RT Journal Article
SR Electronic
T1 Evolutionarily conserved genetic interactions between <em>nphp-4</em> and <em>bbs-5</em> mutations exacerbate ciliopathy phenotypes
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.08.25.457729
DO 10.1101/2021.08.25.457729
A1 Melissa R. Bentley-Ford
A1 Melissa LaBonty
A1 Holly R. Thomas
A1 Courtney J. Haycraft
A1 Mikyla Scott
A1 Cameron LaFayette
A1 Mandy J. Croyle
A1 John M. Parant
A1 Bradley K. Yoder
YR 2021
UL http://biorxiv.org/content/early/2021/08/26/2021.08.25.457729.abstract
AB Primary cilia are sensory and signaling hubs with a protein composition that is distinct from the rest of the cell due to the barrier function of the transition zone (TZ) at the base of the cilium. 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 C. 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 mice 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, viable Nphp4;Bbs5 double mutant mice were not obtained and there were fewer mice than expected carrying three mutant alleles. Additionally, postnatal loss of Bbs5 in mice using a conditional allele compromised survival when combined with a Nphp4 allele. As cilia are 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.