title: Monoallelic ABCA4 Mutations Appear Insufficient to Cause Retinopathy: A Quantitative Autofluorescence Study.
abstract: OBJECTIVE
  To investigate the effect of ABCA4 mutation status on lipofuscin-related quantitative autofluorescence (qAF) in humans and on bisretinoid accumulation in mice.
  
  
  METHODS
  Genotyped parents (n = 26; age 37-64 years) of patients with biallelic ABCA4-related retinopathy underwent in-depth retinal phenotyping including qAF imaging as a surrogate measure for RPE lipofuscin accumulation. In addition, bisretinoids as the main components of autofluorescent lipofuscin at the ocular fundus were quantified in Abca4-/-, Abca4+/-, and wild-type mice.
  
  
  RESULTS
  Index patients showed a retinal phenotype characteristic for ABCA4-related retinopathy, including increased qAF levels. In contrast, qAF measures in carriers of only one ABCA4 mutation were not different from age-matched controls in this sample, and there was no difference between truncating and missense mutations. Also, none of these carriers presented an abnormal phenotype on conventional imaging. One parent with ABCA4-related retinopathy and increased qAF carried an additional ABCA4 mutation, explaining the phenotype under a recessive disease model (pseudodominance). Biochemical analysis in the mouse model revealed direct downstream products (A2PE-H2, at-RALdimer-PE) of the ABCA4 substrate N-Ret-PE to be similar in wild-type and Abca4+/- mice. Both bisretinoids were 12- to 18-fold increased in Abca4-/- mice. Levels of A2E and A2PE in Abca4+/- mice were in between those measured in wild-type and Abca4-/- mice.
  
  
  CONCLUSIONS
  This study indicates that carriers of monoallelic ABCA4 mutations are phenotypically normal. However, biochemical analysis in the Abca4-deficient mouse model suggests detectable effects of one mutation in ABCA4 on the molecular level. The findings may have implications for therapeutic approaches such as gene replacement therapy.
authors.affiliation: Department of Ophthalmology, University of Bonn, Bonn, Germany 2Center for Rare Diseases Bonn (ZSEB), University Hospital of Bonn, Bonn, Germany.
authors.forename: Philipp L
authors.initials: PL
authors.lastname: Müller
authors.affiliation: Department of Ophthalmology, University of Bonn, Bonn, Germany 2Center for Rare Diseases Bonn (ZSEB), University Hospital of Bonn, Bonn, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Gliem
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Mangold
authors.affiliation: Bioscientia Center for Human Genetics, Ingelheim, Germany 5Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany.
authors.forename: Hanno J
authors.initials: HJ
authors.lastname: Bolz
authors.affiliation: Department of Ophthalmology, University of Bonn, Bonn, Germany 6Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Australia.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Finger
authors.affiliation: Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Australia.
authors.forename: Myra
authors.initials: M
authors.lastname: McGuinness
authors.affiliation: Bioscientia Center for Human Genetics, Ingelheim, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Betz
authors.affiliation: Stein Eye Institute, Department of Ophthalmology, University of California-Los Angeles School of Medicine, Los Angeles, California, United States.
authors.forename: Zhichun
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Institute of Human Genetics, University of Regensburg, Regensburg, Germany.
authors.forename: Bernhard H F
authors.initials: BH
authors.lastname: Weber
authors.affiliation: The Nuffield Laboratory of Ophthalmology & Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
authors.forename: Robert E
authors.initials: RE
authors.lastname: MacLaren
authors.affiliation: Department of Ophthalmology, University of Bonn, Bonn, Germany 2Center for Rare Diseases Bonn (ZSEB), University Hospital of Bonn, Bonn, Germany.
authors.forename: Frank G
authors.initials: FG
authors.lastname: Holz
authors.affiliation: Stein Eye Institute, Department of Ophthalmology, University of California-Los Angeles School of Medicine, Los Angeles, California, United States.
authors.forename: Roxana A
authors.initials: RA
authors.lastname: Radu
authors.affiliation: Department of Ophthalmology, University of Bonn, Bonn, Germany 2Center for Rare Diseases Bonn (ZSEB), University Hospital of Bonn, Bonn, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Charbel Issa
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000483:Alleles; D000818:Animals; D003430:Cross-Sectional Studies; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D005260:Female; D005451:Fluorescein Angiography; D005654:Fundus Oculi; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D012164:Retinal Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D055213:Retinal Pigment Epithelium / Q000378:metabolism / Q000473:pathology*; D012189:Retrospective Studies; D041623:Tomography, Optical Coherence
chemical_list: C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters; D004247:DNA