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Published in final edited form as: Exp Eye Res. 2019 Dec 11;190:107893. doi: 10.1016/j.exer.2019.107893

Childhood Glaucoma Genes and Phenotypes: Focus on FOXC1 mutations causing anterior segment dysgenesis and hearing loss

Angela C Gauthier 1, Janey L Wiggs 1,*
PMCID: PMC7425631  NIHMSID: NIHMS1546711  PMID: 31836490

Abstract

Childhood glaucoma is an important cause of blindness world-wide. Eleven genes are currently known to cause inherited forms of glaucoma with onset before age 20. While all the early-onset glaucoma genes cause severe disease, considerable phenotypic variability is observed among mutations carriers. In particular, FOXC1 genetic variants are associated with a broad range of phenotypes including multiple forms of glaucoma and also systemic abnormalities, especially hearing loss. FOXC1 is a member of the forkhead family of transcription factors and is involved in neural crest development necessary for formation of anterior eye structures and also pharyngeal arches that form the middle ear bones. In this study we review the clinical phenotypes reported for known FOXC1 mutations and show that mutations in patients with reported ocular anterior segment abnormalities and hearing loss primarily disrupt the critically important forkhead domain. These results suggest that optimal care for patients affected with anterior segment dysgenesis should include screening for FOXC1 mutations and also testing for hearing loss.

Keywords: Glaucoma, genes, childhood, variable phenotype, hearing loss, anterior segment dysgenesis, FOXC1

Introduction

Glaucoma is a significant cause of blindness in children world-wide (Beck, 2011a; Haddad et al., 2007). Childhood forms of glaucoma are frequently characterized by high intraocular pressure (IOP) resulting from abnormalities of the eye fluid drainage structures (trabecular meshwork), however familial forms of normal-tension glaucoma are also known. High IOP causes irreversible damage to the optic nerve and in elastic pediatric eyes can cause ocular enlargement (buphthalmos) with the associated complications of high myopia, retinal detachment and corneal decompensation related to fracture of the corneal basement membranes. As curative therapies for glaucoma do not currently exist, affected children are subject to a lifetime of medical and surgery treatments directed toward lowering elevated intraocular pressure (Zagora et al., 2015; Ben-Zion et al., 2011; Beck et al., 2011b).

The discovery of genes responsible for pediatric glaucoma is an important step toward the development of clinically useful gene-based screening tests and novel and potentially curative genetic therapies. Eleven genes responsible for childhood forms of glaucoma have been identified so far (Table 1). Four genes are now known to cause congenital glaucoma: CYP1B1 and LTBP2 causing autosomal recessive disease (Ali et al., 2009; Bejjani et al., 1998; Stoilov et al., 1997) and TIE2 (TEK) and ANGPT1 cause dominantly inherited congenital glaucoma with variable expressivity related to development of Schlemm’s canal (Souma et al., 2016; Thomson et al., 2017). Mutations in three genes coding for transcription factors involved in ocular development can cause early-onset glaucoma and anterior segment dysgenesis: FOXC1 (Axenfeld-Rieger syndrome) (Nishimura et al., 1998), PITX2 (Rieger Syndrome) (Semina et al., 1996), PAX6 (Aniridia and Peter’s anomaly) (Jordan et al., 1992; Prosser et al., 1998). Recently CPAMD8 mutations have been identified as a cause of a unique form of autosomal recessive anterior segment dysgenesis that can include congenital cataracts (Cheong et al., 2016; Hollmann et al., 2017). Dominant MYOC (myocilin) missense alleles cause juvenile (onset after age 3) glaucoma (Fingert et al., 2002; Wiggs et al., 1998; Stone et al., 1997). Myocilin is an extracellular matrix protein and disease-causing missense alleles induce ER stress from the misfolded protein response (Donegan et al., 2015). Loss of function MYOC mutations in mice and humans do not cause glaucoma (Kim et al., 2001; Wiggs et al., 2001). FOXC1, PITX2 and PAX6 are regulatory genes that influence development of the ocular anterior segment including structures involved in glaucoma (Fan and Wiggs, 2010). Loss of function dominant alleles cause clinically evident developmental defects that can include glaucoma (Allen et al., 2015). OPTN (optineurin) and TBK1 (tank binding protein 1) cause dominantly inherited early-onset normal tension glaucoma, characterized by profound optic atrophy in the setting of normal IOP (Fingert et al., 2011; Hauser et al., 2006; Rezaie et al., 2002).

