Alternative titles; symbols
HGNC Approved Gene Symbol: RIPPLY2
Cytogenetic location: 6q14.2 Genomic coordinates (GRCh38) : 6:83,853,229-83,857,515 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q14.2 | ?Spondylocostal dysostosis 6 | 616566 | Autosomal recessive | 3 |
By searching for sequences similar to that of zebrafish Ripply1 (300575), Kawamura et al. (2005) identified human RIPPLY2. The deduced 128-amino acid protein contains a WRPW tetrapeptide near its N terminus and a conserved domain of about 50 amino acids found in other Ripply proteins. In zebrafish embryos, Ripply2 was expressed in the paraxial mesoderm and was subsequently confined to the presomitic mesoderm.
Chan et al. (2007) found that Ripply2 was expressed in presomitic mesoderm in day-9.0 and -11.5 mouse embryos, concomitant with somite formation.
Gross (2015) mapped the RIPPLY2 gene to chromosome 6q14.2 based on an alignment of the RIPPLY2 sequence (GenBank BC130460) with the genomic sequence (GRCh38).
Spondylocostal Dysostosis 6
In 2 brothers with segmentation defects of the vertebrae (SCDO6; 616566), McInerney-Leo et al. (2015) identified compound heterozygosity for a nonsense mutation (R80X; 609891.0001) and a splice site mutation (c.240-4T-G; 609891.0002) in the RIPPLY2 gene that segregated with disease in the family. Analysis of in-house sequencing data from 991 individuals with unrelated disorders did not detect any with compound heterozygous variants in RIPPLY2. McInerney-Leo et al. (2015) noted that a rare variant (minor allele frequency less than 0.01) was detected in 1 of 1,982 alleles, thus the probability of 2 rare variants occurring by chance would be 2.54 x 10(-7), and the probability of both segregating appropriately within the family would be even lower. In addition, functional analysis demonstrated significantly reduced transcriptional repression activity with the R80X mutant compared to wildtype RIPPLY2. The authors stated that they were unable to demonstrate a functional consequence of the c.240-4T-G mutation because of its location in the terminal exon splice site consensus sequence and the likely restriction of RIPPLY2 expression to embryogenesis.
Associations Pending Confirmation
For discussion of a possible association between mutation in the RIPPLY2 gene and Klippel-Feil syndrome (see 214300), see 609891.0003.
Chan et al. (2007) obtained Ripply2 -/- mice at the expected mendelian ratio, but all died soon after birth without breathing. At embryonic day 18, Ripply2 -/- mice had shortened tails, truncated body axis, and defects in vertebral bodies, intervertebral discs, and neural arches. Pedicles of neural arches were fused or missing. Ribs in Ripply2 -/- mice were fused and bifurcated and showed loss of symmetry about the left-right axis, and they were reduced in number. Skull and limbs appeared normal. Skeletal malformations observed in Ripply2 -/- mice appeared to be due to defective somite segmentation. Expression of Notch2 (600275) and Uncx4.1 was disrupted in Ripply2 -/- mice. Chan et al. (2007) concluded that RIPPLY2 is involved in somite segmentation and establishment of rostrocaudal polarity.
McInerney-Leo et al. (2015) analyzed the skeletal development of Ripply2 +/- mice at embryonic day 14.5 and observed that 1 of 33 embryos exhibited a slight vertebral defect (unilateral interruption of the lamina of S1), whereas all 40 wildtype embryos were normal. The authors concluded that loss of 1 Ripply1 allele did not cause vertebral defects with significant penetrance. Analysis of similar embryos exposed to short-term mild hypoxia during pregnancy revealed that 4 of 30 heterozygous embryos had mild defects, each involving a single vertebra, compared to 1 of 35 wildtype embryos; thus, hypoxia did not significantly increase the penetrance or severity of vertebral defects in Ripply2 +/- embryos.
