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

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.

• Authors: Rinki Ratnapriya, Xiaowei Zhan, Robert N Fariss, Kari E Branham, David Zipprer, Christina F Chakarova, Yuri V Sergeev, Maria M Campos, Mohammad Othman, James S Friedman, Arvydas Maminishkis, Naushin H Waseem, Matthew Brooks, Harsha K Rajasimha, Albert O Edwards, Andrew Lotery, Barbara E Klein, Barbara J Truitt, Bingshan Li, Debra A Schaumberg, Denise J Morgan, Margaux A Morrison, Eric Souied, Evangelia E Tsironi, Felix Grassmann, Gerald A Fishman, Giuliana Silvestri, Hendrik P N Scholl, Ivana K Kim, Jacqueline Ramke, Jingsheng Tuo, Joanna E Merriam, John C Merriam, Kyu Hyung Park, Lana M Olson, Lindsay A Farrer, Matthew P Johnson, Neal S Peachey, Mark Lathrop, Robert V Baron, Robert P Igo Jr, Ronald Klein, Stephanie A Hagstrom, Yoichiro Kamatani, Tammy M Martin, Yingda Jiang, Yvette Conley, Jose-Alan Sahel, Donald J Zack, Chi-Chao Chan, Margaret A Pericak-Vance, Samuel G Jacobson, Michael B Gorin, Michael L Klein, Rando Allikmets, Sudha K Iyengar, Bernhard H Weber, Jonathan L Haines, Thierry Léveillard, Margaret M Deangelis, Dwight Stambolian, Daniel E Weeks, Shomi S Bhattacharya, Emily Y Chew, John R Heckenlively, Gonçalo R Abecasis, Anand Swaroop
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 23 Issue 21 Pg. 5827-37 (Nov 01 2014) ISSN: 1460-2083 [Electronic] England
• PMID: 24899048 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Published by Oxford University Press 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Chemical References

• FBN2 protein, human
• Fibrillin-2
• Fibrillins
• Microfilament Proteins

Topics

• Adult
• Aged
• Amino Acid Sequence
• Bruch Membrane (metabolism)
• DNA Mutational Analysis
• Exome
• Extracellular Matrix (metabolism)
• Fibrillin-2
• Fibrillins
• Genetic Association Studies
• Genetic Variation
• High-Throughput Nucleotide Sequencing
• Humans
• Macular Degeneration (diagnosis, genetics)
• Male
• Meta-Analysis as Topic
• Microfilament Proteins (genetics, metabolism)
• Middle Aged
• Models, Molecular
• Molecular Sequence Data
• Mutation
• Pedigree
• Protein Conformation
• Protein Stability
• Retina (metabolism, pathology)
• Sequence Alignment