KATNIP – Joubert Syndrome

Joubert syndrome (JS) is an autosomal recessive ciliopathy characterized by the distinctive molar tooth sign, hypotonia, ataxia, and neurodevelopmental impairment. KATNIP encodes katanin‐interacting protein, a scaffold required for activation of the ciliogenesis kinase CILK1 in primary cilia formation.

Biallelic loss-of-function variants in KATNIP have been identified in eight unrelated JS probands. A consanguineous family from India harbored homozygous c.4420del (p.Met1474CysfsTer11) segregating in two affected siblings ([PMID:27245168]). A Roma pedigree presented homozygous c.808del (p.Ser270ValfsTer28) in a 5-year-old male with classical JS features and esophageal atresia ([PMID:40428346]). Additional JS patients carried compound heterozygous or oligogenic KATNIP variants in cohort studies ([PMID:36580738]; [PMID:32164589]).

Inheritance is autosomal recessive with segregation of variants in affected sibs (2 affected relatives) and absent in unaffected family members. All reported alleles are predicted truncating variants (frameshift or nonsense), consistent with a loss-of-function mechanism.

Functional assays demonstrate that knockdown of KATNIP in zebrafish recapitulates ciliopathy phenotypes, which are rescued by wild-type human KATNIP cDNA ([PMID:27245168]). Human disease variant p.Met1474Cys binds CILK1 but fails to induce TDY phosphorylation, restrict cilia length, or normalize ciliation rates in cell models ([PMID:40621737]).

Together, genetic and experimental data provide strong evidence that KATNIP loss-of-function causes Joubert syndrome via impaired CILK1-mediated ciliogenesis. No conflicting reports have been documented.

Key Take-home: Biallelic truncating KATNIP variants underlie autosomal recessive Joubert syndrome, supporting molecular diagnosis and functional validation in clinical care.

References

• Human genetics • 2016 • Identification of a homozygous nonsense mutation in KIAA0556 in a consanguineous family displaying Joubert syndrome. PMID:27245168
• BMC Pediatrics • 2020 • Co-occurrence of mutations in KIF7 and KIAA0556 in Joubert syndrome with ocular coloboma, pituitary malformation and growth hormone deficiency: a case report and literature review. PMID:32164589
• Clinical neurology and neurosurgery • 2023 • Clinical and genetic spectrum from a prototype of ciliopathy: Joubert syndrome. PMID:36580738
• Genes • 2025 • Phenotypic Spectrum of KATNIP-Associated Joubert Syndrome: Possible Association with Esophageal Atresia and Review of the Literature. PMID:40428346
• Journal of Cell Science • 2025 • Human disease variants of KATNIP fail to support CILK1 activation and control of primary cilia. PMID:40621737

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