title: Genetics and Disease Expression in the CNGA3 Form of Achromatopsia: Steps on the Path to Gene Therapy.
abstract: OBJECTIVE
  Achromatopsia (ACHM) is a congenital, autosomal recessive retinal disease that manifests cone dysfunction, reduced visual acuity and color vision, nystagmus, and photoaversion. Five genes are known causes of ACHM. The present study took steps toward performing a trial of gene therapy in ACHM by characterizing the genetics of ACHM in Israel and the Palestinian Territories and analyzing retinal function and structure in CNGA3 ACHM patients from the Israeli-Palestinian population and US patients with other origins.
  
  
  METHODS
  Case series study.
  
  
  METHODS
  Patients with clinically suspected ACHM, cone dysfunction phenotypes, and unaffected family members were included. The protocol was approved by the local institutional review board and informed consent was obtained from all participants.
  
  
  METHODS
  Genetic analyses included homozygosity mapping and exome sequencing. Phenotype was assessed with electroretinography (ERG), optical coherence tomography, psychophysics, and photoaversion testing.
  
  
  METHODS
  Single nucleotide polymorphism microarray, exome analysis, DNA sequence analysis, visual function testing including ERG, and photoaversion.
  
  
  RESULTS
  We identified 148 ACHM patients from 57 Israeli and Palestinian families; there were 16 CNGA3 mutations (5 novel) in 41 families and 5 CNGB3 mutations (1 novel) in 8 families. Two CNGA3 founder mutations underlie >50% of cases. These mutations lead to a high ACHM prevalence of ∼1:5000 among Arab-Muslims residing in Jerusalem. Rod ERG abnormalities (in addition to cone dysfunction) were detected in 59% of patients. Retinal structure in CNGA3 ACHM patients revealed persistent but abnormal foveal cones. Under dark- and light-adapted conditions, patients use rod-mediated pathways. Photoaversion was readily demonstrated with transition from the dark to a dim light background.
  
  
  CONCLUSIONS
  Among Israeli and Palestinian patients, CNGA3 mutations are the leading cause of ACHM. Retinal structural results support the candidacy of CNGA3 ACHM for clinical trials for therapy of cone photoreceptors. Efficacy outcome measures would include chromatic light-adapted psychophysics, with attention to the photoreceptor basis of the response, and quantitation of photoaversion.
authors.affiliation: Department of Ophthalmology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Lina
authors.initials: L
authors.lastname: Zelinger
authors.affiliation: Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Artur V
authors.initials: AV
authors.lastname: Cideciyan
authors.affiliation: Molecular Genetics Laboratory, Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Kohl
authors.affiliation: Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Sharon B
authors.initials: SB
authors.lastname: Schwartz
authors.affiliation: Department of Ophthalmology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Ada
authors.initials: A
authors.lastname: Rosenmann
authors.affiliation: Department of Ophthalmology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Dalia
authors.initials: D
authors.lastname: Eli
authors.affiliation: Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Alexander
authors.initials: A
authors.lastname: Sumaroka
authors.affiliation: Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Alejandro J
authors.initials: AJ
authors.lastname: Roman
authors.affiliation: Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Xunda
authors.initials: X
authors.lastname: Luo
authors.affiliation: Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Cassondra
authors.initials: C
authors.lastname: Brown
authors.affiliation: Department of Ophthalmology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Boris
authors.initials: B
authors.lastname: Rosin
authors.affiliation: Department of Ophthalmology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Anat
authors.initials: A
authors.lastname: Blumenfeld
authors.affiliation: Molecular Genetics Laboratory, Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Wissinger
authors.affiliation: Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Jacobson
authors.affiliation: Department of Ophthalmology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Eyal
authors.initials: E
authors.lastname: Banin
authors.affiliation: Department of Ophthalmology, Hadassah Hebrew University Medical Center, Jerusalem, Israel. Electronic address: dror.sharon1@gmail.com.
authors.forename: Dror
authors.initials: D
authors.lastname: Sharon
mesh_terms: D000293:Adolescent; D000328:Adult; D018912:Arabs / Q000235:genetics; D002648:Child; D003117:Color Vision Defects / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy; D003241:Consanguinity; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000235:genetics*; D004252:DNA Mutational Analysis; D004596:Electroretinography; D005091:Exons / Q000235:genetics; D005260:Female; D018703:Founder Effect; D015870:Gene Expression; D015316:Genetic Therapy; D006801:Humans; D007557:Israel; D007585:Jews / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008967:Molecular Biology; D009154:Mutation; D010375:Pedigree; D020419:Photoreceptor Cells, Vertebrate / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D012162:Retinal Degeneration / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy; D041623:Tomography, Optical Coherence
chemical_list: C518238:CNGA3 protein, human; C415904:CNGB3 protein, human; D054815:Cyclic Nucleotide-Gated Cation Channels