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

 Isabelle Perrault  ;  Jan Halbritter  ;  Jonathan D Porath  ;  Xavier Gérard  ;  Daniela A Braun  ;  Heon Yung Gee  ;  Hanan M Fathy  ;  Sophie Saunier  ;  Valérie Cormier-Daire  ;  Sophie Thomas  ;  Tania Attié-Bitach  ;  Nathalie Boddaert  ;  Michael Taschner  ;  Markus Schueler  ;  Esben Lorentzen  ;  Richard P Lifton  ;  Jennifer A Lawson  ;  Meriem Garfa-Traore  ;  Edgar A Otto  ;  Philippe Bastin  ;  Catherine Caillaud  ;  Josseline Kaplan  ;  Jean-Michel Rozet  ;  Friedhelm Hildebrandt 
 JOURNAL OF MEDICAL GENETICS, Vol.52(10) : 657-665, 2015 
Journal Title
Issue Date
Cilia/genetics* ; Cilia/pathology* ; Eye/pathology* ; Humans ; Kidney/pathology* ; Muscle Proteins/genetics* ; Mutation ; Sequence Analysis, DNA
Genetics ; Molecular genetics ; Ophthalmology ; Renal Medicine
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.
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1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Gee, Heon Yung(지헌영) ORCID logo https://orcid.org/0000-0002-8741-6177
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