EFEMP1 rare variants cause familial juvenile‐onset open‐angle glaucoma

Abstract

Juvenile open‐angle glaucoma (JOAG) is a severe type of glaucoma with onset before age 40 and dominant inheritance. Using exome sequencing we identified 3 independent families from the Philippines with novel EFEMP1 variants (c.238A>T, p.Asn80Tyr; c.1480T>C, p.Ter494Glnext*29; and c.1429C>T, p.Arg477Cys) co‐segregating with disease. Affected variant carriers (N = 34) exhibited severe disease with average age of onset of 16 years and with 76% developing blindness. To investigate functional effects, we transfected COS7 cells with vectors expressing the three novel EFEMP1 variants and showed that all three variants found in JOAG patients caused significant intracellular protein aggregation and retention compared to wild type and also compared to EFEMP1 variants associated with other ocular phenotypes including an early‐onset form of macular degeneration, Malattia Leventinese/Doyne's Honeycomb retinal dystrophy. These results suggest that rare EFEMP1 coding variants can cause JOAG through a mechanism involving protein aggregation and retention, and that the extent of intracellular retention correlates with disease phenotype. This is the first report of EFEMP1 variants causing JOAG, expanding the EFEMP1 disease spectrum. Our results suggest that EFEMP1 mutations appear to be a relatively common cause of JOAG in Filipino families, an ethnically diverse population.

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“…44,45 Although its definitive function remains incompletely understood, EFEMP1 (also known as fibulin-3 or S1-5) has pleiotropic effects beyond its role as an extracellular matrix protein and is associated with a network of protein-protein interactions involving other genes, resulting in variable diseases including POAG in humans. 30,31,[46][47][48][49] Expression of EFEMP1 is downregulated by transforming growth factor-β2, 50 which is highly expressed in the aqueous humor of patients with POAG and may be associated with increased aqueous humor outflow resistance in POAG. 50 Fibulins have overlapping binding sites for several basement-membrane proteins, tropoelastin, fibrillin, fibronectin, and proteoglycans.…”

“…In addition, the findings support the role for EFEMP1 in ocular extracellular matrix and in regulation of intraocular fluid dynamics and IOP. 31 In the eye, EFEMP1 is also strongly expressed in nonpigmented ciliary body epithelium and cornea, has a minor expression in the inner nuclear layer of the retina and optic nerve head, and has a residual expression in the lens. 30 Therefore, CCDC85A and EFEMP1 may enhance an individual's risk for different forms of PG.…”

“…The region in LD with the most significant SNP (P = 2.61 X 10 −6 ) at the CFA10 locus was approximately 1 megabase (MB) in length (from 56,375,894 bp to 57,267,300 bp), as defined by LD (r 2 > 0.2) and P values within 2 orders of magnitude of the most significant SNP. This 1-MB region included the genes cilia and flagella-associated protein 36 (CFAP36), protein phosphatase 4 regulatory subunit 3B (PPP4R3B), polyribonucleotide nucleotidyltransferase 1 (PNPT1), extracellular growth factor containing fibulin extracellular matrix protein 1 (EFEMP1), and coiled-coil domain containing 85A (CCDC85A; Figure 2, Table 1 [30][31][32] ).…”

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“…Gold particle labeling combined with TEM further confirmed extensive THBS1 deposition in a random distribution ( Figure 5 ) compared with WT mice, in which THBS1 was mainly found adjacent to collagen fibrils ( Figure 5B ). These results suggest that THBS1 C1034 formed detrimental extracellular aggregates, unlike other mutant ECM proteins, such as MYOC ( 25 ) and EFEMP1 ( 13 ), that form intracellular aggregates causing early-onset glaucoma.…”

“…Although there are hundreds of genomic loci associated with adult-onset glaucoma and related traits ( 5 – 7 ), there are currently only 10 genes known to cause childhood-onset familial disease. Most of the genes responsible for childhood glaucoma ( CYP1B1 , LTBP2 , PITX2 , PAX6 , FOXC1 , TEK , ANGPT1 , CPAMD8 ) cause abnormal ocular development ( 8 – 11 ), whereas 2 genes, MYOC and EFEMP1 , are ECM proteins with mutations causing intracellular aggregation in TM cells ( 12 , 13 ).…”