IFT80 – Beemer-Langer Syndrome

IFT80 encodes a core component of the intraflagellar transport complex B essential for cilia assembly and Hedgehog signaling. Biallelic mutations in IFT80 have been implicated in skeletal ciliopathies, including Beemer-Langer syndrome (BLS), an autosomal-recessive perinatal lethal chondrodysplasia characterized by short ribs, a narrow thorax, and polydactyly.

In a cohort of four affected fetuses from two unrelated families, two novel missense variants in IFT80 were identified in compound heterozygosity: c.1288G>A (p.Ala430Thr) and c.2048G>T (p.Gly683Val) in all cases, consistent with autosomal-recessive inheritance (4 probands, 2 families) (PMID:30767363). No additional segregation beyond the index fetuses was reported.

Functional studies in a murine Ift80 gene-trap model demonstrated that hypomorphic Ift80 expression leads to perinatal lethality with rib shortening, thoracic constriction, limb anomalies, and impaired Hedgehog pathway activation despite preserved ciliogenesis, phenocopying human skeletal ciliopathies (PMID:21227999).

In vitro silencing of IFT80 in mouse bone marrow stromal cells impaired primary cilia formation and chondrogenic differentiation through downregulation of Hedgehog signaling and altered Wnt activity, which was rescued by Gli2 overexpression (PMID:23333501).

These data support a loss-of-function mechanism for IFT80 in BLS. While the genetic evidence from four fetal cases is preliminary, concordant functional findings across cellular and animal models reinforce the gene-disease link.

Key take-home: Biallelic IFT80 variants should be considered in fetuses presenting with perinatal lethal short-rib polydactyly phenotypes, guiding genetic diagnosis and counseling.

References

• American journal of medical genetics. Part A • 2019 • Mutations in IFT80 cause SRPS Type IV. Report of two families and review. PMID:30767363
• 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
• Experimental cell research • 2013 • IFT80 is essential for chondrocyte differentiation by regulating Hedgehog and Wnt signaling pathways. PMID:23333501

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