Ciliopathies with skeletal anomalies and renal insufficiency due to mutations in the IFT-A gene WDR19.
A subset of ciliopathies, including Sensenbrenner, Jeune, and short-rib polydactyly syndromes are characterized by skeletal anomalies accompanied by multiorgan defects such as chronic renal failure and retinitis pigmentosa. Through exome sequencing we identified compound heterozygous mutations in WDR19 in a Norwegian family with Sensenbrenner syndrome. In a Dutch family with the clinically overlapping Jeune syndrome, a homozygous missense mutation in the same gene was found. Both families displayed a nephronophthisis-like nephropathy. Independently, we also identified compound heterozygous WDR19 mutations by exome sequencing in a Moroccan family with isolated nephronophthisis. WDR19 encodes IFT144, a member of the intraflagellar transport (IFT) complex A that drives retrograde ciliary transport. We show that IFT144 is absent from the cilia of fibroblasts from one of the Sensenbrenner patients and that ciliary abundance and morphology is perturbed, demonstrating the ciliary pathogenesis. Our results suggest that isolated nephronophthisis, Jeune, and Sensenbrenner syndromes are clinically overlapping disorders that can result from a similar molecular cause.
Department of Ophthalmology, Haukeland University Hospital, N-5021 Bergen, Norway.
Cecilie
C
Bredrup
Sophie
S
Saunier
Machteld M
MM
Oud
Torunn
T
Fiskerstrand
Alexander
A
Hoischen
Damien
D
Brackman
Sabine M
SM
Leh
Marit
M
Midtbø
Emilie
E
Filhol
Christine
C
Bole-Feysot
Patrick
P
Nitschké
Christian
C
Gilissen
Olav H
OH
Haugen
Jan-Stephan F
JS
Sanders
Irene
I
Stolte-Dijkstra
Dorus A
DA
Mans
Eric J
EJ
Steenbergen
Ben C J
BC
Hamel
Marie
M
Matignon
Rolph
R
Pfundt
Cécile
C
Jeanpierre
Helge
H
Boman
Eyvind
E
Rødahl
Joris A
JA
Veltman
Per M
PM
Knappskog
Nine V A M
NV
Knoers
Ronald
R
Roepman
Heleen H
HH
Arts
D000293:Adolescent; D000328:Adult; D002648:Child; D002923:Cilia / Q000235:genetics / Q000473:pathology; D019465:Craniofacial Abnormalities / Q000235:genetics; D003598:Cytoskeletal Proteins; D004476:Ectodermal Dysplasia / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005407:Flagella / Q000235:genetics / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008969:Molecular Sequence Data; D009018:Morocco; D020125:Mutation, Missense; D009426:Netherlands; D009664:Norway; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D007690:Polycystic Kidney Diseases / Q000151:congenital / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D012779:Short Rib-Polydactyly Syndrome / Q000235:genetics*; D013896:Thoracic Diseases / Q000235:genetics*; D055815:Young Adult
D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C486869:WDR19 protein, human