Table 1.

Childhood glaucoma genes and phenotypes

Gene Protein Inheritance Phenotypes
CYP1B1 Cytochrome P450 1B1 AR Congenital and juvenile glaucoma
LTBP2 Latent transforming growth factor binding protein 2 AR Congenital glaucoma
CPAMD8 C3 and PZP like alpha-2-macroglobulin domain containing 8 AR Anterior segment dysgenesis
PITX2 Paired like homeodomain 2 AD Anterior segment dysgenesis and classic Reiger syndrome
FOXC1 Forkhead box C1 AD Congenital glaucoma, anterior segment dysgenesis, Axenfeld-Rieger syndrome, juvenile open angle glaucoma
PAX6 Paired box 6 AD Aniridia, corneal keratitis, Peter’s anomaly
MYOC Myocilin AD Juvenile open angle glaucoma, adult-onset open angle glaucoma
TIE2 (TEK) TEK receptor tyrosine kinase AD Congenital glaucoma with variable expressivity
ANGPT1 Angiopoietin 1 AD Congenital glaucoma
OPTN Optineurin AD Normal tension glaucoma
TBK1 TANK binding kinase 1 AD Normal tension glaucoma
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Abbreviations: AD, Autosomal dominant; AR, Autosomal recessive.

Variable phenotypes

Phenotypic variation has been observed in patients with disease caused by childhood glaucoma genes, especially for patients with mutations in CYP1B1, MYOC, PAX6 and FOXC1. Many patients with CYP1B1 mutations are diagnosed with congenital glaucoma during infancy, however some patients do not show evidence of the disease until later in childhood or even teenage years (López-Garrido et al., 2013; Khan et al., 2011; Suri et al., 2009). Similarly, while many MYOC mutations cause disease before age 20, several mutations, including the well-studied Q368X, are known to be responsible for disease in individuals who are not diagnosed with glaucoma until later in life (Nag et al., 2018; Allingham et al., 1998). PAX6 mutations are classically known to cause aniridia (Prosser et al., 1998) but can also cause autosomal dominant keratitis due to limbal stem cell deficiency (Mirzayans et al., 1995; Li et al., 2015). FOXC1 mutations can be responsible for disease with onset ranging from birth (Siggs et al., 2019) to adult (Bailey et al., 2016). Additionally our NEIGHBORHOOD consortium has recently identified SNPs in the FOXC1 5’ UTR that are significantly associated with adult-onset POAG, suggesting that variable expression of FOXC1 may contribute to POAG more commonly (Cooke Bailey et al., 2016).

FOXC1 ocular phenotypes

Forkhead transcription factors are a family of proteins that share a highly conserved forkhead DNA-binding domain and are required for regulation of embryogenesis, cell migration, differentiation and fate determination (Golson and Kaestner, 2016). FOXC1 codes for a member of the forkhead transcription factor family that is required for the migration and specification of the periocular mesenchyme neural-crest derived mesenchymal cells that give rise to important ocular structures related to glaucoma including the stroma of the ciliary body and iris and the trabecular meshwork (Akula et al., 2019).

Both deletions and duplications involving FOXC1 have been implicated in ocular disease (Lehmann et al., 2000; Nishimura et al., 2001) indicating gene dosage as a critical factor in disease development. FOXC1 null mice exhibit clinical features of anterior segment dysgenesis including iris hypoplasia, corectopia, and embryotoxon in mice (Kume et al., 1998; Gould et al., 2004).

