IFT81, encoding an IFT-B core protein, as a very rare cause of a ciliopathy phenotype

Perrault, IsabelleHalbritter, JanPorath, Jonathan DGérard, XavierBraun, Daniela AGee, Heon YungFathy, Hanan MSaunier, SophieCormier-Daire, ValérieThomas, SophieAttié-Bitach, TaniaBoddaert, NathalieTaschner, MichaelSchueler, MarkusLorentzen, EsbenLifton, Richard PLawson, Jennifer AGarfa-Traore, MeriemOtto, Edgar ABastin, PhilippeCaillaud, CatherineKaplan, JosselineRozet, Jean-MichelHildebrandt, Friedhelm2015-12-042015Perrault, I., J. Halbritter, J. D. Porath, X. Gérard, D. A. Braun, H. Y. Gee, H. M. Fathy, et al. 2015. “IFT81, encoding an IFT-B core protein, as a very rare cause of a ciliopathy phenotype.” Journal of Medical Genetics 52 (10): 657-665. doi:10.1136/jmedgenet-2014-102838. http://dx.doi.org/10.1136/jmedgenet-2014-102838.0022-2593http://nrs.harvard.edu/urn-3:HUL.InstRepos:23845278Background: Bidirectional intraflagellar transport (IFT) consists of two major protein complexes, IFT-A and IFT-B. In contrast to the IFT-B complex, all components of IFT-A have recently been linked to human ciliopathies when defective. We therefore hypothesised that mutations in additional IFT-B encoding genes can be found in patients with multisystemic ciliopathies. Methods: We screened 1628 individuals with reno-ocular ciliopathies by targeted next-generation sequencing of ciliary candidate genes, including all IFT-B encoding genes. Results: Consequently, we identified a homozygous mutation in IFT81 affecting an obligatory donor splice site in an individual with nephronophthisis and polydactyly. Further, we detected a loss-of-stop mutation with extension of the deduced protein by 10 amino acids in an individual with neuronal ceroid lipofuscinosis-1. This proband presented with retinal dystrophy and brain lesions including cerebellar atrophy, a phenotype to which the IFT81 variant might contribute. Cultured fibroblasts of this latter affected individual showed a significant decrease in ciliated cell abundance compared with controls and increased expression of the transcription factor GLI2 suggesting deranged sonic hedgehog signalling. Conclusions: This work describes identification of mutations of IFT81 in individuals with symptoms consistent with the clinical spectrum of ciliopathies. It might represent the rare case of a core IFT-B complex protein found associated with human disease. Our data further suggest that defects in the IFT-B core are an exceedingly rare finding, probably due to its indispensable role for ciliary assembly in development.en-USGeneticsMolecular geneticsOphthalmologyRenal MedicineIFT81, encoding an IFT-B core protein, as a very rare cause of a ciliopathy phenotypeJournal Article2015-12-0410.1136/jmedgenet-2014-102838