IFT81, encoding an IFT-B core protein, as a very rare cause of a ciliopathy phenotype.
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.
Laboratory of Genetics in Ophthalmology, INSERM UMR 1163, Paris, France Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
Isabelle
I
Perrault
Division of Endocrinology and Nephrology, Department of Internal Medicine, University Clinic Leipzig, Leipzig, Germany Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Jan
J
Halbritter
Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Jonathan D
JD
Porath
Laboratory of Genetics in Ophthalmology, INSERM UMR 1163, Paris, France Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
Xavier
X
Gérard
Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Daniela A
DA
Braun
Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Heon Yung
HY
Gee
Pediatric Nephrology Unit, University of Alexandria, Alexandria, Egypt.
Hanan M
HM
Fathy
Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France INSERM UMR 1163, Molecular bases of hereditary kidney diseases, Nephronophthisis and Hypodysplasia, Paris, France.
Sophie
S
Saunier
Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France INSERM UMR 1163, Molecular and Physiopathological bases of osteochondrodysplasia, Paris, France.
Valérie
V
Cormier-Daire
Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France INSERM UMR 1163, Embryology and genetics of human malformation, Paris, France.
Sophie
S
Thomas
Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France INSERM UMR 1163, Embryology and genetics of human malformation, Paris, France.
Tania
T
Attié-Bitach
Department of Pediatric Radiology, Hôpital Necker-Enfants Malades, APHP, Descartes University, Paris, France.
Nathalie
N
Boddaert
Department of Structural Cell Biology, Max Planck Institute of Biochemistry, Martinsried, Germany.
Michael
M
Taschner
Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Markus
M
Schueler
Department of Structural Cell Biology, Max Planck Institute of Biochemistry, Martinsried, Germany.
Esben
E
Lorentzen
Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, USA.
Richard P
RP
Lifton
Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Jennifer A
JA
Lawson
Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France INSERM UMR 1163, Cell imaging platform, Paris, France.
Meriem
M
Garfa-Traore
Departments of Pediatrics, University of Michigan, Ann Arbor, USA.
Edgar A
EA
Otto
Trypanosome Cell Biology Unit, Institut Pasteur and CNRS, URA 2581, Paris, France.
Philippe
P
Bastin
Biochemistry Department, Necker Hospital, Paris, France.
Catherine
C
Caillaud
Laboratory of Genetics in Ophthalmology, INSERM UMR 1163, Paris, France Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
Josseline
J
Kaplan
Laboratory of Genetics in Ophthalmology, INSERM UMR 1163, Paris, France Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
Jean-Michel
JM
Rozet
Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
Friedhelm
F
Hildebrandt
D002923:Cilia / Q000235:genetics* / Q000473:pathology*; D005123:Eye / Q000473:pathology*; D006801:Humans; D007668:Kidney / Q000473:pathology*; D009124:Muscle Proteins / Q000235:genetics*; D009154:Mutation; D017422:Sequence Analysis, DNA
C481012:IFT81 protein, human; D009124:Muscle Proteins
Genetics; Molecular genetics; Ophthalmology; Renal Medicine