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The non-coding <jats:italic>GJB1<\/jats:italic> c.-103C\u2009&gt;\u2009T mutation (NM_000166.5) has been reported to cause CMTX1 in multiple families. This study assessed the internal ribosomal entry site (IRES) activity previously reported for the rat <jats:italic>Gjb1<\/jats:italic> P2 5\u2019 untranslated region (UTR). Using a bicistronic assay and transfecting RT4 Schwann cells, IRES activity of the human <jats:italic>GJB1<\/jats:italic> P2 5\u2019 UTR was compared to the <jats:italic>GJB1<\/jats:italic> P2 5\u2019 UTR containing either the c.-103C\u2009&gt;\u2009T mutation or the non-pathogenic c.-102G\u2009&gt;\u2009A variant. No differences in <jats:italic>GJB1<\/jats:italic> P2 5\u2019 UTR IRES activity were observed between the negative control, the wild-type P2 5\u2019 UTR, the c.-103C\u2009&gt;\u2009T 5\u2019 UTR or the c.-102G\u2009&gt;\u2009A 5\u2019 UTR, irrespective of the <jats:italic>GJB1<\/jats:italic> intron being present (<jats:italic>p<\/jats:italic>\u2009=\u2009.429 with intron, and <jats:italic>p<\/jats:italic>\u2009=\u2009.865 without). A theoretical c.-131A\u2009&gt;\u2009G variant was predicted to result in the same RNA secondary structure as the <jats:italic>GJB1<\/jats:italic> c.-103C\u2009&gt;\u2009T P2 5\u2019 UTR. However, no significant difference was observed between expression from the wild-type <jats:italic>GJB1<\/jats:italic> P2 5\u2019 UTR and the <jats:italic>GJB1<\/jats:italic> c.-131A\u2009&gt;\u2009G variant (<jats:italic>p<\/jats:italic>\u2009=\u2009.688). Deletion of the conserved region surrounding the c.-103C\u2009&gt;\u2009T mutation (c.-108_-103del) resulted in significantly higher expression than the c.-103C\u2009&gt;\u2009T mutation alone (<jats:italic>p<\/jats:italic>\u2009=\u2009.019), suggesting that the conserved c.-108_-103 region was not essential for translation. The reporter assays in this study do not recapitulate the previously reported <jats:italic>GJB1<\/jats:italic> IRES activity and suggest an alternate pathogenic mechanism for the c.-103C\u2009&gt;\u2009T CMTX1 non-coding mutation.<\/jats:p>","DOI":"10.1007\/s10048-021-00650-9","type":"journal-article","created":{"date-parts":[[2021,6,5]],"date-time":"2021-06-05T11:02:38Z","timestamp":1622890958000},"page":"149-160","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Revisiting the pathogenic mechanism of the GJB1 5\u2019 UTR c.-103C\u2009&gt;\u2009T mutation causing CMTX1"],"prefix":"10.1007","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6926-0551","authenticated-orcid":false,"given":"Bianca R.","family":"Grosz","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2963-7921","authenticated-orcid":false,"given":"John","family":"Svaren","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1010-6445","authenticated-orcid":false,"given":"Gonzalo","family":"Perez-Siles","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9694-066X","authenticated-orcid":false,"given":"Garth A.","family":"Nicholson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3332-5074","authenticated-orcid":false,"given":"Marina L.","family":"Kennerson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,6,5]]},"reference":[{"key":"650_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/0378-1119(94)00899-4","author":"IM Neuhaus","year":"1995","unstructured":"Neuhaus IM, Dahl G, Werner R (1995) Use of alternate promoters for tissue-specific expression of the gene coding for connexin32. 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