Mutations in the gene encoding IFT dynein complex component WDR34 cause Jeune asphyxiating thoracic dystrophy

Area of Science:

• Cell Biology
• Genetics
• Developmental Biology

Background:

• Intraflagellar transport (IFT) is vital for primary cilia function, regulating growth, maintenance, and signaling pathways like hedgehog.
• The dynein-2 motor complex mediates retrograde IFT, with DYNC2H1 as a key subunit; its deficiency is linked to skeletal ciliopathies.
• Jeune syndrome (asphyxiating thoracic dystrophy) is a spectrum of skeletal ciliopathies associated with IFT protein deficiencies.

Purpose of the Study:

• To investigate the genetic basis of Jeune syndrome and identify novel causative genes.
• To elucidate the role of WDR34 in intraflagellar transport and ciliary function.
• To understand the molecular mechanisms underlying WDR34 mutations in ciliopathies.

Main Methods:

• Exome sequencing and targeted next-generation sequencing panel were employed to identify mutations.
• Three-dimensional protein modeling was used to analyze the impact of identified mutations.
• Immunofluorescence microscopy and co-immunoprecipitation assays were performed to determine WDR34 localization and interactions.

Main Results:

• Eleven mutations in the WDR34 gene were identified in nine families diagnosed with Jeune syndrome.
• WDR34 encodes a protein homologous to a dynein intermediate chain involved in retrograde IFT.
• Mutations affect critical residues for protein-protein interactions; WDR34 localizes to centrioles, basal bodies, and axonemes.
• WDR34 co-immunoprecipitates with DYNLL1 and may link cytoplasmic dynein-1 and dynein-2 motors.

Conclusions:

• WDR34 is essential for ciliary functions critical for normal development and survival.
• WDR34 is likely a previously unrecognized component of the mammalian dynein-IFT machinery.
• Mutations in WDR34 represent a novel cause of Jeune syndrome and highlight the importance of IFT in human development.