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

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

1-11
Ratnapriya, R.
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Zhang, X.
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Farris, R.N.
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Branham, K.E.
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Zipprer, D.
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Chakarova, C.F.
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Sergeev, Y.V.
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Campos, M.M.
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Othman, M.
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Friedman, J.S.
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Maminishkis, A.
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Waseem, N.H.
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Brooks, M.
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Rajasimha, H.K.
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Edwards, A.O.
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Lotery, A.J.
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Ratnapriya, R.
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Zhang, X.
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Farris, R.N.
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Branham, K.E.
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Zipprer, D.
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Chakarova, C.F.
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Sergeev, Y.V.
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Campos, M.M.
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Othman, M.
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Friedman, J.S.
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Maminishkis, A.
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Waseem, N.H.
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Brooks, M.
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Rajasimha, H.K.
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Edwards, A.O.
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Lotery, A.J.
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Ratnapriya, R., Zhang, X. and Farris, R.N. et al. (2014) Rare and common variants in extracellular matrix gene Fibrillin 2 (FBN2) area associated with macular degeneration. Human Molecular Genetics, 1-11. (doi:10.1093/hmg/ddu276). (PMID:24899048)

Record type: Article

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.

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Published date: 4 June 2014
Organisations: Clinical & Experimental Sciences

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Local EPrints ID: 367803
URI: https://eprints.soton.ac.uk/id/eprint/367803
PURE UUID: 4870a0bf-6ade-40f2-96c5-b720e8e538e6
ORCID for A.J. Lotery: ORCID iD orcid.org/0000-0001-5541-4305

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Date deposited: 18 Aug 2014 10:51
Last modified: 20 Jul 2019 01:01

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Contributors

Author: R. Ratnapriya
Author: X. Zhang
Author: R.N. Farris
Author: K.E. Branham
Author: D. Zipprer
Author: C.F. Chakarova
Author: Y.V. Sergeev
Author: M.M. Campos
Author: M. Othman
Author: J.S. Friedman
Author: A. Maminishkis
Author: N.H. Waseem
Author: M. Brooks
Author: H.K. Rajasimha
Author: A.O. Edwards
Author: A.J. Lotery ORCID iD

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