The CLP1 p.R140H mutation does not destabilize the protein, but substantially impairs kinase activity, alters the nuclear localization, reduces the affinity for TSEN proteins affecting tRNA endonuclease activity, and when expressed in Clp1 mutant zebrafish, fails to rescue in vivo phenotypes. In an accompanying manuscript in this issue of Cell (Karaca et al., 2014), show similar biochemical findings in addition to evidence of microcephaly in Clp1-kinase dead mice. Together, our findings support a mechanism by which the patient mutation impacts several of the known functions of CLP1.
