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A new molecular mechanism leading to congenital aniridia has been identified

Congenital aniridia is an autosomal dominant panocular disease associated with pathogenic variants in the PAX6 gene. The RCMG Genetic Epidemiology Laboratory has carried out earlier a molecular genetic study of a large group of Russian patients with congenital aniridia. They identified four non-coding variants in the 5'-untranslating region of the PAX6 gene. Another 14 variants in the same region had been previously described in the literature, but the molecular mechanism of their pathogenicity remained unclear until now.

Five such non-coding variants were experimentally studied in the Functional Genomics Laboratory: four of them were found in Russian patients (c.-128-2delA, c.-125dupG, c.-122dupG, c.-118_- 117del) and one was previously described in the literature (c.-52+5G>C). A comprehensive functional analysis showed that the variants led to a decrease in protein translation efficiency, whereas the mRNA expression level did not decreased significantly. Two variants also affected the splicing passage.

A detailed bioinformatic analysis predicted the presence of an evolutionarily conserved upstream open reading frame (uORF) in the 5'-untranslated region of the PAX6 gene. All the variants studied turned to lead to a shift in this uORF, as a result of which it lengthens and overlaps with the main coding part of the gene, thereby reducing the translation efficiency of the PAX6 protein. Some additional experiments using the luciferase system confirmed this hypothesis.

Thus, it was concluded that an uORF reading frame shift may be a major pathogenicity mechanism for at least 15 of 18 variants in the 5'UTR of the PAX6 gene described in the literature. Moreover, the work also predicted and described additional upstream open reading frames (uORFs) in the 5'UTR of the PAX6 gene, suggesting a possible complex regulation of its translation during embryogenesis.
Filatova AY, Vasilyeva TA, Marakhonov AV, Sukhanova NV, Voskresenskaya AA, Zinchenko RA, Skoblov MY. Upstream ORF frameshift variants in the PAX6 5'UTR cause congenital aniridia. Hum Mutat. 2021 Jun 26. doi: 10.1002/humu.24248. Epub ahead of print. PMID: 34174135.