FOXC1 mutations can cause a broad range of ocular phenotypes: Axenfeld-Rieger syndrome (Nishimura et al., 1998), Peters Anomaly (Honkanen et al., 2003), congenital glaucoma (Siggs et al., 2019), and more recently adult-onset primary open angle glaucoma (Bailey et al., 2016). Frequently FOXC1 mutations are associated with Axenfeld-Rieger anomaly defined by anterior segment dysgenesis with characteristic posterior embryotoxon, iris hypoplasia, and corectopia (Seifi and Walter, 2018). Axenfeld-Rieger syndrome describes patients with Axenfeld-Rieger anomaly and additional systemic features that may include a flat mid-face due to maxillary hypoplasia and a flat broad nose, teeth abnormalities, redundant umbilical skin and congenital heart defects (Lewis et al., 2017). Many patients with Axenfeld-Rieger anomaly or syndrome will also develop glaucoma, however the severity of the anterior segment dysgenesis does not predict glaucoma risk. Recent studies suggest that patients with truncating FOXC1 mutations are more likely to be diagnosed with congenital glaucoma (Siggs et al., 2019).

FOXC1 systemic phenotypes

FOXC1 mutation carriers may also exhibit a range of systemic abnormalities. Patients with large-scale deletions or duplications of the 6pter-6p24 region that includes FOXC1, FOXFQ and FOXF2 can present with a syndromic phenotype defined by hearing loss, cardiac abnormalities, short stature, dental abnormalities, facial dysmorphism and hypertelorism (Gould et al., 2004). De Hauwere syndrome describes a subset of the 6pter-6p24 deletion patients that are characterized by Axenfeld-Rieger syndrome, hydrocephalus and hearing loss (Lowry et al., 2007). Dandy-Walker malformation involving the cerebellum has also been described in patients with FOXC1 mutations (Aldinger et al., 2009). FOXC1 is an important component of the signaling pathways necessary for cardiac development and mutations can cause congenital heart disease and abnormal valve formation (Zhu, 2016). Involvement of FOXC1 in the neural crest migration forming the pharyngeal arches and cardiac neural crest likely underlie these systemic findings in FOXC1 mutation carriers (Kume et al., 2001).

Patients with FOXC1 point mutations and indels (nonsense, frameshift or missense alleles) also can present with a range of ocular and systemic phenotypes (Table 2). Systemic phenotypes associated with FOXC1 mutations are similar in range and scope to those identified in patients with large-scale deletions and duplications suggesting that genetic abnormalities involving FOXC1 are important drivers of the 6pter-6p25 syndromic clinical features.

Table 2.

