KIF3B – Autosomal-Dominant Ciliopathy

KIF3B encodes the motor subunit of the kinesin-2 complex essential for anterograde intraflagellar transport in primary cilia. Pathogenic variants disrupt ciliary assembly and photoreceptor trafficking, leading to a syndromic retinal ciliopathy phenotype in humans. Genetic studies identified heterozygous missense variants in two unrelated families presenting with hallmark ciliopathy features (PMID:32386558).

In Family 1, a de novo c.748G>C (p.Glu250Gln) variant in the kinesin motor domain was found in a proband with hepatic fibrosis, rod-cone dystrophy, and postaxial polydactyly (PMID:32386558). In Family 2, a c.1568T>C (p.Leu523Pro) variant segregated autosomal-dominantly across six generations with predominant retinitis pigmentosa (PMID:32386558).

Segregation analysis demonstrated co-segregation of the c.1568T>C (p.Leu523Pro) allele with disease in at least six affected relatives in a multigenerational pedigree (PMID:32386558). No conflicting or alternative phenotypes have been reported for these alleles.

Functional assays in patient-derived cells showed a significant increase in primary cilia length without loss of protein stability, while zebrafish mRNA rescue experiments revealed impaired rhodopsin trafficking and photoreceptor ciliary elongation for both variants (PMID:32386558). Recent cell-based studies using Kif3a–/–;Kif3b–/– 3T3 cells confirmed that p.Glu250Gln acts as a rigor mutation and p.Leu523Pro impairs motor motility, whereas the Bengal cat p.Ala334Thr allele behaves hypomorphically (PMID:38665936).

Collectively, genetic and experimental data support an autosomal-dominant, gain-of-function/dominant-negative mechanism for KIF3B in human ciliopathy. Additional functional characterization beyond these studies exceeds the scope of current ClinGen scoring.

Key Take-home: Heterozygous KIF3B missense variants cause a clinically actionable autosomal-dominant ciliopathy marked by hepatic fibrosis, retinal degeneration, and polydactyly, enabling targeted genetic testing and functional confirmation in model systems.

References

• American journal of human genetics • 2020 • Mutations in the Kinesin-2 Motor KIF3B Cause an Autosomal-Dominant Ciliopathy. PMID:32386558
• Frontiers in molecular biosciences • 2024 • Characterization of the disease-causing mechanism of KIF3B mutations from ciliopathy patients. PMID:38665936

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