@article{000144197bba4b01bcfd5ccdf4c1e9d1,
title = "Mutations in the Kinesin-2 Motor KIF3B Cause an Autosomal-Dominant Ciliopathy",
abstract = "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.",
keywords = "KIF3B, feline genetics, hepatic fibrosis, kinesin, primary cilia, retinopathy, whole-exome sequencing, zebrafish",
author = "{99 Lives Consortium} and Benjamin Cogn{\'e} and Xenia Latypova and Senaratne, {Lokuliyanage Dona Samudita} and Ludovic Martin and Koboldt, {Daniel C.} and Georgios Kellaris and Lorraine Fievet and {Le Meur}, Guyl{\`e}ne and Dominique Caldari and Dominique Debray and Mathilde Nizon and Eirik Frengen and Bowne, {Sara J.} and Buckley, {Reuben M.} and Danielle Aberdein and Alves, {Paulo C.} and Barsh, {Gregory S.} and Bellone, {Rebecca R.} and Bergstr{\"o}m, {Tomas F.} and Boyko, {Adam R.} and Brockman, {Jeffrey A.} and Casal, {Margret L.} and Castelhano, {Marta G.} and Ottmar Distl and Dodman, {Nicholas H.} and Ellinwood, {N. Matthew} and Fogle, {Jonathan E.} and Forman, {Oliver P.} and Garrick, {Dorian J.} and Ginns, {Edward I.} and Jens H{\"a}ggstr{\"o}m and Harvey, {Robert J.} and Daisuke Hasegawa and Bianca Haase and Helps, {Christopher R.} and Isabel Hernandez and Hyt{\"o}nen, {Marjo K.} and Maria Kaukonen and Kaelin, {Christopher B.} and Tomoki Kosho and Emilie Leclerc and Lear, {Teri L.} and Tosso Leeb and Li, {Ronald H.L.} and Hannes Lohi and Maria Longeri and Magnuson, {Mark A.} and Richard Malik and Mane, {Shrinivas P.} and Terio, {Karen A.}",
note = "Funding Information: We are grateful to the families who participated in this study. We thank Kevin Adams, Westley Heydeck, and Julien Philippe for technical support and advice. We thank Brian Perkins for the IFT52 antibody, and his assistance with zebrafish antibody staining protocols. We also thank Stefan Scholz and Elisabet Teixido from UFZ as well as Tobias Kie{\ss}ling from “Scientific Software Solutions” ( www.tks3.com ) for use and assistance with FishInspector software. This work was supported by US National Institutes of Health grants HD042601 (N.K.), GM121317 (N.K.), DK072301 (N.K. and E.E.D.), and EY007142 (S.P.D.), and by grants from the Foundation Fighting Blindness USA (S.P.D.) and the William Stamps Farish Fund (S.P.D.). N.K. is a Distinguished Valerie and George D. Kennedy Professor. This project was funded in part previously by the National Center for Research Resources R24 RR016094 and the Office of Research Infrastructure Programs OD R24OD010928 , the Phyllis and George Miller Feline Health Fund , Center for Companion Animal Health, School of Veterinary Medicine, University of California – Davis ( 2007-38-FM , 2008-08-F ), the Winn Feline Foundation ( MT07-012 , W12-022 ), and Cat Health Network ( D12FE-509 ) and the University of Missouri, College of Veterinary Medicine Gilbreath McLorn Endowment (L.A.L.). We appreciate the dedicated assistance of Bengal cat breeders for their participation in the research. S.M.P.-J. is funded by the Myers-Dunlap Endowment at Michigan State University . This work was supported by grants from the National Eye Institute ( R01EY012910 to E.A.P., R01EY026904 to K.B. and E.A.P., and P30EY014104 for MEEI core support) and the Foundation Fighting Blindness ( EGI-GE-1218-0753-UCSD to K.B. and E.A.P.). Funding Information: We are grateful to the families who participated in this study. We thank Kevin Adams, Westley Heydeck, and Julien Philippe for technical support and advice. We thank Brian Perkins for the IFT52 antibody, and his assistance with zebrafish antibody staining protocols. We also thank Stefan Scholz and Elisabet Teixido from UFZ as well as Tobias Kie?ling from ?Scientific Software Solutions? (www.tks3.com) for use and assistance with FishInspector software. This work was supported by US National Institutes of Health grants HD042601 (N.K.), GM121317 (N.K.), DK072301 (N.K. and E.E.D.), and EY007142 (S.P.D.), and by grants from the Foundation Fighting Blindness USA (S.P.D.) and the William Stamps Farish Fund (S.P.D.). N.K. is a Distinguished Valerie and George D. Kennedy Professor. This project was funded in part previously by the National Center for Research Resources R24 RR016094 and the Office of Research Infrastructure Programs OD R24OD010928, the Phyllis and George Miller Feline Health Fund, Center for Companion Animal Health, School of Veterinary Medicine, University of California ? Davis (2007-38-FM, 2008-08-F), the Winn Feline Foundation (MT07-012, W12-022), and Cat Health Network (D12FE-509) and the University of Missouri, College of Veterinary Medicine Gilbreath McLorn Endowment (L.A.L.). We appreciate the dedicated assistance of Bengal cat breeders for their participation in the research. S.M.P.-J. is funded by the Myers-Dunlap Endowment at Michigan State University. This work was supported by grants from the National Eye Institute (R01EY012910 to E.A.P. R01EY026904 to K.B. and E.A.P. and P30EY014104 for MEEI core support) and the Foundation Fighting Blindness (EGI-GE-1218-0753-UCSD to K.B. and E.A.P.). Publisher Copyright: {\textcopyright} 2020 American Society of Human Genetics",
year = "2020",
month = jun,
day = "4",
doi = "10.1016/j.ajhg.2020.04.005",
language = "English (US)",
volume = "106",
pages = "893--904",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "6",
}