Correlation of novel PAX6 gene abnormalities in aniridia and clinical presentation

Sannan, Naif S.; Gregory‐Evans, Cheryl Y.; Lyons, Christopher J.; Lehman, Anna; Langlois, Sylvie; Warner, Simon; Zakrzewski, H.; Gregory-Evans, Kevin

doi:10.1016/j.jcjo.2017.04.006

Cited by 19 publications

(22 citation statements)

References 42 publications

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“…4 The subsets of grade 1 do not apply to the cohort reported by Casas-Llera et al, as they only detected grade 2-4 foveal hypoplasia, furthermore we note that their paper was submitted before our latest paper was published. Interestingly, a previous paper by Sannan et al 5 reported a full spectrum of grade 0-4 foveal hypoplasia in a large cohort of PAX6 mutations.…”

Section: Dear Editormentioning

confidence: 97%

Response to spectral-domain optical coherence tomography foveal morphology as a prognostic factor for vision performance in congenital aniridia

Rufai

Thomas

Gottlob

2020

European Journal of Ophthalmology

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We read with interest the study published by Casas-Llera et al. 1 The authors have correlated best-corrected visual acuity (BCVA) with the structural grading system for foveal hypoplasia developed by our unit. 2 Recently, as recommended by Wilk et al., 3 we have updated the grading system to include two subsets of grade 1 foveal hypoplasia: grade 1a, in which nearly normal pit metrics are observed, and grade 1b, in which the pit is only a shallow indent. We recently published our updated and validated grading system, demonstrating that it can predict future vision in infants and young children with foveal hypoplasia. 4 The subsets of grade 1 do not apply to the cohort reported by Casas-Llera et al., as they only detected grade 2-4 foveal hypoplasia, furthermore we note that their paper was submitted before our latest paper was published. Interestingly, a previous paper by Sannan et al. 5 reported a full spectrum of grade 0-4 foveal hypoplasia in a large cohort of PAX6 mutations.Casas-Llera et al. state that the minimum age they considered appropriate to collaborate with optical coherence tomography (OCT) was 4 years. We would like to highlight that handheld OCT is possible in awake infants with nystagmus from birth in our experience, without sedation or dilation, such as in our latest study with infants as young as 28 days old. 4 We accept that a great number of eye departments do not have access to or experience in handheld OCT imaging, therefore it was reasonable for the authors to exclude children too young to cooperate with conventional OCT.Their study demonstrated that higher foveal hypoplasia grades correlated with poorer BCVA, consistent with findings from our unit and others. 2,4 It would be highly valuable to assess whether BCVA in the younger children improved further over time. Our recent prediction study included OCT data for preverbal infants and young

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Section: Dear Editormentioning

confidence: 97%

Response to spectral-domain optical coherence tomography foveal morphology as a prognostic factor for vision performance in congenital aniridia

Rufai

Thomas

Gottlob

2020

European Journal of Ophthalmology

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“…By contrast, missense mutations usually exhibit a moderate impact on PAX6 functionality and are often associated with some atypical PAX6 -associated phenotypes, such as mild forms of iris coloboma or isolated foveal hypoplasia, or more severe phenotypes of Peter’s anomaly and microphthalmia ( Hanson et al, 1999 ; Azuma et al, 2003 ; Nallathambi et al, 2006 ; Jia et al, 2010 ; Thomas et al, 2014 ). However, no obvious genotype-phenotype correlations have been established to date ( Gupta et al, 1998 ; Gronskov et al, 1999 ; Dubey et al, 2015 ; Sannan et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Parental Mosaicism in PAX6 Causes Intra-Familial Variability: Implications for Genetic Counseling of Congenital Aniridia and Microphthalmia

