title: Retinal-specific guanylate cyclase gene mutations in Leber's congenital amaurosis.
abstract: Leber's congenital amaurosis (LCA, MIM 204,000), the earliest and most severe form of inherited retinopathy, accounts for at least 5% of all inherited retinal dystrophies. This autosomal recessive condition is usually recognized at birth or during the first months of life in an infant with total blindness or greatly impaired vision, normal fundus and extinguished electroretinogram (ERG). Nystagmus (pendular type) and characteristic eye poking are frequently observed in the first months of life (digito-ocular sign of Franceschetti). Hypermetropia and keratoconus frequently develop in the course of the disease. The observation by Waardenburg of normal children born to affected parents supports the genetic heterogeneity of LCA. Until now, however, little was known about the pathophysiology of the disease, but LCA is usually regarded as the consequence of either impaired development of photoreceptors or extremely early degeneration of cells that have developed normally. We have recently mapped a gene for LCA to chromosome 17p13.1 (LCA1) by homozygosity mapping in consanguineous families of North African origin and provided evidence of genetic heterogeneity in our sample, as LCA1 accounted for 8/15 LCA families in our series. Here, we report two missense mutations (F589S) and two frameshift mutations (nt 460 del C, nt 693 del C) of the retinal guanylate cyclase (RETGC, GDB symbol GUC2D) gene in four unrelated LCA1 probands of North African ancestry and ascribe LCA1 to an impaired production of cGMP in the retina, with permanent closure of cGMP-gated cation channels.
authors.affiliation: Unité de Recherches sur les Handicaps Génétiques de l'Enfant, INSERM U-393, Hôpital des Enfants-malades, Paris, France.
authors.forename: I
authors.initials: I
authors.lastname: Perrault
authors.forename: J M
authors.initials: JM
authors.lastname: Rozet
authors.forename: P
authors.initials: P
authors.lastname: Calvas
authors.forename: S
authors.initials: S
authors.lastname: Gerber
authors.forename: A
authors.initials: A
authors.lastname: Camuzat
authors.forename: H
authors.initials: H
authors.lastname: Dollfus
authors.forename: S
authors.initials: S
authors.lastname: Châtelin
authors.forename: E
authors.initials: E
authors.lastname: Souied
authors.forename: I
authors.initials: I
authors.lastname: Ghazi
authors.forename: C
authors.initials: C
authors.lastname: Leowski
authors.forename: M
authors.initials: M
authors.lastname: Bonnemaison
authors.forename: D
authors.initials: D
authors.lastname: Le Paslier
authors.forename: J
authors.initials: J
authors.lastname: Frézal
authors.forename: J L
authors.initials: JL
authors.lastname: Dufier
authors.forename: S
authors.initials: S
authors.lastname: Pittler
authors.forename: A
authors.initials: A
authors.lastname: Munnich
authors.forename: J
authors.initials: J
authors.lastname: Kaplan
mesh_terms: D001766:Blindness / Q000151:congenital* / Q000201:enzymology / Q000235:genetics; D002886:Chromosomes, Human, Pair 17; D006152:Cyclic GMP / Q000378:metabolism; D016368:Frameshift Mutation; D006162:Guanylate Cyclase / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D015418:Optic Atrophies, Hereditary / Q000201:enzymology* / Q000235:genetics; D010786:Photoreceptor Cells / Q000378:metabolism; D015183:Restriction Mapping; D012160:Retina / Q000201:enzymology*
chemical_list: D006162:Guanylate Cyclase; D006152:Cyclic GMP