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Centrosomal protein 120 (CEP120) is essential for centriole elongation and ciliogenesis. Autosomal recessive CEP120 mutations manifest as a spectrum of complex ciliopathies, including Joubert syndrome, Meckel syndrome and asphyxiating thoracic dystrophy, reflecting multi-organ involvement and variable severity.
In a cohort of 145 patients with Joubert syndrome, 15 with oral-facial-digital syndrome VI, 21 Meckel syndrome fetuses and one fetus with tectocerebellar dysraphia and occipital encephalocele, plus 346 targeted-sequencing probands, six individuals were found to harbor nine distinct CEP120 variants, accounting for ~1% of ciliopathy cases (PMID:27208211). No clear genotype–phenotype correlation was observed across classical and severe presentations.
The variant spectrum comprises seven predicted loss-of-function alleles—including c.1175C>G (p.Ser392Ter) and c.2917C>T (p.Arg973Ter)—and two missense changes. All changes were detected in trans, consistent with autosomal recessive inheritance.
Functional studies using CRISPR/Cas9 CEP120 knockout in p53-deficient RPE1 cells demonstrated short centrioles devoid of distal and subdistal appendages, impaired recruitment of C2CD3 and Talpid3, and abolished ciliogenesis. A disease-associated p.Ile975Ser variant exhibited reduced binding to C2CD3 and disrupted cilia assembly, supporting a loss-of-function mechanism (PMID:30988386).
Together, genetic and experimental data substantiate CEP120 haploinsufficiency as a cause of autosomal recessive ciliopathies, with loss-of-function variants leading to defective centriole appendage formation and impaired ciliary biogenesis.
Key Take-home: CEP120 genetic testing is recommended in the diagnostic workup of recessive ciliopathies to confirm molecular diagnosis and guide clinical management.
Gene–Disease AssociationModerateSix unrelated probands with nine distinct CEP120 variants in ciliopathy cases (~1% prevalence) ([PMID:27208211]); concordant functional data demonstrates centrosomal and ciliary defects. Genetic EvidenceModerateSix probands carrying seven truncating and two missense alleles in trans; autosomal recessive segregation consistent across families. Functional EvidenceModerateCEP120 knockout disrupts centriole appendage assembly and cilia formation; p.Ile975Ser impairs C2CD3 binding and ciliogenesis ([PMID:30988386]). |