{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T18:55:07Z","timestamp":1790880907380,"version":"4.1.0"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2020,6,15]],"date-time":"2020-06-15T00:00:00Z","timestamp":1592179200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Fondation Maladie Rares","award":["PMO1201204"],"award-info":[{"award-number":["PMO1201204"]}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR-12-BSV1-0007-01"],"award-info":[{"award-number":["ANR-12-BSV1-0007-01"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006005","name":"Agence de la Biom\u00e9decine","doi-asserted-by":"publisher","award":["AMP2016"],"award-info":[{"award-number":["AMP2016"]}],"id":[{"id":"10.13039\/501100006005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006364","name":"French National Cancer Institute","doi-asserted-by":"publisher","award":["PRTK 2016"],"award-info":[{"award-number":["PRTK 2016"]}],"id":[{"id":"10.13039\/501100006364","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fondation Recherche Medicale"},{"DOI":"10.13039\/501100002915","name":"FRM","doi-asserted-by":"publisher","award":["FDT201904008099"],"award-info":[{"award-number":["FDT201904008099"]}],"id":[{"id":"10.13039\/501100002915","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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.<\/jats:p>","DOI":"10.1093\/brain\/awaa152","type":"journal-article","created":{"date-parts":[[2020,4,28]],"date-time":"2020-04-28T19:13:44Z","timestamp":1588101224000},"page":"2027-2038","source":"Crossref","is-referenced-by-count":19,"title":["Synonymous variants in holoprosencephaly alter codon usage and impact the Sonic Hedgehog protein"],"prefix":"10.1093","volume":"143","author":[{"given":"Artem","family":"Kim","sequence":"first","affiliation":[{"name":"Univ Rennes, CNRS, IGDR (Institut de g\u00e9n\u00e9tique et d\u00e9veloppement de Rennes)\u2014UMR 6290, F\u201435000 Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e9r\u00f4me","family":"Le Douce","sequence":"first","affiliation":[{"name":"Univ Rennes, CNRS, IGDR 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Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvie","family":"Odent","sequence":"first","affiliation":[{"name":"Univ Rennes, CNRS, IGDR (Institut de g\u00e9n\u00e9tique et d\u00e9veloppement de Rennes)\u2014UMR 6290, F\u201435000 Rennes, France"},{"name":"Service de G\u00e9n\u00e9tique Clinique, CHU, Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Val\u00e9rie","family":"Dup\u00e9","sequence":"first","affiliation":[{"name":"Univ Rennes, CNRS, IGDR (Institut de g\u00e9n\u00e9tique et d\u00e9veloppement de Rennes)\u2014UMR 6290, F\u201435000 Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00e9ronique","family":"David","sequence":"first","affiliation":[{"name":"Univ Rennes, CNRS, IGDR (Institut de g\u00e9n\u00e9tique et d\u00e9veloppement de Rennes)\u2014UMR 6290, F\u201435000 Rennes, France"},{"name":"Service de G\u00e9n\u00e9tique Mol\u00e9culaire et G\u00e9nomique, CHU, Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Diambra","sequence":"first","affiliation":[{"name":"CREG, CONICET-Universidad Nacional de La Plata, La Plata, CP 1900, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erwan","family":"Watrin","sequence":"first","affiliation":[{"name":"Univ Rennes, CNRS, IGDR (Institut de g\u00e9n\u00e9tique et d\u00e9veloppement de Rennes)\u2014UMR 6290, F\u201435000 Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"de Tayrac","sequence":"first","affiliation":[{"name":"Univ Rennes, CNRS, IGDR (Institut de g\u00e9n\u00e9tique et d\u00e9veloppement de Rennes)\u2014UMR 6290, F\u201435000 Rennes, France"},{"name":"Service de G\u00e9n\u00e9tique Mol\u00e9culaire et G\u00e9nomique, CHU, Rennes, 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