Compound heterozygous mutations in RIPPLY2 associated with vertebral segmentation defects

McInerney-Leo, Aideen, Sparrow, Duncan B., Harris, Jessica, Gardiner, Brooke, Marshall, Mhairi, O'Reilly, Victoria C., Shi, Hongjun, Brown, Matthew A., Leo, Paul, Zankl, Andreas, Dunwoodie, Sally L. and Duncan, Emma (2015) Compound heterozygous mutations in RIPPLY2 associated with vertebral segmentation defects. Human Molecular Genetics, 24 5: 1234-1242. doi:10.1093/hmg/ddu534

Author McInerney-Leo, Aideen
Sparrow, Duncan B.
Harris, Jessica
Gardiner, Brooke
Marshall, Mhairi
O'Reilly, Victoria C.
Shi, Hongjun
Brown, Matthew A.
Leo, Paul
Zankl, Andreas
Dunwoodie, Sally L.
Duncan, Emma
Title Compound heterozygous mutations in RIPPLY2 associated with vertebral segmentation defects
Journal name Human Molecular Genetics   Check publisher's open access policy
ISSN 1460-2083
Publication date 2015-03-01
Year available 2014
Sub-type Article (original research)
DOI 10.1093/hmg/ddu534
Open Access Status DOI
Volume 24
Issue 5
Start page 1234
End page 1242
Total pages 9
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Collection year 2015
Language eng
Abstract Segmentation defects of the vertebrae (SDV) are caused by aberrant somite formation during embryogenesis and result in irregular formation of the vertebrae and ribs. The Notch signal transduction pathway plays a critical role in somite formation and patterning in model vertebrates. In humans, mutations in several genes involved in the Notch pathway are associated with SDV, with both autosomal recessive (MESP2, DLL3, LFNG, HES7) and autosomal dominant (TBX6) inheritance. However, many individuals with SDV do not carry mutations in these genes. Using whole-exome capture and massive parallel sequencing, we identified compound heterozygous mutations in RIPPLY2 in two brothers with multiple regional SDV, with appropriate familial segregation. One novel mutation (c.A238T:p.Arg80*) introduces a premature stop codon. In transiently transfected C2C12 mouse myoblasts, the RIPPLY2 mutant protein demonstrated impaired transcriptional repression activity compared with wild-type RIPPLY2 despite similar levels of expression. The other mutation (c.240-4T>G), with minor allele frequency <0.002, lies in the highly conserved splice site consensus sequence 5′ to the terminal exon. Ripply2 has a well-established role in somitogenesis and vertebral column formation, interacting at both gene and protein levels with SDV-associated Mesp2 and Tbx6. We conclude that compound heterozygous mutations in RIPPLY2 are associated with SDV, a new gene for this condition.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online ahead of print 24 Oct 2014

Document type: Journal Article
Sub-type: Article (original research)
Collections: UQ Centre for Clinical Research Publications
Official 2015 Collection
UQ Diamantina Institute Publications
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Citation counts: TR Web of Science Citation Count  Cited 1 times in Thomson Reuters Web of Science Article | Citations
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Created: Fri, 13 Mar 2015, 16:21:06 EST by Kylie Hengst on behalf of UQ Diamantina Institute