Journal article
Mutations in the Kinesin-2 Motor KIF3B Cause an Autosomal-Dominant Ciliopathy
American Journal of Human Genetics, Vol.106(6), pp.893-904
2020
PMID: 32386558
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.
Details
- Title
- Mutations in the Kinesin-2 Motor KIF3B Cause an Autosomal-Dominant Ciliopathy
- Authors
- Benjamin Cogné (Author) - Nantes UniversitéXenia Latypova (Author) - Nantes UniversitéLokuliyanage Dona Samudita Senaratne (Author) - Oslo University HospitalLudovic Martin (Author) - University of Paris-SudDaniel C Koboldt (Author) - Nationwide Children's HospitalGeorgios Kellaris (Author) - Duke UniversityLorraine Fievet (Author) - Duke UniversityGuylène Le Meur (Author) - Centre Hospitalier Universitaire de NantesDominique Caldari (Author) - Centre Hospitalier Universitaire de NantesDominique Debray (Author) - Hôpital Necker-Enfants MaladesMathilde Nizon (Author) - Nantes UniversitéEirik Frengen (Author) - University of OsloSara J Bowne (Author) - The University of Texas Health Science Center at Houston99 Lives Consortium (Research Group)Robert Harvey (Consortium Member) - University of the Sunshine Coast, Queensland, School of Health and Sport Sciences - Legacy
- Publication details
- American Journal of Human Genetics, Vol.106(6), pp.893-904
- Publisher
- Cell Press
- DOI
- 10.1016/j.ajhg.2020.04.005
- ISSN
- 1537-6605
- PMID
- 32386558
- Organisation Unit
- Centre for Bioinnovation; School of Health and Behavioural Sciences - Legacy; School of Health and Sport Sciences - Legacy; University of the Sunshine Coast, Queensland; School of Health
- Language
- English
- Record Identifier
- 99472705702621
- Output Type
- Journal article
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