KCNJ2 as a candidate gene for Familial Pierre Robin Sequence

Pierre Robin Sequence (PRS) a developmental disorder characterized by cleft palate, very small chin and displaced tongue leading to chronic respiratory and feeding problems in neonates. To date no candidate gene has been reported for isolated PRS. We report identification of a role for KCNJ2 (potassium inward rectifying channel) in isolated PRS. Objectives: To determine the potential of KCNJ2 as a candidate gene for isolated familial PRS. Methods: KCNJ2 was identified though characterisation of the translocation breakpoints in a 3-generation family with isolated PRS and a (2;17) translocation. We analyzed KCNJ2 expression levels in four families affected with isolated PRS and explored the function and spatiotemporal expression of KCNJ2 during orofacial development in mice. Results: Expression of KCNJ2 was significantly lower in PRS affected individuals compared to the controls. There were no changes in expression levels of SOX9 between the PRS and control individuals. Cycloheximide stabilized lymphoblasts from affected PRS individuals showed an improvement in expression levels of KCNJ2 suggesting that the RNA was being degraded, possibly as a result of nonsense mediated decay. In embryonic mice KCNJ2 is expressed in the tongue muscle precursors at e10.5 and was found to be restricted to the tongue muscles at e13.5. Conclusion: This is the first report providing supporting evidence for a potential candidate gene for isolated PRS on chromosome 17q24.1. In addition these findings provide support for the hypothesis that there is a neuromuscular basis to isolated PRS. We suggest the KCNJ2 knockout mouse serves as a model for isolated PRS. This work was supported by NHMRC project grant (284522). NJ is supported by an NHMRC Dental Postgraduate Research Scholarship (237162).