Introduction
Glaucoma is one of the most heritable of all human diseases (Wang et
al., 2017) and exhibits both Mendelian (childhood onset) and complex
(adult onset) inheritance (Wiggs and Pasquale, 2017). Affected patients
typically develop elevated intraocular pressure (IOP) that causes
irreversible degeneration of retinal ganglion cells and the optic nerve
(Weinreb et al., 2016). Increased IOP in most patients is caused by
impaired drainage of intraocular fluid from the eye through the
trabecular meshwork and outflow pathways (Weinreb et al., 2014).
Patients with childhood-onset glaucoma, defined as diagnosis before age
40, are affected by severe disease characterized by very high IOP, and
without treatment are likely to become blind over their lifetimes
(Papadopoulos et al., 2020). Juvenile-onset primary open-angle glaucoma
(JOAG) is one type of childhood glaucoma that typically exhibits
dominant inheritance. MYOC mutations account for disease in
15-20% of JOAG families primarily with European Caucasian ancestry andMYOC does not appear to be a major cause of disease in other
ethnic groups (Liu et al., 2021). To investigate the genetic etiology of
JOAG in an ethnically diverse population, we identified and recruited 14
JOAG pedigrees from regions throughout the Philippines.
EFEMP1 (EGF-containing fibulin-like extracellular matrix protein 1) also
known as Fibulin 3 is a member of the Fibulin family of extracellular
matrix proteins characterized by tandem arrays of EGF (epidermal growth
factor)-like domains and a C-terminal fibulin-type module (Figure 1B)
(Kobayashi et al., 2007). Among the fibulin family members,EFEMP1 has higher ocular expression (Wagner et al., 2013) and is
known to contribute to other ocular phenotypes. Common SNPs nearEFEMP1 on chromosome 2p16 have been associated with adult-onset
glaucoma (POAG) (Gharahkhani et al., 2021) as well as IOP (Khawaja et
al., 2018) and cup-to-disc ratio (CDR) an optic nerve quantitative trait
related to POAG risk (Springelkamp et al., 2015). A low frequencyEFEMP1 variant p.Arg140Trp, present in 2 individuals in gnomAD
has been identified in 5 affected individuals from an adult-onset POAG
African-American family (Mackay et al., 2015) and a stop loss variant
(Ter494Gluext*29) has been reported in 3 affected members of a Chinese
POAG family (Liu et al., 2020). A single EFEMP1 missense allele
(p.Arg345Trp) is known to cause Malattia Leventinese (MLVT) (also known
as Doyne’s Honeycomb dystrophy (DHRD; MIM:126600), a rare autosomal
dominant retinal degeneration characterized by extracellular deposits
(drusen) beneath the retinal pigment epithelium (RPE) (Stone et al.,
1999). Among the many patients affected by MLVT/DHRD, only p.Arg345Trp
has been identified as a causative mutation. Recently it has been
suggested that the Arg345 residue is a mutation hot spot and that
founder effects are not likely to account for the predominance of this
mutation in MLVT/DHRD patients (Vaclavik et al., 2020). Notably,
wildtype EFEMP1 is a secreted protein, while the p.Arg345Trp mutations
leads to protein misfolding and reduced secretion (Marmorstein et al.,
2002).
Here, we report three independent families from the Philippines with
novel EFEMP1 rare variants segregating with JOAG. Functional
studies suggest that the disease-associated EFEMP1 variants cause
protein misfolding and intracellular aggregation and retention. These
results expand the spectrum of EFEMP1 associated disease to
include childhood glaucoma.