<scp><i>PAX6</i></scp> allelic heterogeneity in <scp>Mexican</scp> congenital aniridia patients: expanding the mutational spectrum with seven novel pathogenic variants

Pérez-Solórzano, Sofía; Chacón‐Camacho, Oscar F.; Astiazarán, Mirena C; Ledesma-Gil, Gerardo; Zenteno, Juan Carlos

doi:10.1111/ceo.12982

Cited by 5 publications

(3 citation statements)

References 34 publications

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“…One of the previously identified variants, c.140A>G, was described as a missense variant p.(Gln47Arg) located within the PAX6 DNA-binding paired domain (PD) and affects its function [14,15]. In the present study, we showed that the functional effect of this SNV is a consequence of splicing disruption rather than a dysfunctional protein.…”

Section: Discussionmentioning

confidence: 51%

Functional reassessment of PAX6 single nucleotide variants by in vitro splicing assay

et al. 2018

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Nucleotide variants that disrupt normal splicing might be the cause of a large number of diseases. Nevertheless, because of the complexity of splicing regulation, it is not always possible to accurately predict the effect of nucleotide sequence changes on splicing events and mRNA structure. Thereby, a number of newly identified nucleotide variants are falsely classified as VUS (a variant of uncertain significance). In the present study we used the minigene assay to analyze the functional consequences of six intronic (c.142−5T>G, c.142−14C>G, c.142−64A>C, c.141+4A>G, c.1032+ 6T>G, c.682+4delA), one missense (c.140A>G) and one synonymous (c.174C>T) variants in the PAX6 gene found in patients with congenital aniridia. We revealed that all except one (c.142−64A>C) variants lead to the disruption of normal splicing patterns resulting in premature termination codon formation followed by mRNA degradation through the nonsense mediated decay pathway. This produces a null allele of the PAX6 gene. That allowed us to reclassify the analyzed variants as loss-of-function and to establish their functional role.

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Section: Discussionmentioning

confidence: 51%

Functional reassessment of PAX6 single nucleotide variants by in vitro splicing assay

et al. 2018

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“…In Patient 2, the mutation c.718C>T (p.Arg240X) in exon 9 has been consistently reported according to LOVD. Another mutation c.718delC at this site has been reported recently ( 26 ). These two mutations are predicted to result in a premature stop codon and produce a truncated PAX6 protein.…”

Section: Discussionmentioning

confidence: 76%

Two Paired Box 6 mutations identified in Chinese patients with classic congenital aniridia and cataract

Gao

Chen

et al. 2018

Mol Med Report

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Congenital aniridia is a rare genetic disorder characterized by a variable degree of hypoplasia or absence of iris. It is frequently associated with keratopathy, cataract, juvenile-onset glaucoma and foveal and optic nerve hypoplasia. Mutations in the Paired Box 6 (PAX6) gene on chromosome 11p13 have been demonstrated to cause aniridia. The aim of the present study was to investigate the genetic variations of PAX6 in two sporadic patients from southern China with classic congenital aniridia and cataract. Complete ophthalmic and physical examinations were performed, including best-corrected visual acuity, intraocular pressure, slit-lamp examination, fundus examination, optical coherence tomography, ultrasound biomicroscopy, and Pentacam scanning. Genomic DNA was extracted from leukocytes of peripheral blood collected from the two patients, their unaffected parents and 200 unrelated control subjects from the same population. Exons 4–13 of the PAX6 gene were amplified by polymerase chain reaction and sequenced directly. Patient 1 was affected with aniridia accompanied by congenital cataract and nystagmus. A novel heterozygous PAX6 frameshift mutation c.277delG (p.Glu93SerfsX31) in exon 6 was identified in this patient. Patient 2 was presented with aniridia, congenital cataract, lens subluxation and glaucoma. A recurrent nonsense mutation c.718C>T (p.Arg240X) in exon 9 was identified in this patient. The present results expand the mutation spectrum of PAX6 and will be valuable for genetic counseling in the affected families. Additionally, the identification of these mutations reiterates the importance of PAX6 in ocular development and sheds light on the pathogenesis of congenital aniridia.

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“…The c.183C˃G found in the proband from Family 2 results in premature insertion of a stop codon, p.(Tyr61*). This variant has been previously reported in one sporadic case with aniridia (Perez-Solorzano et al, 2017). As it was not present in either parent and paternity testing was performed, we have considered it to be de novo.…”

Section: Molecular Genetic Analysismentioning

confidence: 95%

Phenotype Variability in Czech Patients Carrying PAX6 Disease-Causing Variants

Moravikova,

Kozmik,

Hlavata

et al. 2020

Fol. Biol.

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The aim of this study was to report PAX6 disease-causing variants in six Czech families, to describe the associated phenotypes, and to perform functional assessment of the splice site variants. Detailed ophthalmic examination was performed. The PAX6 coding region was directly sequenced in three probands. Two probands were analysed by exome sequencing and one by genome sequencing. The effect of two variants on pre-mRNA splicing was evaluated using an exon trapping assay. Six different heterozygous PAX6 variants were identified, with c.111_120del and c.1183+1G>T being novel. Both c.1183+1G>T and c.1032+1G>A were proved to cause aberrant splicing with exon skipping and subsequent frameshift. The phenotypic features were variable between and within families. One individual, aged 31 years, presented with mild unilateral ptosis accompanied by aniridia in the right eye, partial aniridia in the left eye, and bilateral congenital cataracts, without marked foveal hypoplasia. Bilateral microcornea, partial aniridia, congenital cataracts, and a large posterior segment coloboma were found in another proband, aged 32 years. One child, aged 8 years, had bilateral high myopia, optic nerve colobomas, anterior polar cataracts, but no iris defects. Another individual, aged 46 years, had bilateral congenital ptosis, iris hypoplasia, keratopathy with marked fibrovascular pannus, anterior polar cataract, and foveal hypoplasia combined with impaired glucose tolerance. However, his daughter, aged 11 years, showed classical features of aniridia. Our study extends the genetic spectrum of PAX6 disease-causing variants and confirms that the associated phenotypic features may be very broad and different to the ‘classical’ aniridia.

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PAX6 allelic heterogeneity in Mexican congenital aniridia patients: expanding the mutational spectrum with seven novel pathogenic variants

Cited by 5 publications

References 34 publications

Functional reassessment of PAX6 single nucleotide variants by in vitro splicing assay

Functional reassessment of PAX6 single nucleotide variants by in vitro splicing assay

Two Paired Box 6 mutations identified in Chinese patients with classic congenital aniridia and cataract

Phenotype Variability in Czech Patients Carrying PAX6 Disease-Causing Variants

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