title: Determining consequences of retinal membrane guanylyl cyclase (RetGC1) deficiency in human Leber congenital amaurosis en route to therapy: residual cone-photoreceptor vision correlates with biochemical properties of the mutants.
abstract: The GUCY2D gene encodes retinal membrane guanylyl cyclase (RetGC1), a key component of the phototransduction machinery in photoreceptors. Mutations in GUCY2D cause Leber congenital amaurosis type 1 (LCA1), an autosomal recessive human retinal blinding disease. The effects of RetGC1 deficiency on human rod and cone photoreceptor structure and function are currently unknown. To move LCA1 closer to clinical trials, we characterized a cohort of patients (ages 6 months-37 years) with GUCY2D mutations. In vivo analyses of retinal architecture indicated intact rod photoreceptors in all patients but abnormalities in foveal cones. By functional phenotype, there were patients with and those without detectable cone vision. Rod vision could be retained and did not correlate with the extent of cone vision or age. In patients without cone vision, rod vision functioned unsaturated under bright ambient illumination. In vitro analyses of the mutant alleles showed that in addition to the major truncation of the essential catalytic domain in RetGC1, some missense mutations in LCA1 patients result in a severe loss of function by inactivating its catalytic activity and/or ability to interact with the activator proteins, GCAPs. The differences in rod sensitivities among patients were not explained by the biochemical properties of the mutants. However, the RetGC1 mutant alleles with remaining biochemical activity in vitro were associated with retained cone vision in vivo. We postulate a relationship between the level of RetGC1 activity and the degree of cone vision abnormality, and argue for cone function being the efficacy outcome in clinical trials of gene augmentation therapy in LCA1.
authors.affiliation: Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. jacobsos@mail.med.upenn.edu
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Jacobson
authors.forename: Artur V
authors.initials: AV
authors.lastname: Cideciyan
authors.forename: Igor V
authors.initials: IV
authors.lastname: Peshenko
authors.forename: Alexander
authors.initials: A
authors.lastname: Sumaroka
authors.forename: Elena V
authors.initials: EV
authors.lastname: Olshevskaya
authors.forename: Lihui
authors.initials: L
authors.lastname: Cao
authors.forename: Sharon B
authors.initials: SB
authors.lastname: Schwartz
authors.forename: Alejandro J
authors.initials: AJ
authors.lastname: Roman
authors.forename: Melani B
authors.initials: MB
authors.lastname: Olivares
authors.forename: Sam
authors.initials: S
authors.lastname: Sadigh
authors.forename: King-Wai
authors.initials: KW
authors.lastname: Yau
authors.forename: Elise
authors.initials: E
authors.lastname: Heon
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Stone
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Dizhoor
mesh_terms: D000293:Adolescent; D000328:Adult; D020134:Catalytic Domain; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007223:Infant; D057130:Leber Congenital Amaurosis / Q000201:enzymology* / Q000628:therapy; D008297:Male; D020125:Mutation, Missense; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism*; D055815:Young Adult
chemical_list: D011956:Receptors, Cell Surface; C110715:guanylate cyclase 1; D006162:Guanylate Cyclase