This is a response to a letter by Mazzeu (1).
In our recent publication in the Journal of Biological Chemistry, we show that Ryk interacts with Vangl2 to control planar cell polarity (PCP). We further show that Wnt5a signals through Ryk and that the Ryk−/−;Vangl2−/− embryos resemble the Wnt5a−/− embryos (2). We have speculated that RYK might be involved in the etiology of Robinow syndrome, as mutations in human WNT5A cause dominant Robinow syndrome (DRS) and mutations in ROR2, another WNT5A receptor (3), cause recessive Robinow syndrome (RRS) (4, 5). It is encouraging to learn that a role of RYK mutations in DRS is being tested (1), but no mutations yet were found in the sequenced exons of RYK in 24 DRS patients. However, in a larger screening, sequencing all RYK exons and RYK regulatory elements might identify mutations in RYK in DRS patients. It should be noted that even defective WNT5A signaling is a major cause of DRS, mutations in one particular WNT5A signaling component may not be common in the DRS patients. For instance, WNT5A mutations were found in only two DRS cases (3).
We have previously shown that Ror2 regulates Wnt5a signaling (6). As the Ror2−/− embryos show more severe phenotypes and resemble the Wnt5a−/− embryos more than the Ryk−/− embryos, it is likely that mutations in RYK cause RRS too. It is also possible that mutations in RYK may result in milder disease phenotypes that are difficult to identify. Screening for RYK mutations in RRS patients will help to clarify these possibilities.
References
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