In 2 brothers (family SKDP-10) with segmentation defects of the vertebrae (SCDO6; 616566), McInerney-Leo et al. (2015) identified compound heterozygosity for 2 mutations in the RIPPLY2 gene: a c.238A-T transversion (c.238A-T, NM_001009994) in exon 3 of the RIPPLY2 gene, resulting in an arg80-to-ter (R80X) substitution, and a c.240-4T-G transversion in intron 3 (609891.0002) at the 5-prime predicted splice acceptor site for exon 4. Their unaffected parents were each heterozygous for 1 of the mutations, as was the unaffected maternal grandmother, whereas their unaffected sister did not carry either of the mutations. McInerney-Leo et al. (2015) noted that the R80X mutation causes loss of 49 C-terminal amino acids, including the highly conserved Ripply homology domain required for direct protein-protein interaction with the T-box domain of TBX6 (602427). Functional analysis in transiently transfected C2C12 mouse myoblasts demonstrated significantly reduced transcriptional repression activity with the R80X mutant compared to wildtype RIPPLY2. The authors stated that they were unable to demonstrate a functional consequence of the c.240-4T-G mutation because of its location in the terminal exon splice site consensus sequence and the likely restriction of RIPPLY2 expression to embryogenesis.
For discussion of the c.240-4T-G transversion (c.240-4T-G, NM_001009994) in intron 3 of the RIPPLY2 gene that was found in compound heterozygous state in 2 brothers with spondylocostal dysostosis-6 (SCDO6; 616566) by McInerney-Leo et al. (2015), see 609891.0001.
This variant is classified as a variant of unknown significance because its contribution to Klippel-Feil syndrome (KFS; see 214300) has not been confirmed.
In a 13.75-year-old Turkish boy with features of Klippel-Feil syndrome and situs inversus totalis, who was negative for mutation in genes associated with KFS, disorders of primary ciliary dyskinesia, heterotaxy, or segmentation defects of the vertebrae, Karaca et al. (2015) identified homozygosity for a 1-bp deletion (c.299delT, NM_001009994) in the RIPPLY2 gene, causing a frameshift within the conserved segment of the RIPPLY protein domain (Leu100fs). His unaffected first-cousin parents and an unaffected sib were heterozygous for the deletion. The proband had short stature, scoliosis, short neck with decreased mobility, and low posterior hairline, and imaging studies revealed fusion of the cervical vertebrae as well as situs inversus totalis. Other features included upward displacement of the scapula (Sprengel deformity), pectus excavatum of the upper sternum and pectus carinatum of the lower sternum, patent foramen ovale, and solitary kidney.
Chan, T., Kondow, A., Hosoya, A., Hitachi, K., Yukita, A., Okabayashi, K., Nakamura, H., Ozawa, H., Kiyonari, H., Michiue, T., Ito, Y., Asashima, M. Ripply2 is essential for precise somite formation during mouse early development. FEBS Lett. 581: 2691-2696, 2007. [PubMed: 17531978] [Full Text: https://doi.org/10.1016/j.febslet.2007.05.017]
Gross, M. B. Personal Communication. Baltimore, Md. 9/22/2015.
Karaca, E., Yuregir, O. O., Bozdogen, S. T., Aslan, H., Pehlivan, D., Jhangiani, S. N., Akdemir, Z. C., Gambin, T., Bayram, Y., Atik, M. M., Erdin, S., Muzny, D., Gibbs, R. A., Lupski, J. R., The Baylor-Hopkins Center for Mendelian Genomics. Rare variants in the Notch signaling pathway describe a novel type of autosomal recessive Klippel-Feil syndrome. Am. J. Med. Genet. 167A: 2795-2799, 2015. [PubMed: 26238661] [Full Text: https://doi.org/10.1002/ajmg.a.37263]
Kawamura, A., Koshida, S., Hijikata, H., Ohbayashi, A., Kondoh, H., Takada, S. Groucho-associated transcriptional repressor Ripply1 is required for proper transition from the presomitic mesoderm to somites. Dev. Cell 9: 735-744, 2005. [PubMed: 16326386] [Full Text: https://doi.org/10.1016/j.devcel.2005.09.021]
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. Compound heterozygous mutations in RIPPLY2 associated with vertebral segmentation defects. Hum. Molec. Genet. 24: 1234-1242, 2015. [PubMed: 25343988] [Full Text: https://doi.org/10.1093/hmg/ddu534]