IFT80 – Jeune Asphyxiating Thoracic Dystrophy

IFT80 (HGNC:29262) has been implicated in autosomal recessive Jeune asphyxiating thoracic dystrophy (Jeune syndrome, MONDO:0018770), a skeletal ciliopathy defined by a constricted thoracic cage, shortened long bones, and respiratory insufficiency. Two unrelated probands presenting with typical ATD phenotypes were reported harboring presumed IFT80 mutations (PMID:19137595; PMID:30406012). No additional segregation data beyond index cases have been documented. Reported variant includes NM_020800.3:c.2155C>T (p.Arg719Cys) in IFT80 affecting homo-dimerization (PMID:29658880). Based on two probands with consistent phenotype and genotype, gene–disease association is classified as Limited.

Functional studies support a loss-of-function mechanism: a hypomorphic Ift80 mouse model recapitulates JATD features including narrow thorax, shortened long bones, and perinatal lethality, with reduced Hedgehog pathway activation in mouse fibroblasts (PMID:21227999). Structural and rescue assays demonstrate that disruption of the IFT80 C-terminal dimerization domain prevents ciliogenesis, confirming its essential role in IFT complex assembly (PMID:29658880). Chondrocyte differentiation assays show that IFT80 silencing impairs primary cilia formation, downregulates collagen II and aggrecan expression, and dysregulates Hedgehog and Wnt signaling pathways critical for skeletal development (PMID:23333501). No conflicting studies have been reported. Key take-home: IFT80 variant screening should be incorporated in the diagnostic work-up of suspected autosomal recessive Jeune syndrome.

References

• Pediatric pulmonology • 2009 • Ciliopathy spectrum expanded? Jeune syndrome associated with foregut dysmotility and malrotation. PMID:19137595
• Respiratory medicine case reports • 2018 • An unusual case of hypercapnic respiratory failure. PMID:30406012
• Human molecular genetics • 2011 • An Ift80 mouse model of short rib polydactyly syndromes shows defects in hedgehog signalling without loss or malformation of cilia. PMID:21227999
• eLife • 2018 • Crystal structure of intraflagellar transport protein 80 reveals a homo-dimer required for ciliogenesis. PMID:29658880
• Experimental cell research • 2013 • IFT80 is essential for chondrocyte differentiation by regulating Hedgehog and Wnt signaling pathways. PMID:23333501

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