| 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
|
|
WOS Category
|
GENETICS & HEREDITY
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
| Resource |
| Mice |
RBRC02227 |
