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Published on: August 20, 2019
Disrupted intraflagellar transport due to IFT74 variants causes Joubert syndrome
Minna Luo1, Zaisheng Lin2, Tian Zhu3
1National Human Genetic Resources Center, National Research Institute for Family Planning, Beijing, China.
Insights
Intraflagellar transport 74 (IFT74) gene variants cause Joubert syndrome (JBTS), a ciliopathy. This study reveals IFT74 dysfunction impacts cilia formation and signaling, offering insights into JBTS pathogenesis.
Area of Science:
- Genetics
- Cell Biology
- Developmental Biology
Background:
- Ciliopathies are genetic disorders arising from defects in cilia, crucial cellular organelles.
- Joubert syndrome (JBTS) is a ciliopathy characterized by cerebellar hypoplasia and developmental delays.
- The role of intraflagellar transport (IFT) in JBTS pathogenesis is not well understood.
Purpose of the Study:
- To investigate the impact of IFT dysfunction in Joubert syndrome.
- To identify genes within the IFT complex associated with JBTS.
Main Methods:
- Exome sequencing was employed to screen for pathogenic variants in IFT genes within a cohort of JBTS patients.
- Functional studies were conducted using a zebrafish model and patient-derived fibroblasts to assess the pathogenicity of identified variants.
Main Results:
- IFT74 was identified as a gene associated with JBTS in three families, with affected individuals carrying truncated or missense variants.
- The p.Q179E missense variant in IFT74 showed reduced rescue effects in zebrafish.
- Patient fibroblasts with IFT74 variants exhibited impaired ciliogenesis, altered protein distribution, and disrupted hedgehog signaling.
Conclusions:
- IFT74 is a newly identified JBTS-related gene.
- The study elucidates cellular and biochemical mechanisms underlying IFT74 dysfunction in JBTS.
Purpose:
Ciliopathies are a group of disorders caused by defects of the cilia. Joubert syndrome (JBTS) is a recessive and pleiotropic ciliopathy that causes cerebellar vermis hypoplasia and psychomotor delay. Although the intraflagellar transport (IFT) complex serves as a key module to maintain the ciliary structure and regulate ciliary signaling, the function of IFT in JBTS remains largely unknown. We aimed to explore the impact of IFT dysfunction in JBTS.
Methods:
Exome sequencing was performed to screen for pathogenic variants in IFT genes in a JBTS cohort. Animal model and patient-derived fibroblasts were used to evaluate the pathogenic effects of the variants.
Results:
We identified IFT74 as a JBTS-associated gene in three unrelated families. All the affected individuals carried truncated variants and shared one missense variant (p.Q179E) found only in East Asians. The expression of the human p.Q179E-IFT74 variant displayed compromised rescue effects in zebrafish ift74 morphants. Attenuated ciliogenesis; altered distribution of IFT proteins and ciliary membrane proteins, including ARL13B, INPP5E, and GPR161; and disrupted hedgehog signaling were observed in patient fibroblasts with IFT74 variants.
Conclusion:
IFT74 is identified as a JBTS-related gene. Cellular and biochemical mechanisms are also provided.
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