CSPP1 – Joubert syndrome

Joubert syndrome (JS) is a rare autosomal recessive neurodevelopmental ciliopathy marked by cerebellar vermis hypoplasia and a constellation of neurological features including microcephaly, global developmental delay, and seizures (PMID:38586154). Recent case reports have elucidated the contribution of CSPP1 variants to JS, with one Frontiers in Pediatrics study (2024) identifying novel compound heterozygous variants that disrupt the protein’s normal function, thereby implicating CSPP1 in the pathogenesis of the syndrome (PMID:38586154).

Genetic evidence supporting the CSPP1–JS association is compelling. Multiple independent studies report a total of over 23 probands with deleterious variants and segregation observed in families, including one cohort with 19 affected individuals (PMID:24360808). Among the variant spectrum, truncating mutations such as c.3211_3212insA (p.Ala1071AspfsTer8) are emblematic of the loss‐of‐function mechanism underlying the disorder.

Functional studies have further substantiated this gene–disease link. In vitro assays utilizing hTERT-RPE1 cells and in vivo zebrafish models have demonstrated that loss of CSPP1 impairs ciliogenesis and alters Hedgehog signaling pathways critical for neurodevelopment, providing mechanistic insight into JS pathophysiology (PMID:20519441, PMID:31412255).

Integration of the genetic and functional findings reveals a coherent narrative: CSPP1 loss-of-function disrupts primary cilia formation and function, a defect that translates into the multilayered clinical features of JS. Although additional evidence exists beyond the standard ClinGen scoring maximum, the current data firmly support a strong association between CSPP1 variants and Joubert syndrome.

These findings not only refine our understanding of JS etiology but also enhance diagnostic precision. The identification of pathogenic CSPP1 alleles can guide genetic testing and inform clinical management, offering tangible benefits for patient stratification and counseling.

Key take‑home: Robust genetic and experimental data validate CSPP1 as a causative gene in Joubert syndrome, cementing its role in precision diagnostics and future therapeutic exploration.

References

• Frontiers in Pediatrics • 2024 • Novel compound heterozygous variants in the CSPP1 gene causes Joubert syndrome: case report and literature review of the CSPP1 gene's pathogenic mechanism PMID:38586154
• American Journal of Human Genetics • 2014 • Mutations in CSPP1, encoding a core centrosomal protein, cause a range of ciliopathy phenotypes in humans PMID:24360803
• Molecular Biology of the Cell • 2010 • CSPP is a ciliary protein interacting with Nephrocystin 8 and required for cilia formation PMID:20519441
• Cell Reports • 2019 • A CEP104-CSPP1 Complex Is Required for Formation of Primary Cilia Competent in Hedgehog Signaling PMID:31412255
• The Journal of Clinical Investigation • 2020 • Dysfunction of the ciliary ARMC9/TOGARAM1 protein module causes Joubert syndrome PMID:32453716

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