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The molecular mechanisms that control and fine-tune the formation of this type of gait are unknown. Here, we take advantage of one strain of domesticated rabbits, the<jats:italic>sauteur d\u2019Alfort<\/jats:italic>, that exhibits an abnormal locomotion behavior defined by the loss of the typical jumping that characterizes wild-type rabbits. Strikingly, individuals from this strain frequently adopt a bipedal gait using their front legs. Using a combination of experimental crosses and whole genome sequencing, we show that a single locus containing the RAR related orphan receptor B gene (<jats:italic>RORB<\/jats:italic>) explains the atypical gait of these rabbits. We found that a splice-site mutation in an evolutionary conserved site of<jats:italic>RORB<\/jats:italic>results in several aberrant transcript isoforms incorporating intronic sequence. This mutation leads to a drastic reduction of RORB-positive neurons in the spinal cord, as well as defects in differentiation of populations of spinal cord interneurons. Our results show that<jats:italic>RORB<\/jats:italic>function is required for the performance of saltatorial locomotion in rabbits.<\/jats:p>","DOI":"10.1371\/journal.pgen.1009429","type":"journal-article","created":{"date-parts":[[2021,3,26]],"date-time":"2021-03-26T01:09:45Z","timestamp":1616720985000},"page":"e1009429","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":12,"title":["A loss-of-function mutation in RORB disrupts saltatorial locomotion in rabbits"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9882-7775","authenticated-orcid":true,"given":"Miguel","family":"Carneiro","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4319-5154","authenticated-orcid":true,"given":"Jennifer","family":"Vieillard","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2540-2471","authenticated-orcid":true,"given":"Pedro","family":"Andrade","sequence":"additional","affiliation":[]},{"given":"Samuel","family":"Boucher","sequence":"additional","affiliation":[]},{"given":"Sandra","family":"Afonso","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0041-1996","authenticated-orcid":true,"given":"Jos\u00e9 A.","family":"Blanco-Aguiar","sequence":"additional","affiliation":[]},{"given":"Nuno","family":"Santos","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9393-9540","authenticated-orcid":true,"given":"Jo\u00e3o","family":"Branco","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6055-8298","authenticated-orcid":true,"given":"Pedro J.","family":"Esteves","sequence":"additional","affiliation":[]},{"given":"Nuno","family":"Ferrand","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6418-5460","authenticated-orcid":true,"given":"Klas","family":"Kullander","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4085-6968","authenticated-orcid":true,"given":"Leif","family":"Andersson","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2021,3,25]]},"reference":[{"key":"pgen.1009429.ref001","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1111\/j.1469-7793.2001.0041b.x","article-title":"Spinal circuitry of sensorimotor control of locomotion","volume":"533","author":"DA McCrea","year":"2001","journal-title":"J Physiol"},{"key":"pgen.1009429.ref002","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1152\/physrev.00028.2005","article-title":"Dynamic sensorimotor interactions in locomotion","volume":"86","author":"S Rossignol","year":"2006","journal-title":"Physiol Rev"},{"key":"pgen.1009429.ref003","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1126\/science.3975635","article-title":"Neurobiological bases of rhythmic motor acts in vertebrates","volume":"228","author":"S. 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