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Protein transport across the TZ is mediated in part by the BBSome, and mutations disrupting TZ and BBSome proteins cause human ciliopathy syndromes. Ciliopathies have phenotypic variability even among patients with identical genetic variants, suggesting a role for modifier loci. To identify potential ciliopathy modifiers, we performed a mutagenesis screen on nphp-4 mutant Caenorhabditis elegans and uncovered a novel allele of bbs-5. Nphp-4;bbs-5 double mutant worms have phenotypes not observed in either individual mutant strain. To test whether this genetic interaction is conserved, we also analyzed zebrafish and mouse mutants. While Nphp4 mutant zebrafish appeared overtly normal, Bbs5 mutants exhibited scoliosis. When combined, Nphp4;Bbs5 double mutant zebrafish did not exhibit synergistic effects, but the lack of a phenotype in Nphp4 mutants makes interpreting these data difficult. In contrast, Nphp4;Bbs5 double mutant mice were not viable and there were fewer mice than expected carrying three mutant alleles. In addition, postnatal loss of Bbs5 in mice using a conditional allele compromised survival when combined with an Nphp4 allele. As cilia are still formed in the double mutant mice, the exacerbated phenotype is likely a consequence of disrupted ciliary signaling. Collectively, these data support an evolutionarily conserved genetic interaction between Bbs5 and Nphp4 alleles that may contribute to the variability in ciliopathy phenotypes.<\/jats:p>","DOI":"10.1093\/genetics\/iyab209","type":"journal-article","created":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T12:07:15Z","timestamp":1638360435000},"source":"Crossref","is-referenced-by-count":17,"title":["Evolutionarily conserved genetic interactions between\n                    <i>nphp-4<\/i>\n                    and\n                    <i>bbs-5<\/i>\n                    mutations exacerbate ciliopathy phenotypes"],"prefix":"10.1093","volume":"220","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9646-1420","authenticated-orcid":false,"given":"Melissa R","family":"Bentley-Ford","sequence":"first","affiliation":[{"name":"Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"LaBonty","sequence":"additional","affiliation":[{"name":"Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly R","family":"Thomas","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney J","family":"Haycraft","sequence":"additional","affiliation":[{"name":"Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikyla","family":"Scott","sequence":"additional","affiliation":[{"name":"Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cameron","family":"LaFayette","sequence":"additional","affiliation":[{"name":"Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mandy J","family":"Croyle","sequence":"additional","affiliation":[{"name":"Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reagan S","family":"Andersen","sequence":"additional","affiliation":[{"name":"Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M","family":"Parant","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley K","family":"Yoder","sequence":"additional","affiliation":[{"name":"Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,11,22]]},"reference":[{"key":"2022010607425706200_iyab209-B1","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1002\/cne.901980305","article-title":"Sensory control of Dauer larva formation in Caenorhabditis elegans","volume":"198","author":"Albert","year":"1981","journal-title":"J Comp Neurol"},{"key":"2022010607425706200_iyab209-B2","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1167\/iovs.61.10.17","article-title":"BBSome component BBS5 is required for cone photoreceptor protein trafficking and outer 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