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Mutations in the Kinesin-2 Motor KIF3B Cause an Autosomal-Dominant Ciliopathy
- Source :
- 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
- Publication Year :
- 2020
- Publisher :
- HAL CCSD, 2020.
-
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.
- Subjects :
- Male
Heterozygote
Rhodopsin
[SDV]Life Sciences [q-bio]
Kinesins
Biology
Retina
03 medical and health sciences
Young Adult
KIFAP3
Intraflagellar transport
Report
Retinitis pigmentosa
Genetics
medicine
Animals
Humans
KIF3A
Photoreceptor Cells
Amino Acid Sequence
Cilia
Genetics (clinical)
Exome sequencing
Zebrafish
030304 developmental biology
Genes, Dominant
0303 health sciences
Cilium
030305 genetics & heredity
Middle Aged
medicine.disease
Ciliopathies
Pedigree
Ciliopathy
Phenotype
Child, Preschool
Larva
Mutation
Cats
Kinesin
Female
sense organs
Genome-Wide Association Study
Subjects
Details
- Language :
- English
- ISSN :
- 00029297 and 15376605
- Database :
- OpenAIRE
- Journal :
- 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
- Accession number :
- edsair.doi.dedup.....a48a8e4787ee74d7e392a0a9500b3f4d