FOXC1 mutations and ocular and hearing phenotypes

Protein variant Protein domain cDNA variant Hearing Phenotype Ocular Phenotype Reference
Q2X Active 1 c.4C>T NR ARA Komatireddy et al., 2003
R4fs Active 1 c.12delC NR Glaucoma Chakrabarti et al., 2009
S9fsX89 Active 1 c.26–47ins Deafness Iris hypoplasia, corectopia Kawase et al., 2001
Q23X Active 1 c.67C>T Hearing loss ARA, glaucoma Mirzayans et al., 2001
R28_30del Active 1 c.81_89del9 NR Glaucoma Chakrabarti et al., 2009
A31_33del Active 1 c.92_100del9 NR Glaucoma Kaur et al., 2009
A31fsX41 Active 1 c.93_102del10 No systemic findings ARA, glaucoma Michael et al., 2016
A31fsX41 Active 1 c.93_102del10 No systemic findings ARA, glaucoma Mears et al., 1998
G33fsX41 Active 1 c.99_108del10 NR ARA Nishimura et al., 2001
G34fsX8 Active 1 c.100_109del10 NR PE, glaucoma Souzeau et al., 2017
A39fsX42 Active 1 c.116_123del8 NR ARA Nishimura et al., 2001
Y47X Active 1 c.141C>G NR Glaucoma Medina-Trillo et al., 2015
S48X Active 1 c.143C>A No systemic findings PE, corectopia Weisschuh et al., 2006
A51fsX73 Active 1 c.153_163del11 NR ARA, glaucoma Nishimura et al., 1998
Y64X After
Active 1		 c.192C>G NR ARA, glaucoma Carmona et al., 2017
Q70fsX73 Forkhead c.210delG Hearing loss ARA, glaucoma Swiderski RE et al. 1999
P79T Forkhead c.235C>A Hearing loss ARA, glaucoma Suzuki T et al., 2001
P79R Forkhead c.236C>G NR Iris hypoplasia, glaucoma Weisschuh et al., 2006
P79L Forkhead c.236C>T NR ARA Saleem et al., 2003
P79L Forkhead c.236C>T NR ARA Nishimura et al., 1998
S82T Forkhead c.245G>C Hearing loss ARA, glaucoma Mears et al., 1998
A85P Forkhead c.253G>C NR ARA, glaucoma Fuse et al., 2007
L86F Forkhead c.256C>T NR ARA, glaucoma Saleem et al., 2003
I87M Forkhead c.261C>G No systemic findings ARA, glaucoma Mears et al., 1998
T88fsX100 Forkhead c.262_265insC NR ARA Nishimura et al., 2001
A90T Forkhead c.268G>A No systemic findings PE, glaucoma Souzeau et al., 2017
A90D Forkhead c.269C>A NR Glaucoma Siggs et al., 2019
I91S Forkhead c.272T>G NR ARA, glaucoma Kawase et al., 2001
I91T Forkhead c.272T>C NR ARA Mortemousque et al.,2004
D96GfsX210 Forkhead c.286dupG NR PE, glaucoma D’Haene et al., 2011
D96fsX305 Forkhead c.286insG NR ARA, glaucoma Kawase et al., 2001
Q106X Forkhead c.316C>T NR ARA, glaucoma D’Haene et al., 2011
Q106X Forkhead c.316C>T NR ARA, glaucoma Souzeau et al., 2017
Q106RfsX75 Forkhead c.317delA Normal hearing ARA, glaucoma Kim et al., 2013
M109V Forkhead c.325A>G Hearing loss Corectopia D’Haene et al., 2011
F112SfsX69 Forkhead c.335del Hearing Loss ARA, glaucoma D’Haene et al., 2011
F112S Forkhead c.335T>C NR ARA, glaucoma Nishimura et al., 1998
F112S Forkhead c.335T>C NR ARA, glaucoma Honkanen et al., 2003
Y115S Forkhead c.339T>C Middle-ear deafness ARA, glaucoma Weisschuh et al., 2006
D117TfsX64 Forkhead c.349delG NR ARA, glaucoma Siggs et al., 2019
Q120X Forkhead c.358C>T NR ARA, glaucoma Weisschuh et al., 2008
Q123X Forkhead c.367C>T NR ARA, glaucoma Komatireddy et al., 2003
I126M Forkhead c.378C>G NR ARA, glaucoma Nishimura et al., 1998
H128R Forkhead c.378A>G NR Glaucoma Chakrabarti et al., 2009
R127H Forkhead c.380G>A NR ARA, glaucoma Kawase et al., 2001
R127L Forkhead c.380T>G NR ARA, glaucoma Du et al., 2016
