CEP120 – Jeune asphyxiating thoracic dystrophy

Jeune asphyxiating thoracic dystrophy (JATD) is an autosomal recessive skeletal ciliopathy characterized by a narrow, small thoracic cage and variable skeletal and extra-skeletal anomalies. The genetic basis of JATD is heterogeneous, with at least nine genes encoding ciliary proteins implicated to date. Recent exome sequencing in two consanguineous Saudi families identified a shared ancestral homozygous haplotype harboring a novel CEP120 variant, implicating this centriolar protein in JATD pathogenesis (PMID:25361962).

Whole-exome sequencing revealed NM_001375405.1:c.595G>C (p.Ala199Pro) segregating homozygously in affected members of both Saudi families. Targeted CEP120 sequencing in additional Saudi and European cohorts uncovered the identical missense change in two more unrelated families, yielding four independent homozygous probands and confirming a significant genome-wide linkage signal at the CEP120 locus (LOD>3) (PMID:25361962). These data establish an autosomal recessive inheritance pattern with clear segregation in consanguineous and outbred populations.

The c.595G>C (p.Ala199Pro) substitution affects a highly conserved residue within CEP120, likely disrupting centriolar function. No other recurrent or founder alleles have been reported to date, and the variant spectrum remains limited to this hypomorphic missense change in JATD. Population databases show absence of this variant in controls, supporting pathogenicity and a founder effect in Middle Eastern and European cohorts.

Functional studies in patient-derived fibroblasts demonstrate marked reduction in cilium number and abnormal centriole counts, consistent with impaired ciliary assembly. In zebrafish morphants, knockdown of cep120 produces pleiotropic phenotypes characteristic of ciliary dysfunction—including body curvature, hydrocephalus, otolith defects, and pronephric disorganization—mirroring human JATD features (PMID:25361962).

Complementary mechanistic insights arise from CEP120 knockout in p53-deficient RPE1 cells, where loss of CEP120 or expression of a disease-associated I975S mutant impairs distal and subdistal centriole appendage assembly, disrupts recruitment of C2CD3 and Talpid3, and abrogates ciliogenesis (PMID:30988386). These concordant cellular and in vivo models underscore a loss-of-function mechanism through defective centriole elongation and ciliary biogenesis.

Together, genetic linkage in four families, clear autosomal recessive segregation, and concordant functional evidence support a Strong clinical validity for the CEP120–JATD association. CEP120 screening is therefore warranted in patients with suspected AR Jeune asphyxiating thoracic dystrophy to inform diagnosis, genetic counseling, and potential future therapies.

References

• Human Molecular Genetics • 2015 • A founder CEP120 mutation in Jeune asphyxiating thoracic dystrophy expands the role of centriolar proteins in skeletal ciliopathies. PMID:25361962
• Scientific Reports • 2019 • CEP120 interacts with C2CD3 and Talpid3 and is required for centriole appendage assembly and ciliogenesis. PMID:30988386

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