1. Ciliopathies with skeletal anomalies and renal insufficiency due to mutations in the IFT-A gene WDR19.
- Author
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Bredrup C, Saunier S, Oud MM, Fiskerstrand T, Hoischen A, Brackman D, Leh SM, Midtbø M, Filhol E, Bole-Feysot C, Nitschké P, Gilissen C, Haugen OH, Sanders JS, Stolte-Dijkstra I, Mans DA, Steenbergen EJ, Hamel BC, Matignon M, Pfundt R, Jeanpierre C, Boman H, Rødahl E, Veltman JA, Knappskog PM, Knoers NV, Roepman R, and Arts HH
- Subjects
- Adolescent, Adult, Child, Craniofacial Abnormalities genetics, Cytoskeletal Proteins, Exome genetics, Female, Fibroblasts metabolism, Flagella genetics, Flagella pathology, Humans, Intracellular Signaling Peptides and Proteins, Male, Molecular Sequence Data, Morocco, Netherlands, Norway, Oligonucleotide Array Sequence Analysis, Pedigree, Polycystic Kidney Diseases congenital, Young Adult, Cilia genetics, Cilia pathology, Ectodermal Dysplasia genetics, Mutation, Missense, Polycystic Kidney Diseases genetics, Proteins genetics, Short Rib-Polydactyly Syndrome genetics, Thoracic Diseases genetics
- Abstract
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., (Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2011
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