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Hum Mol Genet. 2014 Nov 1;23(21):5827-37. doi: 10.1093/hmg/ddu276. Epub 2014 Jun 4.

Rare and common variants in extracellular matrix gene Fibrillin 2 (FBN2) are associated with macular degeneration.

Author information

1
Neurobiology Neurodegeneration and Repair Laboratory.
2
Center for Statistical Genetics, Department of Biostatistics and.
3
Biological Imaging Core.
4
Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI 48109, USA.
5
Department of Genetics, UCL-Institute of Ophthalmology, Bath Street, London EC1V 9EL, UK.
6
Ophthalmic Genetics and Visual Function Branch.
7
Section of Epithelial and Retinal Physiology and Disease.
8
Institute for Molecular Biology, University of Oregon and Oregon Retina, Eugene, OR 97401, USA.
9
Faculty of Medicine, Clinical and Experimental Sciences, University of Southampton, Southampton SO16 6YD, UK.
10
Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and, Public Health, Madison, WI 53726, USA.
11
Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44106, USA.
12
Center for Human Genetics Research, Vanderbilt University, Nashville, TN 37232, USA.
13
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA, Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah, Salt Lake City, UT 84132, USA.
14
Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah, Salt Lake City, UT 84132, USA.
15
Hôpital Intercommunal de Créteil, Hôpital Henri Mondor - Université Paris Est Créteil 94000, France.
16
Department of Ophthalmology, University of Thessaly School of Medicine, Larissa, Greece.
17
Institute of Human Genetics, University of Regensburg, Regensburg 93053, Germany.
18
Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60607, USA.
19
Centre for Vision and Vascular Science, Queen's University, Belfast, UK.
20
Wilmer Eye Institute, Johns Hopkins University, 600 N. Wolfe Street, Baltimore, MD 21287, USA.
21
Retina Service and Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA.
22
The Fred Hollows Foundation, Auckland, New Zealand, School of Social Sciences, University of New South Wales, Sydney, Australia.
23
Section of Immunopathology and.
24
Department of Ophthalmology and.
25
Department of Ophthalmology, Seoul National University Bundang Hospital, Seoul 463-707, Republic of Korea.
26
Departments of Medicine (Section of Biomedical Genetics), Ophthalmology and Biostatistics, Neurology, Epidemiology, Boston University Schools of Medicine and Public Health, Boston, MA 02215, USA.
27
Texas Biomedical Research Institute, San Antonio, TX 78245, USA.
28
Cleveland Clinic Foundation, Cole Eye Institute, Cleveland, OH 44195, USA, Louis Stokes Cleveland VA Medical Center, Cleveland, OH 44195, USA.
29
Department of Genetics, Institut de la Vision - Inserm Université Pierre et Marie Curie UMR-S 968, Paris, France.
30
Department of Human Genetics and.
31
Cleveland Clinic Foundation, Cole Eye Institute, Cleveland, OH 44195, USA.
32
Oregon Health & Science University, Portland, OR 97239, USA.
33
Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
34
Health Promotion and Development, School of Nursing, 440 Victoria Building, 3500 Victoria St, Pittsburgh, PA 15261, USA.
35
Bascom Palmer Eye Institute and Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33125, USA.
36
Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
37
Department of Ophthalmology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
38
Macular Degeneration Center, Casey Eye Institute, Oregon Health and Science, University, Portland, OR 97201, USA.
39
Department of Ophthalmology and Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
40
Department of Ophthalmology, and Department of Genetics, University of Pennsylvania, Philadelphia, PA 9104, USA.
41
Department of Human Genetics and Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
42
Clinical Trials Branch, Division of Epidemiology and Clinical Applications, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
43
Neurobiology Neurodegeneration and Repair Laboratory, swaroopa@nei.nih.gov.

Abstract

Neurodegenerative diseases affecting the macula constitute a major cause of incurable vision loss and exhibit considerable clinical and genetic heterogeneity, from early-onset monogenic disease to multifactorial late-onset age-related macular degeneration (AMD). As part of our continued efforts to define genetic causes of macular degeneration, we performed whole exome sequencing in four individuals of a two-generation family with autosomal dominant maculopathy and identified a rare variant p.Glu1144Lys in Fibrillin 2 (FBN2), a glycoprotein of the elastin-rich extracellular matrix (ECM). Sanger sequencing validated the segregation of this variant in the complete pedigree, including two additional affected and one unaffected individual. Sequencing of 192 maculopathy patients revealed additional rare variants, predicted to disrupt FBN2 function. We then undertook additional studies to explore the relationship of FBN2 to macular disease. We show that FBN2 localizes to Bruch's membrane and its expression appears to be reduced in aging and AMD eyes, prompting us to examine its relationship with AMD. We detect suggestive association of a common FBN2 non-synonymous variant, rs154001 (p.Val965Ile) with AMD in 10 337 cases and 11 174 controls (OR = 1.10; P-value = 3.79 × 10(-5)). Thus, it appears that rare and common variants in a single gene--FBN2--can contribute to Mendelian and complex forms of macular degeneration. Our studies provide genetic evidence for a key role of elastin microfibers and Bruch's membrane in maintaining blood-retina homeostasis and establish the importance of studying orphan diseases for understanding more common clinical phenotypes.

PMID:
24899048
PMCID:
PMC4189898
DOI:
10.1093/hmg/ddu276
[Indexed for MEDLINE]
Free PMC Article

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