De novo variants in an extracellular matrix protein coding gene, fibulin-5 (FBLN5) are associated with pseudoexfoliation

• Published in: European journal of human genetics : EJHG Vol. 27; no. 12; pp. 1858 - 1866
• Main Authors: Padhy, Biswajit, Kapuganti, Ramani Shyam, Hayat, Bushra, Mohanty, Pranjya Paramita, Alone, Debasmita Pankaj
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.12.2019; Springer International Publishing
• Subjects: Adult; Aged; Aged, 80 and over; Amino Acid Oxidoreductases - genetics; Capillary electrophoresis; Elastin; Elastin - genetics; Exfoliation Syndrome - genetics; Exfoliation Syndrome - pathology; Exons; Extracellular matrix; Extracellular Matrix - genetics; Extracellular Matrix - metabolism; Extracellular Matrix Proteins - genetics; Female; Gene expression; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Lens Capsule, Crystalline - metabolism; Lens Capsule, Crystalline - pathology; Lysyl oxidase; Male; Matrix protein; Middle Aged; mRNA; Pathogenesis; Polymorphism, Single Nucleotide - genetics; Proteins; Risk factors; Tropoelastin; Western blotting
• ISSN: 1018-4813; 1476-5438; 1476-5438
• DOI: 10.1038/s41431-019-0482-6

Fibulin-5 (FBLN5), an extracellular scaffold protein, plays a crucial role in the activation of Lysyl oxidase like-1 (LOXL1), a tropoelastin crosslinking enzyme, and subsequent deposition of elastin in the extracellular matrix. Following study identifies polymorphisms within FBLN5 gene as risk factors and its aberrant expression in the pathogenesis of an ocular disorder, pseudoexfoliation (PEX). Exons and exon-intron boundaries within FBLN5 gene were scanned through fluorescence-based capillary electrophoresis for polymorphisms as risk factors for PEX pathogenesis in recruited study subjects with Indian ethnicity. mRNA and protein expression of FBLN5 was checked in lens capsule of study subjects through qRT-PCR and western blotting, respectively. In vitro functional analysis of risk variants was done through luciferase reporter assays. Thirty study subjects from control and PEX affected groups were scanned for potential risk variants. Putative polymorphisms identified by scanning were further evaluated for genetic association in a larger sample size comprising of 338 control and 375 PEX affected subjects. Two noncoding polymorphisms, hg38 chr14:g.91947643G>A (rs7149187:G>A) and hg38 chr14:g.91870431T>C (rs929608:T>C) within FBLN5 gene are found to be significantly associated with PEX as risk factors with a p-value of 0.005 and 0.004, respectively. Molecular assays showed a decreased expression of FBLN5 at both mRNA and protein level in lens capsule of pseudoexfoliation syndrome (PEXS) affected subjects than control. This study unravels two novel risk variants within FBLN5 gene in the pathogenesis of PEX. Further, a decreased expression of FBLN5 in PEXS affected lens capsules implicates a pathogenic link between extracellular matrix maintenance and onset of PEX.