et al. 2018

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Mutations in PAX6 are involved in several developmental eye disorders. These disorders have considerable phenotypic variability, ranging from panocular forms of congenital aniridia and microphthalmia to isolated anomalies of the anterior or posterior segment. Here, we describe 3 families with variable inter-generational ocular expression of aniridia, iris coloboma, or microphthalmia, and an unusual transmission of PAX6 mutations from an unaffected or mildly affected parent; all of which raised suspicion of gonosomal mosaicism. We first identified two previously known nonsense mutations and one novel likely pathogenic missense variant in PAX6 in probands by means of targeted NGS. The subsequent segregation analysis by Sanger sequencing evidenced the presence of highly probable mosaic events in paternal blood samples. Mosaicism was further confirmed by droplet digital PCR analysis in several somatic tissues of mosaic fathers. Quantification of the mutant allele fraction in parental samples showed a marked deviation from 50%, with a range between 12 and 29% depending on cell type. Gonosomal mosaicsm was definitively confirmed in one of the families thanks to the availability of a sperm sample from the mosaic father. Thus, the recurrence risk in this family was estimated to be about one-third. This is the first report confirming parental PAX6 mosaicism as a cause of disease recurrence in aniridia and other related phenotypes. In addition, we demonstrated that post-zygotic mosaicism is a frequent and underestimated pathogenic mechanism in aniridia, explaining intra-familial phenotypic variability in many cases. Our findings may have substantial implications for genetic counseling in congenital aniridia. Thus, we also highlight the importance of comprehensive genetic screening of parents for new sporadic cases with aniridia or related developmental eye disease to more accurately assess recurrence risk. In conclusion, somatic and/or gonosomal mosaicism should be taken into consideration as a genetic factor to explain not only families with unaffected parents despite multiple affected children but also variable expressivity, apparent de novo cases, and even uncharacterized cases of aniridia and related developmental eye disorders, apparently lacking PAX6 mutations.

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“… 15 Recently, a phase 2 clinical trial has begun for the treatment of aniridia patients using a topical formulation of the drug, Ataluren (ClinicalTrials.gov: NCT02647359 ). 16 Ataluren targets the mutant allele by suppressing premature stop codons created by nonsense mutations. 17 Therefore, its potential efficacy is limited to those patients with premature stop mutations where substitution with another amino acid does not disrupt the function of the protein.…”

Section: Introductionmentioning

confidence: 99%

Protecting Pax6 3′ UTR from MicroRNA-7 Partially Restores PAX6 in Islets from an Aniridia Mouse Model

Yongblah

Alford

Ryan

et al. 2018

Molecular Therapy - Nucleic Acids

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Aniridia is a rare congenital syndrome that is associated with reduced visual acuity and progressive loss of vision. Aniridia patients may also develop systemic health issues associated with defects in the pancreas, digestive, and central nervous systems. The spectrum of symptoms associated with aniridia is due to haploinsufficiency of the paired box 6 gene (PAX6) and its role in the development and maintenance of the affected tissues. Here, we isolated pancreatic islets from mice heterozygous for Pax6 to test whether a Pax6-specific miRNA suppression (target protector) strategy can restore PAX6 protein levels. We show that miR-7 and miR-375 target specific sites within the Pax6 3′ UTR in a mouse pancreatic β-insulinoma cell line. Tough decoys (Tuds) against miR-7 and miR-375 increase expression of a mouse Pax6 3′ UTR luciferase reporter and increase PAX6 protein levels in these cells. Finally, we demonstrate that the shielding of the miR-7 binding site with a target protector restores PAX6 protein levels in the Pax6 heterozygous islets. The data presented here represent a proof of concept for RNA-based therapy for the progressive defects associated with aniridia and suggest the target protector approach may be a useful therapeutic strategy for other haploinsufficiency diseases.

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Correlation of novel PAX6 gene abnormalities in aniridia and clinical presentation

Cited by 19 publications

References 42 publications

Response to spectral-domain optical coherence tomography foveal morphology as a prognostic factor for vision performance in congenital aniridia

Response to spectral-domain optical coherence tomography foveal morphology as a prognostic factor for vision performance in congenital aniridia

Parental Mosaicism in PAX6 Causes Intra-Familial Variability: Implications for Genetic Counseling of Congenital Aniridia and Microphthalmia

Protecting Pax6 3′ UTR from MicroRNA-7 Partially Restores PAX6 in Islets from an Aniridia Mouse Model

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