L130F Forkhead c.388C>T NR ARA, glaucoma Ito et al., 2007
S131L Forkhead c.392C>T NR ARA, glaucoma Nishimura et al., 1998
S131X Forkhead c.392C>A NR Glaucoma D’Haene et al., 2011
S131W Forkhead c.392C>G NR ARA D’Haene et al., 2011
C135Y Forkhead c.402G>A NR Glaucoma Chakrabarti et al., 2009
V137del Forkhead c.409_411del NR PE, glaucoma Siggs et al., 2019
K138E Forkhead c.412A>G NR PE, glaucoma D’Haene et al., 2011
P146fs Forkhead c.437_453del17 Hearing loss ARA, glaucoma Fuse et al., 2007
G149D Forkhead c.446G>A NR ARA, glaucoma Weisschuh et al., 2006
W152R Forkhead c.454T>C Mild deafness ARA, glaucoma Michael et al., 2016
W152G Forkhead c.454T>G NR Glaucoma Ito et al., 2009
W152X Forkhead c.456G>A NR ARA, glaucoma Cella et al., 2006
T153P Forkhead c.457A>C Hearing loss PE, glaucoma Siggs et al., 2019
M161V Forkhead c.481A>G Middle-ear deafness ARA, glaucoma Weisschuh et al., 2006
M161K Forkhead c.482T>A NR ARA, glaucoma Panicker et al., 2002
M161K Forkhead c.482T>A NR ARA, glaucoma Komatireddy et al., 2003
E163X Forkhead c.487G>T Hearing Loss Glaucoma Siggs et al., 2019
G165R Forkhead c.494G>C NR ARA, glaucoma Murphy et al., 2004
R169P Forkhead c.506G>C Hearing loss ARA Murphy et al., 2004
R170W Forkhead c.508C>T Hearing Loss ARA, glaucoma Gripp et al., 2013
Q200fsX109 After
Forkhead		 c.599_617del19 NR ARA Souzeau et al., 2017
P202RfsX113 After
Forkhead		 c.605delC NR ARA, glaucoma D’Haene et al., 2011
A204RfsX111 After
Forkhead		 c.609delC NR ARA, glaucoma Kelberman et al., 2011
I223PfsX87 Inhibitory c.666_681del16 NR PE glaucoma Souzeau et al., 2017
G231VfsX73 Inhibitory c.692_696del5 NR ARA, glaucoma D’Haene et al., 2011
L240VfsX65 Inhibitory c.718_719delCT No systemic findings ARA, glaucoma Cella et al., 2006
L240VfsX65 Inhibitory c.718_719delCT NR Glaucoma Siggs et al., 2019
L240RfsX75 Inhibitory c.719delT + Glaucoma Hariri et al.,2018
L246fsX68 Inhibitory c.738delG NR Iris atrophy, glaucoma Weisschuh et al., 2006
D261RfsX45 Inhibitory c.780dup NR NR D’Haene et al., 2011
S272RfsX43 Inhibitory c.816_817delinsG NR NR D’Haene et al., 2011
A291fs Inhibitory c.853dup25 NR Glaucoma Chakrabarti et al., 2009
P297S Inhibitory c.889C>T NR Glaucoma Fetterman et al., 2009
P297S Inhibitory c.889C>T NR Glaucoma Medina-Trillo et al., 2016
S309CfsX84 Inhibitory c.925_949del25 NR Glaucoma Souzeau et al., 2017
E327AfsX200 Inhibitory c.980_981del NR NR D’Haene et al., 2011
G379Gins After
Inhibitory		 c.1142_1144insGGC No systemic findings Iris atrophy, glaucoma Yang et al., 2015
M400SfsX129 After
inhibitory		 c.1193_1196dup Congenital deafness Iris atrophy, glaucoma Reis et al., 2016
S422X After
Inhibitory		 c.1265C>A NR ARA, glaucoma Souzeau et al., 2017
G452insR After
Inhibitory		 c.1362_1364insCGG No systemic findings Iris atrophy, glaucoma Yang et al., 2015
Y497X Active 2 c.1491C>G NR Glaucoma D’Haene et al., 2011
Y497X Active 2 c.1491C>G Hearing Loss PE, glaucoma Souzeau et al., 2017
N503fsX15 Active 2 c.1511delT NR ARA, glaucoma Weisschuh et al., 2006
F504fsX518 Active 2 c.1512delG NR ARA Nishimura et al., 2001
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Abbreviations: ARA, Axenfeld-Rieger anomaly; PE, Posterior embryotoxon; NR = Not reported.

