2. Academic Validation
  3. Mutations in the Kinesin-2 Motor KIF3B Cause an Autosomal-Dominant Ciliopathy

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

  • Am J Hum Genet. 2020 Jun 4;106(6):893-904. doi: 10.1016/j.ajhg.2020.04.005.
Benjamin Cogné 1,  Xenia Latypova 2,  Lokuliyanage Dona Samudita Senaratne 3,  Ludovic Martin 4,  Daniel C Koboldt 5,  Georgios Kellaris 6,  Lorraine Fievet 6,  Guylène Le Meur 7,  Dominique Caldari 8,  Dominique Debray 9,  Mathilde Nizon 1,  Eirik Frengen 3,  Sara J Bowne 10,  99 Lives Consortium,  Elizabeth L Cadena 10,  Stephen P Daiger 11,  Kinga M Bujakowska 12,  Eric A Pierce 12,  Michael Gorin 13,  Nicholas Katsanis 14,  Stéphane Bézieau 1,  Simon M Petersen-Jones 15,  Laurence M Occelli 15,  Leslie A Lyons 16,  Laurence Legeai-Mallet 17,  Lori S Sullivan 10,  Erica E Davis 18,  Bertrand Isidor 19
Affiliations

Affiliations

  • 1 CHU Nantes, Service de Génétique Médicale, 9 quai Moncousu, 44093 Nantes Cedex 1, France; Université de Nantes, CNRS, INSERM, l'institut du thorax, 44000 Nantes, France.
  • 2 CHU Nantes, Service de Génétique Médicale, 9 quai Moncousu, 44093 Nantes Cedex 1, France; Université de Nantes, CNRS, INSERM, l'institut du thorax, 44000 Nantes, France; Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27701, USA.
  • 3 Department of Medical Genetics, Oslo University Hospital and University of Oslo, 0407 Oslo, Norway.
  • 4 University of Paris, INSERM U1163, Institut Imagine, 75015 Paris, France.
  • 5 The Institute for Genomic Medicine at Nationwide Children's Hospital, Columbus, OH 43205, USA.
  • 6 Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27701, USA.
  • 7 Service d'Ophtalmologie, Hôtel Dieu, CHU de Nantes, 44093 Nantes, France.
  • 8 Service de Pédiatrie, Hôpital Mère-Enfants, CHU de NANTES, 44093 Nantes, France.
  • 9 Unité d'Hépatologie pédiatrique, Centre de référence de l'atrésie des voies biliaires et des cholestases génétiques Hôpital NECKER, 75015 Paris, France.
  • 10 Human Genetics Center, School of Public Health, University of TX Health Science Center at Houston, Houston, TX 77030, USA.
  • 11 Human Genetics Center, School of Public Health, University of TX Health Science Center at Houston, Houston, TX 77030, USA; Ruiz Department of Ophthalmology and Visual Science, University of TX Health Science Center at Houston, Houston, TX 77030, USA.
  • 12 Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USA.
  • 13 Jules Stein Eye Institute and Department of Ophthalmology, University of California Los Angeles, Los Angeles, CA 90095, USA.
  • 14 Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27701, USA; Advanced Center for Translational and Genetic Medicine (ACT-GeM), Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA; Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
  • 15 Department of Small Animal Clinical Studies, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA.
  • 16 Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA.
  • 17 University of Paris, INSERM U1163, Institut Imagine, 75015 Paris, France; Service de Génétique, Hôpital Necker-Enfants Malades, AP-HP, 75015 Paris, France.
  • 18 Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27701, USA; Advanced Center for Translational and Genetic Medicine (ACT-GeM), Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA; Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Electronic address: [email protected].
  • 19 CHU Nantes, Service de Génétique Médicale, 9 quai Moncousu, 44093 Nantes Cedex 1, France; Université de Nantes, CNRS, INSERM, l'institut du thorax, 44000 Nantes, France. Electronic address: [email protected].
PMID: 32386558 DOI: 10.1016/j.ajhg.2020.04.005
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.

Figures