Mutations in the Kinesin-2 Motor KIF3B Cause an Autosomal-Dominant Ciliopathy

Autor: Julia H. Wildschutte, Marta G. Castelhano, Max F. Rothschild, Maria Kaukonen, Georgios Kellaris, Joshua A. Stern, Stéphane Bézieau, Laurence Legeai-Mallet, Shrinivas P. Mane, Dominique Debray, Hannes Lohi, Ottmar Distl, Laurence M. Occelli, Kinga M. Bujakowska, Marjo K. Hytönen, Oliver P. Forman, Elizabeth A. Wilcox, Richard Malik, Tosso Leeb, Ronald H.L. Li, Elizabeth L. Cadena, William F. Swanson, Teri L. Lear, Yoshihiko Yu, Robert J. Harvey, Dominique Caldari, Erica E. Davis, Bianca Haase, Eric A. Pierce, Reuben M. Buckley, Stephen P. Daiger, L. Martin, D. Aberdein, Clare Rusbridge, Simon M. Petersen-Jones, Edward I. Ginns, Daniel C. Koboldt, Benjamin Cogné, Lokuliyanage Dona Samudita Senaratne, Michael B. Gorin, Niels C Pedersen, Margret L. Casal, Xenia Latypova, Adam R. Boyko, Isabel Hernandez, Tomoki Kosho, Sara J. Bowne, Nicholas H. Dodman, Tomas F. Bergström, Nicholas Katsanis, Rebecca R. Bellone, Guylène Le Meur, Bertrand Isidor, Daisuke Hasegawa, Christopher B. Kaelin, Mathilde Nizon, Karen A. Terio, Paulo C. Alves, Leslie A. Lyons, Christopher R Helps, Eirik Frengen, Emilie Leclerc, William J. Murphy, Beth Shapiro, Mark A. Magnuson, Lorraine Fievet, Maria Longeri, Rory J. Todhunter, Jeffrey A. Brockman, Lori S. Sullivan, Dorian J. Garrick, Jens Häggström, Jonathan E. Fogle, N. Matthew Ellinwood, Wesley C. Warren, John S. Munday, Gregory S. Barsh
Přispěvatelé: Université Paris Cité (UPC), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Zdroj: American Journal of Human Genetics
American Journal of Human Genetics, Elsevier (Cell Press), 2020, 106, pp.893-904. ⟨10.1016/j.ajhg.2020.04.005⟩
Am J Hum Genet
ISSN: 0002-9297
1537-6605
DOI: 10.1016/j.ajhg.2020.04.005⟩
Popis: Kinesin-2 enables ciliary assembly and maintenance as an anterograde intraflagellar transport (IFT) motor. Molecular motor activity is driven by a heterotrimeric complex comprised of KIF3A and KIF3B or KIF3C plus one non-motor subunit, KIFAP3. Using exome sequencing, we identified heterozygous KIF3B variants in two unrelated families with hallmark ciliopathy phenotypes. In the first family, the proband presents with hepatic fibrosis, retinitis pigmentosa, and postaxial polydactyly; he harbors a de novo c.748G>C (p.Glu250Gln) variant affecting the kinesin motor domain encoded by KIF3B. The second family is a six-generation pedigree affected predominantly by retinitis pigmentosa. Affected individuals carry a heterozygous c.1568T>C (p.Leu523Pro) KIF3B variant segregating in an autosomal-dominant pattern. We observed a significant increase in primary cilia length in vitro in the context of either of the two mutations while variant KIF3B proteins retained stability indistinguishable from wild type. Furthermore, we tested the effects of KIF3B mutant mRNA expression in the developing zebrafish retina. In the presence of either missense variant, rhodopsin was sequestered to the photoreceptor rod inner segment layer with a concomitant increase in photoreceptor cilia length. Notably, impaired rhodopsin trafficking is also characteristic of recessive KIF3B models as exemplified by an early-onset, autosomal-recessive, progressive retinal degeneration in Bengal cats; we identified a c.1000G>A (p.Ala334Thr) KIF3B variant by genome-wide association study and whole-genome sequencing. Together, our genetic, cell-based, and in vivo modeling data delineate an autosomal-dominant syndromic retinal ciliopathy in humans and suggest that multiple KIF3B pathomechanisms can impair kinesin-driven ciliary transport in the photoreceptor.
Databáze: OpenAIRE
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