Aberrant expression of PAX6 gene associated with classical aniridia: identification and functional characterization of novel noncoding mutations

The PAX6 is essential for ocular morphogenesis and is known to be highly sensitive to changes in gene expression, where neither over- nor under-expression ensures normal ocular development. Two unrelated probands with classical aniridia who were previously considered "PAX6-negative", were...

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Bibliographic Details
Published in:Journal of human genetics 2021-03, Vol.66 (3), p.333-338
Main Authors: Lee, Junwon, Suh, Yoonjong, Jeong, Han, Kim, Gu-Hwan, Byeon, Suk Ho, Han, Jinu, Lim, Hyun Taek
Format: Article
Language:English
Subjects:
5' Untranslated Regions
Aniridia
Deep learning
Gene expression
Genomes
Morphogenesis
Mutation
Pax6 protein
Whole genome sequencing
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Summary:The PAX6 is essential for ocular morphogenesis and is known to be highly sensitive to changes in gene expression, where neither over- nor under-expression ensures normal ocular development. Two unrelated probands with classical aniridia who were previously considered "PAX6-negative", were studied by whole-genome sequencing. Through the use of multiple in silico deep learning-based algorithms, we identified two novel putative causal mutations, c.-133_-132del in the 5' untranslated region (5'-UTR) and c.-52 + 5G>A in an intron upstream of the PAX6 gene. The luciferase activity was significantly increased and VAX2 binding was disrupted with the former 5'-UTR variant compared with wild-type sequence, which resulted in a striking overexpression of PAX6. The minigene assay showed that the c.-52 + 5G>A mutation caused defective splicing, which resulted in the formation of truncated transcripts.
ISSN:1434-5161
1435-232X
DOI:10.1038/s10038-020-00829-2