UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Short-Rib Polydactyly and Jeune Syndromes Are Caused by Mutations in WDR60.

McInerney-Leo, AM; Schmidts, M; Cortés, CR; Leo, PJ; Gener, B; Courtney, AD; Gardiner, B; ... Wicking, C; + view all (2013) Short-Rib Polydactyly and Jeune Syndromes Are Caused by Mutations in WDR60. Am J Hum Genet , 93 (3) pp. 515-523. 10.1016/j.ajhg.2013.06.022. Green open access

[img]
Preview
Text
1-s2.0-S0002929713002917-main.pdf

Download (1MB) | Preview

Abstract

Short-rib polydactyly syndromes (SRPS I-V) are a group of lethal congenital disorders characterized by shortening of the ribs and long bones, polydactyly, and a range of extraskeletal phenotypes. A number of other disorders in this grouping, including Jeune and Ellis-van Creveld syndromes, have an overlapping but generally milder phenotype. Collectively, these short-rib dysplasias (with or without polydactyly) share a common underlying defect in primary cilium function and form a subset of the ciliopathy disease spectrum. By using whole-exome capture and massive parallel sequencing of DNA from an affected Australian individual with SRPS type III, we detected two novel heterozygous mutations in WDR60, a relatively uncharacterized gene. These mutations segregated appropriately in the unaffected parents and another affected family member, confirming compound heterozygosity, and both were predicted to have a damaging effect on the protein. Analysis of an additional 54 skeletal ciliopathy exomes identified compound heterozygous mutations in WDR60 in a Spanish individual with Jeune syndrome of relatively mild presentation. Of note, these two families share one novel WDR60 missense mutation, although haplotype analysis suggested no shared ancestry. We further show that WDR60 localizes at the base of the primary cilium in wild-type human chondrocytes, and analysis of fibroblasts from affected individuals revealed a defect in ciliogenesis and aberrant accumulation of the GLI2 transcription factor at the centrosome or basal body in the absence of an obvious axoneme. These findings show that WDR60 mutations can cause skeletal ciliopathies and suggest a role for WDR60 in ciliogenesis.

Type: Article
Title: Short-Rib Polydactyly and Jeune Syndromes Are Caused by Mutations in WDR60.
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.ajhg.2013.06.022
Publisher version: http://dx.doi.org/10.1016/j.ajhg.2013.06.022
Additional information: This is an open access article as indicated via the Publisher Version link above.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/1400961
Downloads since deposit
78Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item