IFT81, encoding an IFT-B core protein, as a very rare cause of a ciliopathy phenotype. Issue 10 (14th August 2015)

• Record Type: Journal Article
• Authors: Perrault, Isabelle; Halbritter, Jan; Porath, Jonathan D; Gérard, Xavier; Braun, Daniela A; Gee, Heon Yung; Fathy, Hanan M; Saunier, Sophie; Cormier-Daire, Valérie; Thomas, Sophie; Attié-Bitach, Tania; Boddaert, Nathalie; Taschner, Michael; Schueler, Markus; Lorentzen, Esben; Lifton, Richard P; Lawson, Jennifer A; Garfa-Traore, Meriem; Otto, Edgar A; Bastin, Philippe; Caillaud, Catherine; Kaplan, Josseline; Rozet, Jean-Michel; Hildebrandt, Friedhelm
• Is Part Of: Journal of medical genetics. Volume 52:Issue 10(2015)
• Page Start: 657
• Page End: 665
• Publication Date: 2015-08-14
• Subjects: Genetics -- Molecular genetics -- Ophthalmology -- Renal Medicine; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmedgenet-2014-102838
• Languages: English
• ISSNs: 1468-6244

Abstract

Abstract : Background: 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.