identified mutations in the nicotinamide adenine dinucleotide (NAD) synthase gene NMNAT1 encoding nicotinamide mononucleotide adenylyltransferase 1 in eight families with LCA, including the family in which LCA was originally linked to the LCA9 locus. Notably, all individuals with NMNAT1 mutations also have macular colobomas, which are severe degenerative entities of the central retina (fovea) devoid of tissue and photoreceptors. Functional assays of the proteins encoded by the mutant alleles identified in our study showed that the mutations reduce the enzymatic activity of NMNAT1 in NAD biosynthesis and affect protein folding. Of note, recent characterization of the slow Wallerian degeneration (Wlds) mouse model, in which prolonged axonal survival after injury is observed, identified NMNAT1 as a neuroprotective protein when ectopically expressed. Our findings identify a new disease mechanism underlying LCA and provide the first link between endogenous NMNAT1 dysfunction and a human nervous system disorder.

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