Universität zu Köln

Mueller, Philipp L., Gliem, Martin, Mangold, Elisabeth, Bolz, Hanno J., Finger, Robert P., McGuinness, Myra ORCID: 0000-0002-5422-040X, Betz, Christian, Jiang, Zhichun, Weber, Bernhard H. F., MacLaren, Robert E., Holz, Frank G., Radu, Roxana A. and Issa, Peter Charbel ORCID: 0000-0002-0351-6673 (2015). Monoallelic ABCA4 Mutations Appear Insufficient to Cause Retinopathy: A Quantitative Autofluorescence Study. Invest. Ophthalmol. Vis. Sci., 56 (13). S. 8179 - 8187. ROCKVILLE: ASSOC RESEARCH VISION OPHTHALMOLOGY INC. ISSN 1552-5783

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Abstract

PURPOSE. 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-H-2, 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Mueller, Philipp L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gliem, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Mangold, Elisabeth UNSPECIFIED UNSPECIFIED UNSPECIFIED Bolz, Hanno J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Finger, Robert P. UNSPECIFIED UNSPECIFIED UNSPECIFIED McGuinness, Myra UNSPECIFIED orcid.org/0000-0002-5422-040X UNSPECIFIED Betz, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Jiang, Zhichun UNSPECIFIED UNSPECIFIED UNSPECIFIED Weber, Bernhard H. F. UNSPECIFIED UNSPECIFIED UNSPECIFIED MacLaren, Robert E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Holz, Frank G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Radu, Roxana A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Issa, Peter Charbel UNSPECIFIED orcid.org/0000-0002-0351-6673 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-386107
DOI:	10.1167/iovs.15-17629
Journal or Publication Title:	Invest. Ophthalmol. Vis. Sci.
Volume:	56
Number:	13
Page Range:	S. 8179 - 8187
Date:	2015
Publisher:	ASSOC RESEARCH VISION OPHTHALMOLOGY INC
Place of Publication:	ROCKVILLE
ISSN:	1552-5783
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language RETINAL-PIGMENT EPITHELIUM; STARGARDT-DISEASE GENE; CONE-ROD DYSTROPHY; MACULAR DEGENERATION; FUNDUS AUTOFLUORESCENCE; TRANSPORTER GENE; MOUSE MODEL; LIPOFUSCIN; MICE; FLAVIMACULATUS Multiple languages Ophthalmology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/38610