Short-rib polydactyly and Jeune Syndromes are caused by mutations in WDR60

McInerney-Leo, Aideen M., Schmidts, Miriam, Cortés, Claudio R., Leo, Paul J., Gener, Blanca, Courtney, Andrew D., Gardiner, Brooke, Harris, Jessica A., Lu, Yeping, Marshall, Mhairi, Scrambler, Peter J., Beales, Philip L., Brown, Matthew A., Zankl, Andreas, Mitchison, Hannah M., Duncan, Emma L., Wicking, Carol and UK10K Consortium (2013) Short-rib polydactyly and Jeune Syndromes are caused by mutations in WDR60. American Journal of Human Genetics, 93 3: 515-523. doi:10.1016/j.ajhg.2013.06.022

Author McInerney-Leo, Aideen M.
Schmidts, Miriam
Cortés, Claudio R.
Leo, Paul J.
Gener, Blanca
Courtney, Andrew D.
Gardiner, Brooke
Harris, Jessica A.
Lu, Yeping
Marshall, Mhairi
Scrambler, Peter J.
Beales, Philip L.
Brown, Matthew A.
Zankl, Andreas
Mitchison, Hannah M.
Duncan, Emma L.
Wicking, Carol
UK10K Consortium
Total Author Count Override 18
Title Short-rib polydactyly and Jeune Syndromes are caused by mutations in WDR60
Formatted title
Short-rib polydactyly and Jeune Syndromes are caused by mutations in WDR60
Journal name American Journal of Human Genetics   Check publisher's open access policy
ISSN 0002-9297
Publication date 2013-09-05
Sub-type Article (original research)
DOI 10.1016/j.ajhg.2013.06.022
Open Access Status
Volume 93
Issue 3
Start page 515
End page 523
Total pages 9
Place of publication Cambridge, MA, United States
Publisher Cell Press
Collection year 2014
Language eng
Formatted 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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

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Created: Thu, 31 Oct 2013, 15:32:55 EST by Susan Allen on behalf of UQ Diamantina Institute