WDR19 and Jeune Syndrome

Autosomal recessive mutations in WDR19 have been implicated in Jeune syndrome, a skeletal ciliopathy characterized by short ribs, limb shortening, and thoracic dystrophy. In a Dutch family, exome sequencing identified a homozygous c.1034T>G (p.Val345Gly) variant segregating with Jeune syndrome in one proband (PMID:22019273). This variant is absent or extremely rare in population databases and parents were confirmed heterozygous, supporting AR inheritance and co-segregation.

Functional studies demonstrate that WDR19 (IFT144) is essential for retrograde intraflagellar transport. In C. elegans, loss of the DYF-2 orthologue disrupted ciliary assembly and motility (PMID:16957054). In mouse Ift144 mutants, hypomorphic and null alleles recapitulate Jeune-like skeletal anomalies including polydactyly, short limbs, and rib defects, accompanied by aberrant hedgehog signaling (PMID:22228095). These models confirm haploinsufficiency of WDR19 leads to skeletal ciliopathy, mirroring the human Jeune phenotype.

Key Take-home: Biallelic WDR19 mutations cause Jeune syndrome via disrupted IFT-A function, supporting its use in genetic diagnosis and counseling.

References

• American journal of human genetics • 2011 • Ciliopathies with skeletal anomalies and renal insufficiency due to mutations in the IFT-A gene WDR19. PMID:22019273
• Molecular biology of the cell • 2006 • Caenorhabditis elegans DYF-2, an orthologue of human WDR19, is a component of the intraflagellar transport machinery in sensory cilia. PMID:16957054
• Human molecular genetics • 2012 • Mutations in mouse Ift144 model the craniofacial, limb and rib defects in skeletal ciliopathies. PMID:22228095

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