Mutations in CSPP1 lead to classical Joubert syndrome.

Area of Science:

• Genetics
• Cell Biology
• Developmental Biology

Background:

• Joubert syndrome and related disorders (JSRDs) are a group of genetically heterogeneous conditions characterized by a malformation of the mid-hindbrain.
• These disorders arise from mutations affecting primary cilia, which are crucial cellular organelles involved in various signaling pathways.
• Causative mutations often lead to dysfunction of primary cilia, resulting in diverse clinical manifestations affecting multiple organs.

Purpose of the Study:

• To investigate the genetic basis of Joubert syndrome and related disorders (JSRDs).
• To identify novel genes implicated in the pathogenesis of JSRDs.
• To elucidate the role of CSPP1 in neural development and primary cilia function.

Main Methods:

• Whole-exome sequencing was performed to identify mutations in affected individuals.
• CSPP1 gene mutations were identified in six individuals with classical JSRDs.
• Functional studies including protein localization, expression analysis, and ciliogenesis assays were conducted in patient-derived fibroblasts and in vitro models.

Main Results:

• Predicted null mutations in CSPP1 were identified in six individuals with JSRDs.
• CSPP1 protein localizes to centrosomes, spindle poles, and primary cilia.
• Affected fibroblasts exhibited abrogated CSPP1 protein levels and impaired ciliogenesis, indicating CSPP1's role in neural-specific primary cilia functions.

Conclusions:

• CSPP1 mutations are a cause of Joubert syndrome and related disorders (JSRDs).
• CSPP1 plays a critical role in the neural-specific functions of primary cilia.
• The findings expand our understanding of the genetic architecture of JSRDs and the cellular mechanisms underlying these disorders.