Synonymous variants in holoprosencephaly alter codon usage and impact the Sonic Hedgehog protein

Synonymous single nucleotide variants (sSNVs) have been implicated in various genetic disorders through alterations of pre-mRNA splicing, mRNA structure and miRNA regulation. However, their impact on synonymous codon usage and protein translation remains to be elucidated in clinical context. Here, w...

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Autores principales: Kim, Artem, Le Douce, Jerome, Diab, Farah, Ferovova, Monika, Dubourg, Christèle, Odent, Sylvie, Dupé, Valérie, David, Véronique, Diambra, Luis Aníbal, Watrin, Erwan, Tayrac, Marie de
Formato: Articulo
Lenguaje:Inglés
Publicado: 2020
Materias:
Biología
brain development
genetics
clinical practice
synonymous variants
codon usage
Acceso en línea:http://sedici.unlp.edu.ar/handle/10915/145345
Aporte de:
SEDICI (UNLP) de Universidad Nacional de La Plata
id I19-R120-10915-145345
record_format dspace
institution Universidad Nacional de La Plata
institution_str I-19
repository_str R-120
collection SEDICI (UNLP)
language Inglés
topic Biología
brain development
genetics
clinical practice
synonymous variants
codon usage
spellingShingle Biología
brain development
genetics
clinical practice
synonymous variants
codon usage
Kim, Artem
Le Douce, Jerome
Diab, Farah
Ferovova, Monika
Dubourg, Christèle
Odent, Sylvie
Dupé, Valérie
David, Véronique
Diambra, Luis Aníbal
Watrin, Erwan
Tayrac, Marie de
Synonymous variants in holoprosencephaly alter codon usage and impact the Sonic Hedgehog protein
topic_facet Biología
brain development
genetics
clinical practice
synonymous variants
codon usage
description Synonymous single nucleotide variants (sSNVs) have been implicated in various genetic disorders through alterations of pre-mRNA splicing, mRNA structure and miRNA regulation. However, their impact on synonymous codon usage and protein translation remains to be elucidated in clinical context. Here, we explore the functional impact of sSNVs in the Sonic Hedgehog (SHH) gene, identified in patients affected by holoprosencephaly, a congenital brain defect resulting from incomplete forebrain cleavage. We identified eight sSNVs in SHH, selectively enriched in holoprosencephaly patients as compared to healthy individuals, and systematically assessed their effect at both transcriptional and translational levels using a series of in silico and in vitro approaches. Although no evidence of impact of these sSNVs on splicing, mRNA structure or miRNA regulation was found, five sSNVs introduced significant changes in codon usage and were predicted to impact protein translation. Cell assays demonstrated that these five sSNVs are associated with a significantly reduced amount of the resulting protein, ranging from 5% to 23%. Inhibition of the proteasome rescued the protein levels for four out of five sSNVs, confirming their impact on protein stability and folding. Remarkably, we found a significant correlation between experimental values of protein reduction and computational measures of codon usage, indicating the relevance of in silico models in predicting the impact of sSNVs on translation. Considering the critical role of SHH in brain development, our findings highlight the clinical relevance of sSNVs in holoprosencephaly and underline the importance of investigating their impact on translation in human pathologies.
format Articulo
Articulo
author Kim, Artem
Le Douce, Jerome
Diab, Farah
Ferovova, Monika
Dubourg, Christèle
Odent, Sylvie
Dupé, Valérie
David, Véronique
Diambra, Luis Aníbal
Watrin, Erwan
Tayrac, Marie de
author_facet Kim, Artem
Le Douce, Jerome
Diab, Farah
Ferovova, Monika
Dubourg, Christèle
Odent, Sylvie
Dupé, Valérie
David, Véronique
Diambra, Luis Aníbal
Watrin, Erwan
Tayrac, Marie de
author_sort Kim, Artem
title Synonymous variants in holoprosencephaly alter codon usage and impact the Sonic Hedgehog protein
title_short Synonymous variants in holoprosencephaly alter codon usage and impact the Sonic Hedgehog protein
title_full Synonymous variants in holoprosencephaly alter codon usage and impact the Sonic Hedgehog protein
title_fullStr Synonymous variants in holoprosencephaly alter codon usage and impact the Sonic Hedgehog protein
title_full_unstemmed Synonymous variants in holoprosencephaly alter codon usage and impact the Sonic Hedgehog protein
title_sort synonymous variants in holoprosencephaly alter codon usage and impact the sonic hedgehog protein
publishDate 2020
url http://sedici.unlp.edu.ar/handle/10915/145345
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