PAX6 missense variants in two families with isolated foveal hypoplasia and nystagmus: evidence of paternal postzygotic mosaicism

Aniridia is a pan-ocular genetic developmental eye disorder characterized by complete or partial iris and foveal hypoplasia, for which there is no treatment currently. Progressive sight loss can arise from cataracts, glaucoma, and aniridia-related keratopathy, which can be managed conservatively or through surgical intervention. The vast majority of patients harbor heterozygous mutations involving the PAX6 gene, which is considered the master transcription factor of early eye development. Over the past decades, several disease models have been investigated to gain a better understanding of the molecular pathophysiology, including several mouse and zebrafish strains and, more recently, human-induced pluripotent stem cells (hiPSCs) derived from aniridia patients. The latter provides a more faithful cellular system to study early human eye development. This review outlines the main aniridia-related animal and cellular models used to study aniridia and highlights the key discoveries that are bringing us closer to a therapy for patients.

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“…[ 1 5 ] Recent reports have also shown the presence of paternal mosaicism in four aniridia families. [ 6 7 ]…”

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confidence: 99%

PAX6 disease models for aniridia

Abdolkarimi

Cunha²,

Lahne

et al. 2022

Indian Journal of Ophthalmology

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“…Genetic defects of PAX6 have been found in aniridia, a pan-ocular disorder characterized by the absence or hypoplasia of the iris, nystagmus and foveal hypoplasia 68 , the latter comprising thinning of macular inner and outer retinal layers consistent with misdirected foveal development 69 . Recently, a phenotype characterized by isolated foveal hypoplasia with nystagmus has been also linked to PAX6 variation 70 . Given the known inter- and intra-familial phenotypic variability observed in PAX6 -associated disorders 71 , 72 , variable expressivity cannot be discarded for the identified variant.…”

Section: Discussionmentioning

confidence: 99%

Multi-omics analysis in human retina uncovers ultraconserved cis-regulatory elements at rare eye disease loci

Lopez Soriano,

Dueñas Rey,

Mukherjee

et al. 2024

Nat Commun

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Cross-species genome comparisons have revealed a substantial number of ultraconserved non-coding elements (UCNEs). Several of these elements have proved to be essential tissue- and cell type-specific cis-regulators of developmental gene expression. Here, we characterize a set of UCNEs as candidate CREs (cCREs) during retinal development and evaluate the contribution of their genomic variation to rare eye diseases, for which pathogenic non-coding variants are emerging. Integration of bulk and single-cell retinal multi-omics data reveals 594 genes under potential cis-regulatory control of UCNEs, of which 45 are implicated in rare eye disease. Mining of candidate cis-regulatory UCNEs in WGS data derived from the rare eye disease cohort of Genomics England reveals 178 ultrarare variants within 84 UCNEs associated with 29 disease genes. Overall, we provide a comprehensive annotation of ultraconserved non-coding regions acting as cCREs during retinal development which can be targets of non-coding variation underlying rare eye diseases.

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“…Genetic defects of PAX6 have been found in aniridia, a pan-ocular disorder characterized by the absence or hypoplasia of the iris, nystagmus and foveal hypoplasia (Cunha et al, 2019), the latter comprising thinning of macular inner and outer retinal layers consistent with misdirected foveal development (Pedersen et al, 2020). Recently, a phenotype characterized by isolated foveal hypoplasia with nystagmus has been also linked to PAX6 variation (Lima Cunha et al, 2021). Given the known inter- and intra-familial phenotypic variability observed in PAX6 -associated disorders (Dubey et al, 2015; Yokoi et al, 2016), variable expressivity cannot be discarded for the identified variant.…”

Section: Discussionmentioning

confidence: 99%

Multi-omics analysis in human retina uncovers ultraconservedcis-regulatory elements at rare eye disease loci

Soriano

Rey

Mukherjee

et al. 2023

Preprint

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Cross-species genome comparisons have revealed a substantial number of ultraconserved non-coding elements (UCNEs). Several of these elements have proved to be essential tissue- and cell type-specificcis-regulators of developmental gene expression. Here, we characterized a set of UCNEs, as candidate CREs (cCREs) during retinal development and evaluate the contribution of their genomic variation to rare eye diseases, for which pathogenic non-coding variants are emerging. Integration of bulk and single-cell retinal multi-omics data revealed 594 genes under potentialcis-regulatory control of UCNEs, of which 45 are implicated in rare eye disease. Mining of candidatecis-regulatory UCNEs in WGS data derived from the rare eye disease cohort of Genomics England revealed 178 ultrarare variants within 84 UCNEs associated with 29 disease genes. Overall, we provide a comprehensive annotation of ultraconserved non-coding regions acting as cCREs during retinal development which can be targets of non-coding variation underlying rare eye diseases.

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PAX6 missense variants in two families with isolated foveal hypoplasia and nystagmus: evidence of paternal postzygotic mosaicism

Cited by 10 publications

References 20 publications

PAX6 disease models for aniridia

PAX6 disease models for aniridia

Multi-omics analysis in human retina uncovers ultraconserved cis-regulatory elements at rare eye disease loci

Multi-omics analysis in human retina uncovers ultraconservedcis-regulatory elements at rare eye disease loci

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