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

Isabelle Perrault (1) , Jan Halbritter (2, 3) , Jonathan D. Porath (2) , Xavier Gerard (1) , Daniela A. Braun (2) , Heon Yung Gee (2) , Hanan M. Fathy (4) , Sophie Saunier (1) , Valérie Cormier-Daire (1) , Sophie Thomas (1) , Tania Attie-Bitach (1) , Nathalie Boddaert (5) , Michael Taschner (6) , Markus Schueler (2) , Esben Lorentzen (6) , Richard P. Lifton (7) , Jennifer A. Lawson (2) , Meriem Garfa-Traore (1) , Edgar A. Otto (8) , Philippe Bastin (9) , Catherine Caillaud (10) , Josseline Kaplan (1) , Jean-Michel Rozet (1) , Friedhelm Hildebrandt (11, 2)

1 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
2 Division of Nephrology
3 University Clinic, Leipzig
4 Pediatric Nephrology Unit
5 Service de Radiologie et imagerie médicale [CHU Necker]
6 MPIB - Max-Planck-Institut für Biochemie = Max Planck Institute of Biochemistry
7 YSM - Yale School of Medicine [New Haven, Connecticut]
8 University of Michigan [Ann Arbor]
9 Biologie Cellulaire des Trypanosomes
10 Hôpital Necker - Enfants Malades [AP-HP]
11 HHMI - Howard Hughes Medical Institute [Chevy Chase]

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 renoocular 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.

Domaines: Microbiologie et Parasitologie

Isabelle Perrault, Jan Halbritter, Jonathan D. Porath, Xavier Gerard, Daniela A. Braun, et al.. IFT81, encoding an IFT-B core protein, as a very rare cause of a ciliopathy phenotype. Journal of Medical Genetics, 2015, 52 (10), pp.657-665. ⟨10.1136/jmedgenet-2014-102838⟩. ⟨pasteur-01301204⟩