FOXC1 and Hearing Loss

Patients with large-scale deletions and other copy number variations (CNVs) involving chromosome 6p25 and FOXC1 frequently are affected with hearing loss in addition to anterior ocular dysgenesis (D’haene et al., 2011; Gould et al., 2004). Although a precise role for FOXC1 in hearing or ear development is not well understood, during development, neural crest cells migrate from the dorsal hindbrain to specific locations in pharyngeal arch (PA) 1 and 2, to form the middle ear bones (malleus, incus and stapes) (Ritter and Martin, 2019). As FOXC1 contributes to neural crest migration in the pharyngeal arches, its possible that FOXC1 mutations can interfere with this process. Defective FOXC1 can lead to abnormal development and ossification of facial bones (Xu et al., 2018) and Foxc1−/− mice have abnormal cranial facial bone development, and failed ossification of the middle ear bones (Inman et al., 2013).

To gain a better understanding of the role of FOXC1 in hearing and deafness we reviewed published reports of FOXC1 variants and recorded information on hearing and ocular findings (Tables 2 and 3 and Figure 1) by searching PubMed with terms “FOXC1” and “Mutation” or “6p25” or “Ring chromosome 6”. We excluded publications that were not in English, did not describe human genetic variants or were not accessible online.

Table 3.

Chromosome 6p25 abnormalities and ocular and hearing phenotypes

6p25 Variant Hearing Phenotype Ocular Phenotype Reference
.084 Mb deletion NR PE, iris atrophy, glaucoma D’Haene et al, 2011
0.98 Mb deletion Hearing loss ARA, glaucoma Reis et al, 2012
1.10 Mb deletion Hearing loss ARA, glaucoma Reis et al, 2012
1.3 Mb deletion Hearing loss ARA Reis et al, 2012
1.3 Mb deletion Hearing Loss Congenital glaucoma Siggs et al., 2019
1.4 Mb deletion NR Normal Ophthalmic exam Ovaert et al., 2017
1.5 Mb deletion Normal hearing Axenfeld-Rieger syndrome, congenital glaucoma Reis et al, 2012
1.5 Mb deletion NR PE, iris atrophy, glaucoma Sadagopan et al., 2015
2.1 Mb deletion Conductive hearing defect Anterior segment dysgenesis Anderlid et al, 2003
2.1 Mb deletion Abnormal auditory brainstem response Congenital glaucoma Nakane et al., 2013
2.21 MB deletion Hearing loss Myopia Bedoyan et al, 2011
2.54 Mb deletion Hearing Loss ARA Vernon et al., 2013
2.6 Mb deletion Middle ear malformations and hearing loss Iris hypoplasia, glaucoma D’Haene et al, 2011
2.6 Mb duplication NR PE, iris atrophy, glaucoma Sadagopan et al., 2015
2.7 Mb deletion Sensorineural deafness PE, iris atrophy, glaucoma Martinez-Glez et al., 2007
3.4 Mb deletion Hearing loss Glaucoma Weegerink et al, 2016
3.4 Mb deletion Hearing loss Glaucoma Weegerink et al, 2016
3.4 Mb deletion Hearing loss PE Weegerink et al, 2016
3.4 Mb deletion Middle ear hearing loss PE, glaucoma D’Haene et al, 2011
3.9 Mb deletion Normal hearing Strabismus Cellini et al, 2012
34 kb deletion Hearing loss PE, glaucoma D’Haene et al, 2011
4.7 Mb deletion Hearing loss ARA D’Haene et al, 2011
4.8 Mb deletion Conductive hearing loss PE, iris atrophy Le Caignec et al., 2005
5.06 Mb deletion and 1 Mb duplication Hearing loss Corectopia Linhares et al, 2015
5.4 kb deletion NR PE D’Haene et al, 2011
5.5 Mb deletion Hearing loss PE, corneal opacity Le Caignec et al., 2005
6 Mb deletion Normal auditory brainstem response, but no speech Normal Ophthalmic exam Piccione et al., 2012
6.6 Mb deletion Normal hearing ARA, glaucoma Tonoki et al, 2011
6p25 microdeletion Sensorineural deafness ARA Kapoor et al, 2011
6p25-6p22 deletion NR ARA Suzuki et al., 2006
6p25-6pter deletion Normal hearing ARA Maclean et al, 2005
6p25-6pter deletion Normal hearing PE, glaucoma Tonoki et al, 2011
6p25-6pter deletion Normal hearing Axenfeld-Rieger syndrome, congenital glaucoma Reis et al, 2012
6p25-6pter deletion Hearing loss ARA, glaucoma Gould et al, 2004
6p25-6pter deletion Normal hearing ARA Gould et al, 2004
6pter deletion Normal hearing PE Lin et al, 2005
6p25 to 6pter deletion Hearing loss ARA Lin et al, 2005
6pter microdeletion Normal hearing Anterior segment dysgenesis Guillen-Navarro et al, 1997
Ring chromosome 6, 6 Mb deletion on 6p Hearing loss Peter’s anomaly, glaucoma Zhang et al, 2004
Ring chromosome 6, 1.8 Mb distal 6p deletion Hearing loss Ocular features not recorded Pace et al., 2017
Ring chromosome 6, 6p deletion Normal auditory brainstem response, but no speech PE, iris atrophy, glaucoma Corona-Rivera et al., 2018
Ring chromosome 6, 6p25.2 deletion 1.78 Mb NR Anterior segment dysgenesis, microphthalmia Zhang et al., 2016
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Abbreviations: ARA, Axenfeld-Rieger anomaly; PE, Posterior embryotoxon; NR, Not reported.

