A novel, non-stop mutation in FOXE3 causes an autosomal dominant form of variable anterior segment dysgenesis including Peters anomaly

Abstract

Anterior segment dysgenesis (ASD) is a spectrum of disorders that affect the anterior ocular chamber. Clinical studies on a Newfoundland family over the past 30 years show that 11 relatives have a variable ocular phenotype ranging from microcornea to Peters anomaly, segregating as an autosomal dominant trait. To determine the molecular etiology of the variable ASD in this family, we sequenced nine functional candidate genes and identified 44 variants. A point mutation in FOXE3, which codes for a transcription factor involved in the formation of the lens and surrounding structures, co-segregated with the variable ocular phenotype. This novel mutation (c.959G4T) substitutes the stop codon for a leucine residue, predicting the addition of 72 amino acids to the C-terminus of FOXE3. Two recent reports have also identified non-stop mutations in FOXE3 in patients with variable ocular phenotypes and predict an extended protein. Although FOXE3 is a lens-specific gene, we successfully isolated complementary DNA from lymphoblasts of an affected family member, and our sequencing results show that the c.959T allele is absent, suggesting that it may be degraded at the RNA level. Though preliminary, our results challenge the notion that an extended FOXE3 protein causes ASD, and instead suggests a mechanism of haploinsufficiency in the case of non-stop mutations. This study adds to several reports that suggest that autosomal-dominant mutations within FOXE3 cause ASD and has important clinical utility, especially for the diagnosis of mildly affected patients.

Exome sequencing in developmental eye disease leads to identification of causal variants in GJA8, CRYGC, PAX6 and CYP1B1

“…7 As an example, mutations in the gene FOXE3 may be found in patients with cataract, disorders of the anterior segment and microphthalmia ( Figure 1). [8][9][10] The developmental ocular anomaly of coloboma, due to delay in closure of the optic fissure, may affect the iris, choroid, retina and/or optic disc. 11 It is frequently associated with microphthalmia or anophthalmia.…”

The Use of Autozygosity Mapping and Next-Generation Sequencing in Understanding Anterior Segment Defects Caused by an Abnormal Development of the Lens

“…The dyl lens takes on a smaller, more irregular and disorganized form with significantly fewer lens fibre cells since the anterior lens epithelium fails to proliferate and produce secondary lens fibre cells in this mouse mutant [101] . It has been proposed that, in wild-type animals, Foxe3 downregulates Prox1 which subsequently reduces the expression of Cdkn1c , a gene that prevents the progression of the cell cycle [101, 103,104] . This mechanism of regulation is disrupted in mouse mutants and is likely to account for the absent proliferation of anterior lens epithelium cells in dyl mice [103] .…”

“…It has been proposed that, in wild-type animals, Foxe3 downregulates Prox1 which subsequently reduces the expression of Cdkn1c , a gene that prevents the progression of the cell cycle [101, 103,104] . This mechanism of regulation is disrupted in mouse mutants and is likely to account for the absent proliferation of anterior lens epithelium cells in dyl mice [103] . Foxe3 has been identified as a regulator of crystallin gene Cryaα during lens development.…”

“…There are several reports of FOXE3 mutations in humans, including 7 accounts of heterozygous variant discovery [4,102,103,106] , and 10 reports of autosomal recessive mutations [6,102,[107][108][109] . FOXE3 mutations have been reported in association with a variety of abnormalities that are linked but not limited to lens development [102] .…”

Novel mutations in PXDN cause microphthalmia and anterior segment dysgenesis

“…9 FOXC1 and PITX2 disruptions, either mutations or deletions, have been estimated to account for 6-40% of patients with anterior segment dysgenesis, [10][11] but are frequently associated with systemic findings, such as dental and umbilical anomalies in patients with PITX2 haploinsufficiency and cardiac and hearing deficits in patients with FOXC1 haploinsufficiency. 11 Mutations in FOXE3, PITX3, PAX6, B3GALTL, MAF, COL4A1, CYP1B1 and SH3PXD2B have also been described in patients with anterior segment dysgenesis, 9,[12][13][14][15][16][17][18][19] but there is considerable genetic heterogeneity similar to A/M and many genes remain unidentified. Next-generation sequencing has proven to be an outstandingly successful technology for new gene identification, 20 and we present our results for two families, a sibship with complex microphthalmia and anterior segment dysgenesis and a sporadic male patient with unilateral microphthalmia anterior segment dysgenesis.…”