IFT172 – Jeune Syndrome

IFT172 is a core component of anterograde intraflagellar transport required for primary cilium assembly. Autosomal recessive variants in IFT172 have been implicated in Jeune syndrome, a short-rib thoracic dysplasia subtype (Jeune syndrome). Initial recognition of IFT172 in Jeune and related skeletal ciliopathies arose from sequencing and functional assays in model organisms.

Genetic evidence includes biallelic IFT172 variants identified in three families (PMID:25168386). Reported variant classes comprise missense (e.g., c.770T>C (p.Leu257Pro) (PMID:25168386)) and truncating alleles. Overall, fewer than five unrelated cases with Jeune features and IFT172 mutations have been described, and no segregation data are available.

Functional studies demonstrate that IFT172 alleles disrupt ciliary assembly and intraflagellar transport. Hypomorphic and null variants show reduced ciliary localization of IFT proteins in patient cells, while zebrafish crispant and mutant embryos exhibit axial and ciliary defects reminiscent of thoracic dysplasia (PMID:36533556).

Rescue experiments in zebrafish and cellular assays restore ciliary trafficking upon wild-type IFT172 complementation, confirming a loss-of-function mechanism (PMID:25168386; PMID:36533556).

No conflicting data disputing IFT172 in Jeune syndrome have been reported, although modifier alleles may influence phenotypic severity. Additional deep-intronic and structural variant analyses remain to be undertaken.

Together, the current genetic and experimental data support a limited clinical validity for IFT172 in Jeune syndrome. Key Take-home: Biallelic IFT172 loss-of-function variants underlie autosomal recessive Jeune syndrome and should be included in diagnostic gene panels.

References

• Human molecular genetics • 2015 • Mutations in IFT172 cause isolated retinal degeneration and Bardet-Biedl syndrome. PMID:25168386
• Disease models & mechanisms • 2022 • Variable phenotypes and penetrance between and within different zebrafish ciliary transition zone mutants. PMID:36533556

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