RESUMO
In addition to its activity in nicotinamide adenine dinucleotide (NAD(+)) synthesis, the nuclear nicotinamide mononucleotide adenyltransferase NMNAT1 acts as a chaperone that protects against neuronal activity-induced degeneration. Here we report that compound heterozygous and homozygous NMNAT1 mutations cause severe neonatal neurodegeneration of the central retina and early-onset optic atrophy in 22 unrelated individuals. Their clinical presentation is consistent with Leber congenital amaurosis and suggests that the mutations affect neuroprotection of photoreceptor cells.
Assuntos
Amaurose Congênita de Leber/genética , Degeneração Macular/genética , Mutação , Nicotinamida-Nucleotídeo Adenililtransferase/genética , Atrofia Óptica/genética , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Estudos de Coortes , Predisposição Genética para Doença , Humanos , Amaurose Congênita de Leber/complicações , Amaurose Congênita de Leber/epidemiologia , Degeneração Macular/complicações , Degeneração Macular/epidemiologia , Mutação/fisiologia , Atrofia Óptica/complicações , Atrofia Óptica/epidemiologia , Polimorfismo de Nucleotídeo Único/fisiologia , Índice de Gravidade de Doença , Adulto JovemRESUMO
Leber congenital amaurosis (LCA) is a severe hereditary retinal dystrophy responsible for congenital or early-onset blindness. The most common disease-causing mutation (>10%) is located deep in intron 26 of the CEP290 gene (c.2991+1655A>G). It creates a strong splice donor site that leads to insertion of a cryptic exon encoding a premature stop codon. In the present study, we show that the use of antisense oligonucleotides (AONs) allow an efficient skipping of the mutant cryptic exon and the restoration of ciliation in fibroblasts of affected patients. These data support the feasibility of an AON-mediated exon skipping strategy to correct the aberrant splicing.
