CBY1 – Joubert Syndrome

Joubert syndrome is an autosomal recessive ciliopathy characterized by the molar tooth sign, cerebellar ataxia, developmental delay, abnormal neonatal breathing and polydactyly. CBY1 encodes a centriolar distal-end protein critical for cilia formation and function. Loss-of-function (LOF) variants in CBY1 were identified in three affected individuals from two independent families, implicating biallelic CBY1 deficiency in Joubert syndrome (PMID:33131181).

Inheritance is autosomal recessive, with two LOF variants reported: c.189_190del (p.Gly64_Val65insTer) and c.64_65dup (p.Asn23fs). Both variants segregate with disease in the families and are predicted to induce nonsense-mediated decay of CBY1 transcript (PMID:33131181).

Segregation analysis in two pedigrees revealed concordant homozygosity of these LOF alleles in affected siblings, supporting co-segregation of CBY1 variants with Joubert syndrome (PMID:33131181).

Functional studies in zebrafish demonstrated that cby1 depletion causes classic ciliopathy phenotypes including defective motile cilia, cerebellar hypoplasia–like features and abnormal body curvature, mirroring human Joubert syndrome (PMID:33131181).

Patient fibroblast assays showed reduced CBY1 mRNA levels consistent with transcript degradation, absence of CBY1 protein by immunofluorescence, decreased ciliogenesis, increased ciliary length and reduced levels of AHI1 and ARL13B in cilia (PMID:33131181).

The combined genetic and experimental evidence supports a loss-of-function mechanism for CBY1 in autosomal recessive Joubert syndrome. CBY1 should be included in gene panels for Joubert and related ciliopathies to facilitate molecular diagnosis and management.

References

• Human Mutation • 2020 • Loss of CBY1 results in a ciliopathy characterized by features of Joubert syndrome PMID:33131181

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