RRC ID 32640
Author McInerney-Leo AM, Sparrow DB, Harris JE, Gardiner BB, Marshall MS, O'Reilly VC, Shi H, Brown MA, Leo PJ, Zankl A, Dunwoodie SL, Duncan EL.
Title Compound heterozygous mutations in RIPPLY2 associated with vertebral segmentation defects.
Journal Hum Mol Genet
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.
Volume 24(5)
Pages 1234-42
Published 2015-3-1
DOI 10.1093/hmg/ddu534
PII ddu534
PMID 25343988
MeSH Animals Basic Helix-Loop-Helix Transcription Factors / genetics Basic Helix-Loop-Helix Transcription Factors / metabolism Bone Diseases, Developmental / genetics* Cells, Cultured Codon, Nonsense DNA Mutational Analysis Disease Models, Animal Exome Exons Female Gene Frequency Heterozygote* High-Throughput Nucleotide Sequencing Male Mice Mice, Inbred C57BL Mice, Knockout Mutant Proteins / genetics Mutation* Pedigree Quantitative Trait, Heritable RNA Splicing Repressor Proteins / genetics* Repressor Proteins / metabolism Somites / metabolism Spine / pathology T-Box Domain Proteins Transcription Factors / genetics Transcription Factors / metabolism
IF 5.101
Times Cited 20
Mice RBRC02227