INPP5E – Joubert Syndrome

INPP5E encodes inositol polyphosphate-5-phosphatase E, a critical regulator of phosphoinositide composition at the primary cilium. Biallelic variants in INPP5E underlie autosomal recessive Joubert syndrome, characterized by cerebellar vermis hypoplasia, the ‘‘molar tooth sign,’’ hypotonia, ataxia, oculomotor apraxia, and developmental delay.

Early case reports described a 20-year-old woman with classical imaging but normal cognition, harboring a homozygous INPP5E mutation, segregating with two affected brothers, illustrating intrafamilial variability (3 probands + 2 relatives) ([PMID:20446224]).

Renal involvement was reported in a child with end-stage renal disease carrying homozygous c.1303C>G (p.Arg435Gly) in INPP5E, broadening the phenotypic spectrum to include nephronophthisis ([PMID:25818971]).

Defective ciliogenesis was demonstrated in two sisters with a novel homozygous c.1565G>C (p.Gly522Ala) variant. Patient fibroblasts showed reduced cilium length and number, confirming INPP5E’s role in ciliary stability ([PMID:29052317]).

In a cohort of 59 patients from 55 families, molecular analysis in 35 families identified INPP5E among 11 causal genes, underscoring genetic heterogeneity and establishing ~9 unrelated probands with INPP5E-linked Joubert syndrome ([PMID:32139166]).

Functional studies further support pathogenicity: zebrafish pde6d mutants fail to target INPP5E to cilia, with rescue by wild-type PDE6D but not mutant, demonstrating prenyl-dependent trafficking ([PMID:24166846]). MKS1 mutant fibroblasts show decreased ciliary INPP5E, supporting a loss-of-function mechanism downstream of ARL13B ([PMID:26490104]).

Collectively, autosomal recessive inheritance, segregation in multiple families, a spectrum of missense and loss-of-function alleles, and concordant cellular and animal models establish a Definitive gene–disease association. Key take-home: inclusion of INPP5E in diagnostic panels enables accurate molecular diagnosis, informs prognosis, and guides genetic counseling.

References

• Neuropediatrics • 2009 • Normal cognitive functions in joubert syndrome. PMID:20446224
• The Turkish journal of pediatrics • 2014 • Development of end-stage renal disease at a young age in two cases with Joubert syndrome. PMID:25818971
• American journal of medical genetics. Part A • 2017 • Defective ciliogenesis in INPP5E-related Joubert syndrome. PMID:29052317
• Pediatric neurology • 2020 • Clinical and Molecular Diagnosis of Joubert Syndrome and Related Disorders. PMID:32139166
• Human mutation • 2014 • A homozygous PDE6D mutation in Joubert syndrome impairs targeting of farnesylated INPP5E protein to the primary cilium. PMID:24166846
• Journal of medical genetics • 2016 • MKS1 regulates ciliary INPP5E levels in Joubert syndrome. PMID:26490104

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