Figure 1. Gene location of FOXC1 mutations.

Figure 1.

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The location of the mutations listed in Table 2 are shown. Variants shown in red font are reported in patients with hearing loss. Abbreviations: AD1, Active Domain 1; AD2, Active Domain 2.

Our review identified 82 different FOXC1 human mutations (Table 2) and 42 6p25 deletions, duplications or ring chromosomes that include the FOXC1 genomic region (Table 3). Of the 82 FOXC1 mutations reported in patients with ocular disease, 17 reported abnormal hearing (Table 2; Figure 1). Fifteen of the 17 mutations found in patients reporting hearing loss either caused a frameshift or premature stop codon in Active Domain 1, leading to the loss of the forkhead domain, or a framshrift, nonsense or missense change located in the forkhead domain itself (Figure 1). Only one mutation within the forkhead domain (Q106RfsX75) reported normal hearing (Kim et al., 2013). Unfortunately, in many cases, there is no mention of the hearing phenotype or the case is reported with “no systemic findings,” making it difficult to determine whether or not hearing tests were conducted (Table 2).

Of the 38 reported cases of 6p25 deletions or duplications 20 (53%) have described hearing defects as part of the clinical presentation and 2 of 4 patients with ring chromosome 6 involving the FOXC1 genomic region also reported hearing loss (Table 3). Nine patients with 6p deletions reported have normal hearing and two patients were reported to have normal auditory brainstem response but no speech (Table 3) suggesting variable expressivity of the hearing phenotype. Similar to the reports for the FOXC1 mutations (Table 2) 7 of the 6p25 deletion, duplication or ring chromosome reports did not comment on hearing.

The results of this literature review show that FOXC1 mutations that cause both anterior segment dysgenesis and hearing loss most likely disrupt the critical forkhead domain. The forkhead domain is necessary for proper FOXC1 nuclear localization and DNA binding, and disruptions to this part of the gene are the most deleterious to protein function (Saleem et al., 2004). There are however, many patients with FOXC1 mutations involving the forkhead domain that do not report hearing problems. This observation may be due to variable expressivity of the hearing phenotype, or could implicate a second gene or other factors that impact hearing pathogenesis. Alternatively, hearing tests may not have been done or may not have been noted in the report.

Summary

Currently 11 genes are known to cause early-onset glaucoma and variable phenotypes in mutation carriers is frequently observed. In this review we focused on the spectrum of phenotypes found in patients with FOXC1 mutations with an emphasis on hearing loss. We determined that of the majority of FOXC1 mutations reported in the literature in patients with anterior segment dysgenesis and hearing loss disrupt the critically important forkhead domain necessary for DNA binding and transcriptional regulation. We also find that approximately 50% of patients reported with 6p25 deletions, duplications or ring chromosomes also report hearing abnormalities. These results overall suggest that FOXC1 mutations are capable of causing hearing defects and that patients with FOXC1 mutations should undergo hearing testing.

Highlights.

  • Eleven genes responsible for childhood forms of glaucoma are currently known.

  • Variable clinical features can be observed in patients with mutations in childhood glaucoma genes.

  • FOXC1 mutations can cause ocular and systemic disease.

  • FOXC1 mutations causing ocular disease and hearing loss are primarily located in the forkhead domain.

Acknowledgements

This work was supported in part by the March of Dimes Foundation, NIH/NEI P30 EY014104 and a student fellowship grant from Yale University Medical School (ACG).

Footnotes

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