Upstream ORF frameshift variants in the<i>PAX6</i>5ʹUTR cause congenital aniridia

Filatova, Alexandra; Vasilyeva, T.A.; Marakhonov, Andrey V.; Sukhanova, Natella V.; Voskresenskaya, A. A.; Зинченко, Р. А.; Skoblov, Mikhail

doi:10.1002/humu.24248

Cited by 11 publications

(14 citation statements)

References 48 publications

(100 reference statements)

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“…Several previous studies revealed genetic variants that disrupt the existing uORFs and thereby lead to Mendelian disorders and malignancies ( 8 , 11 ). In the present study, we implemented a software tool to annotate the effects of genetic variants located in annotated uORFs.…”

Section: Resultsmentioning

confidence: 99%

Annotation of uORFs in the OMIM genes allows to reveal pathogenic variants in 5′UTRs

Filatova

Reveguk

Piatkova

et al. 2023

Nucleic Acids Research

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An increasing number of studies emphasize the role of non-coding variants in the development of hereditary diseases. However, the interpretation of such variants in clinical genetic testing still remains a critical challenge due to poor knowledge of their pathogenicity mechanisms. It was previously shown that variants in 5′-untranslated regions (5′UTRs) can lead to hereditary diseases due to disruption of upstream open reading frames (uORFs). Here, we performed a manual annotation of upstream translation initiation sites (TISs) in human disease-associated genes from the OMIM database and revealed ∼4.7 thousand of TISs related to uORFs. We compared our TISs with the previous studies and provided a list of ‘high confidence’ uORFs. Using a luciferase assay, we experimentally validated the translation of uORFs in the ETFDH, PAX9, MAST1, HTT, TTN,GLI2 and COL2A1 genes, as well as existence of N-terminal CDS extension in the ZIC2 gene. Besides, we created a tool to annotate the effects of genetic variants located in uORFs. We revealed the variants from the HGMD and ClinVar databases that disrupt uORFs and thereby could lead to Mendelian disorders. We also showed that the distribution of uORFs-affecting variants differs between pathogenic and population variants. Finally, drawing on manually curated data, we developed a machine-learning algorithm that allows us to predict the TISs in other human genes.

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Section: Resultsmentioning

confidence: 99%

Annotation of uORFs in the OMIM genes allows to reveal pathogenic variants in 5′UTRs

Filatova

Reveguk

Piatkova

et al. 2023

Nucleic Acids Research

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“…Defined chromosome deletions varied from 0.35 to 7.5 Mb in size. The 138 small intragenic PAX6 variants included 53 nonsense pathogenic variants, 30 splicing changes, 34 frame shifts, 8 CTE (C-terminal extension), 2 start codon losses, 7 missense pathogenic variants, and 4 pathogenic variants in 5′-UTR sequence ( Supplementary Tables S1 and S2 ) [ 3 , 4 , 5 , 6 ].…”

Section: Resultsmentioning

confidence: 99%

“…Mutations identified in 139 index patients were described in our previous publications [ 3 , 4 , 5 , 6 ], while for 60 families. 46 mutations were newly reported.…”

Section: Methodsmentioning

confidence: 99%

Relative Frequencies of PAX6 Mutational Events in a Russian Cohort of Aniridia Patients in Comparison with the World’s Population and the Human Genome

Vasilyeva

Marakhonov

Kutsev

et al. 2022

IJMS

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Genome-wide sequencing metadata allows researchers to infer bias in the relative frequencies of mutational events and to predict putative mutagenic models. In addition, much less data could be useful in the evaluation of the mutational frequency spectrum and the prevalent local mutagenic process. Here we analyzed the PAX6 gene locus for mutational spectra obtained in our own and previous studies and compared them with data on other genes as well as the whole human genome. MLPA and Sanger sequencing were used for mutation searching in a cohort of 199 index patients from Russia with aniridia and aniridia-related phenotypes. The relative frequencies of different categories of PAX6 mutations were consistent with those previously reported by other researchers. The ratio between substitutions, small indels, and chromosome deletions in the 11p13 locus was within the interval previously published for 20 disease associated genomic loci, but corresponded to a higher end due to very high frequencies of small indels and chromosome deletions. The ratio between substitutions, small indels, and chromosome deletions for disease associated genes, including the PAX6 gene as well as the share of PAX6 missense mutations, differed considerably from those typical for the whole genome.

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“…The 5′UTR region of the PAX6 gene plays an important role in keeping mRNA stability and controlling translation ( Plaisancié et al, 2018 ). Variations in the 5′UTR region would disturb the splicing process ( Tarilonte et al, 2022 ); it has been observed in a previous report that the deletion of c.-128-2delA has been found to induce the skipping of exon 3 ( Filatova et al, 2021 ). Our minigene assay results also support the importance of the 5′UTR region based on the fact that the replacement of the invariant A residue at −2 of the acceptor in intron 2 by G also leads to the skipping of exon 3 .…”

Section: Discussionmentioning

confidence: 99%

Diversity of clinical phenotypes in a cohort of Han Chinese patients with PAX6 variants

Huang

Peng²,

Xie³

et al. 2023

Front. Genet.

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The PAX6 gene plays an important role in ocular development. Mutations of the PAX6 gene may result in a series of ocular abnormalities, including congenital aniridia, anterior segment dysgenesis (ASD), progressive corneal opacification, glaucoma, and hypoplasia of the fovea and optic nerve, leading to reduced visual acuity and even blindness. This study aimed to describe the diversity of clinical features caused by PAX6 pathogenic variants in 45 Han Chinese patients from 23 unrelated families. All patients underwent detailed clinical assessment. Genetic testing was performed to identify pathogenic variations in the PAX6 gene by next-generation sequencing, minigene splicing assay, RT-qPCR, and long-range PCR. Twenty pathogenic variations were detected in the PAX6 gene from 12 pedigrees and 11 sporadic patients, of which 12 were previously reported and 8 were novel. The clinical phenotypes obtained as a result of the PAX6 gene mutations were complicated and vary among patients, even among those who carried the same variants. Genetic testing is helpful for differential diagnosis. Our genetic findings will expand the spectrum of pathogenic variations in the PAX6 gene. PAX6 pathogenic variants not only cause defects in ocular tissues, such as the iris and retina, but also lead to maldevelopment of the whole eye, resulting in microphthalmia.

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Upstream ORF frameshift variants in thePAX65ʹUTR cause congenital aniridia

Cited by 11 publications

References 48 publications

Annotation of uORFs in the OMIM genes allows to reveal pathogenic variants in 5′UTRs

Annotation of uORFs in the OMIM genes allows to reveal pathogenic variants in 5′UTRs

Relative Frequencies of PAX6 Mutational Events in a Russian Cohort of Aniridia Patients in Comparison with the World’s Population and the Human Genome

Diversity of clinical phenotypes in a cohort of Han Chinese patients with PAX6 variants

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