Compound heterozygous mutations in RIPPLY2 associated with vertebral segmentation defects

McInerney-Leo, A.M., Sparrow, D.B., Harris, J.E., Gardiner, B.B., Marshall, M.S., O'Reilly, V.C., Shi, H., Brown, M.A., Leo, P.J., Zankl, A., Dunwoodie, S.L., & Duncan, E.L. (2015) Compound heterozygous mutations in RIPPLY2 associated with vertebral segmentation defects. Human Molecular Genetics, 24(5), pp. 1234-1242.

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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. © The Author 2014.

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ID Code: 94185
Item Type: Journal Article
Refereed: Yes
Additional Information: Cited By :1
Export Date: 14 March 2016
Correspondence Address: Duncan, E.L.; Department of Endocrinology, Royal Brisbane and Women's Hospital, Butterfield Road, Australia
Chemicals/CAS: Basic Helix-Loop-Helix Transcription Factors; Codon, Nonsense; Mesp2 protein, mouse; Mutant Proteins; Repressor Proteins; Ripply2 protein, mouse; Tbx6 protein, mouse; Transcription Factors
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Keywords: mutant protein, RIPPLY2 protein, unclassified drug, basic helix loop helix transcription factor, Mesp2 protein, mouse, repressor protein, Ripply2 protein, mouse, stop codon, Tbx6 protein, mouse, transcription factor, animal experiment, Article, autosomal dominant inheritance, consensus sequence, controlled study, defense mechanism, female, gene frequency, gene interaction, gene mutation, gene sequence, genetic association, human, male, molecular cloning, mouse, nonhuman, priority journal, protein protein interaction, segmentation defect of the vertebrae, signal transduction, spine disease, animal, bone dysplasia, C57BL mouse, cell culture, disease model, exome, exon, genetics, heterozygote, high throughput sequencing, knockout mouse, metabolism, mutation, nucleotide sequence, pathology, pedigree, quantitative trait, RNA splicing, somite, spine, Vertebrata, Animals, Basic Helix-Loop-Helix Transcription Factors, Bone Diseases, Developmental, Cells, Cultured, Codon, Nonsense, Disease Models, Animal, DNA Mutational Analysis, Exons, High-Throughput Nucleotide Sequencing, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutant Proteins, Quantitative Trait, Heritable, Repressor Proteins, Somites, Transcription Factors
DOI: 10.1093/hmg/ddu534
ISSN: 0964-6906
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2015 Oxford University Press
Deposited On: 30 Mar 2016 05:50
Last Modified: 30 Mar 2016 22:00

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