Dataset Information

Insights into the FOXE3 Transcriptional Network from Exploration of the Impact of a Regulatory Variant in Complex Microphthalmia

ABSTRACT: FOXE3 encodes a highly conserved transcription factor essential for lens development, which is critical for proper eye formation. Biallelic variants in FOXE3 are associated with ocular anomalies, particularly complex microphthalmia (CM), characterized by defects in both the anterior segment and lens. Using next-generation sequencing (NGS) and Sanger sequencing, we identified a heterozygous nonsense variant in compound heterozygosity with a novel single nucleotide variant (SNV) located in a conserved non-coding region 3 kb upstream of FOXE3 in a patient with CM. Genetically engineered mouse lines carrying either the non-coding variant (Foxe3rv) or a frameshift mutation (Foxe3-) in homozygosity (Foxe3rv/rv and Foxe3-/-), along with compound heterozygous (Foxe3rv/Foxe3-) animals, revealed significant differences in the prevalence of ocular anomalies between wild-type controls and mice with homozygous or compound heterozygous mutations, highlighting the detrimental impact of these genetic variants. Furthermore, the progressive decline in FOXE3 protein levels across genotypes underscores its essential role in normal lens development and overall eye structure. These findings illuminate the intricate relationship between genetic variants and their effects on protein functionality and phenotype. In addition, our analysis demonstrated that the non-coding variant impairs USF2 binding, while Usf2 knockdown underscored its essential role in downregulating Foxe3, positioning it as a promising candidate gene in ocular development. These insights emphasize the importance of identifying disease-causing non-coding variants to enhance diagnostic precision for ocular developmental defects and to enrich our understanding of the regulatory mechanisms that govern eye development genes. Finally, this work provides new elements to understand the general mechanisms of ocular growth which, when impaired, leads to microphthalmia.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Epithelial Cell, Embryonic Stem Cell

SUBMITTER: Ino Karemaker

LAB HEAD: Lucas Fares-Taie

PROVIDER: PXD058162 | Pride | 2025-08-25

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	20170316_Fusion1_SA_IK_ext_DNApd_FOXE3_IB10_dimethyl_Forward.raw	Raw
	20170316_Fusion1_SA_IK_ext_DNApd_FOXE3_IB10_dimethyl_Reverse.raw	Raw
	20170415_Fusion1_SA_IK_ext_DNApd_FOXE3_CCERx_dimethyl_Forward.raw	Raw
	20170415_Fusion1_SA_IK_ext_DNApd_FOXE3_CCERx_dimethyl_Reverse.raw	Raw
	20220429_Exploris1_SA_MB_ToulouseEXT_DNApd_dimethyl_forward.raw	Raw

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Publications

Insights Into the FOXE3 Transcriptional Network and Disease Mechanisms From the Investigation of a Regulatory Variant Driving Complex Microphthalmia.

Plaisancié Julie J Angée Clémentine C Erjavec Elisa E Raymond-Letron Isabelle I Douet Jean-Yves JY Goetz Mathilde M Vincent-Delorme Catherine C Karemaker Ino D ID Baltissen Marijke M Vermeulen Michiel M Valdivia Leonardo L Jabot-Hanin Fabienne F David Pierre P Hadjadj Djihad D Monsef Yanad Abou YA Lyazrhi Faouzi F Calvas Patrick P Rozet Jean-Michel JM Chassaing Nicolas N Fares-Taie Lucas L

Investigative ophthalmology & visual science 20250801 11

<h4>Purpose</h4>FOXE3 encodes a highly conserved, lens-enriched transcription factor essential for eye development. Biallelic mutations in FOXE3 are associated with a spectrum of ocular anomalies, ranging from congenital cataracts to complex microphthalmia (CM), with severity and penetrance correlating with genotype. This study aimed to investigate the regulatory landscape of FOXE3 and its contribution to CM.<h4>Methods</h4>In a patient with CM, a truncating FOXE3 variation (p.Cys240*) was ident ...[more]

PMID: 40833324

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