CEP120 – Joubert Syndrome

CEP120 encodes a centrosomal protein essential for centriole elongation and ciliogenesis. Joubert syndrome is an autosomal recessive ciliopathy characterized by cerebellar vermis hypoplasia, the molar tooth sign, hypotonia, ataxia, and respiratory dysregulation (MONDO:0018772). Initial linkage of CEP120 to Joubert syndrome was unexpected given its prior association with Jeune asphyxiating thoracic dystrophy.

Genetic evidence stems from exome and targeted sequencing in 491 individuals with Joubert syndrome or related ciliopathies. Six unrelated probands harbored nine distinct CEP120 variants, accounting for nearly 1% of Joubert syndrome cases ([PMID:27208211]). All affected individuals displayed biallelic variants consistent with autosomal recessive inheritance.

The variant spectrum comprises predominantly loss-of-function alleles: eight truncating (nonsense and frameshift) and splice-site mutations. For example, c.1175C>G (p.Ser392Ter) was identified in a classical Joubert syndrome case, while other alleles such as c.2924T>G (p.Ile975Ser) link to more severe ciliopathy phenotypes ([PMID:27208211]).

Phenotypic presentations ranged from mild classical Joubert syndrome in four patients to complex ciliopathy features in two fetuses, including tectocerebellar dysraphia with occipital encephalocele and skeletal anomalies. No clear genotype–phenotype correlation was observed between mutation type or location and clinical severity.

Functional studies in p53-deficient RPE1 cells demonstrate that CEP120 knockout leads to short centrioles lacking distal and subdistal appendages, impaired recruitment of C2CD3 and Talpid3, and failure of cilia assembly ([PMID:30988386]).

The disease-associated variant c.2924T>G (p.Ile975Ser) exhibits reduced binding to C2CD3 and perturbs ciliary formation, supporting a loss-of-function mechanism underlying Joubert syndrome pathogenesis ([PMID:30988386]).

Integration of genetic and experimental data confirms that recessive CEP120 loss-of-function disrupts centriole appendage assembly and ciliogenesis, leading to Joubert syndrome. Further studies may refine genotype–phenotype correlations and explore therapeutic exon-skipping strategies.

Key take-home: Biallelic loss-of-function variants in CEP120 cause autosomal recessive Joubert syndrome via defective centriole assembly and ciliogenesis, informing molecular diagnosis and genetic counseling.

References

• Journal of medical genetics • 2016 • Mutations in CEP120 cause Joubert syndrome as well as complex ciliopathy phenotypes. PMID:27208211
• Scientific Reports • 2019 • CEP120 interacts with C2CD3 and Talpid3 and is required for centriole appendage assembly and ciliogenesis. PMID:30988386

Evidence Based Scoring (AI generated)