Most mutations described in VRK1have been private missense mutations in the large kinase domain (residues 37-275), leading to motor neuron disease without brain involvement. In Ashkenazi Jews there is a founder mutation (VRK1R358X, rs137853063), with a heterozygote carrier frequency of ~ 1/230. This nonsense mutation is associated with a severe phenotype including severe congenital microcephaly and childhood onset SMA.
Recessive inheritance and the increased severity associated with nonsense mutations suggest that the pathophysiology is loss of VRK1 function. VRK1 is normally a nuclear protein, and mutations have been shown to result in its mislocalization in patient cells, leading to Cajal Bodies disassembly and to defects in neurite outgrowth and branching. VRK1 has also been shown to be important for cortical neuronal migration, where it acts upstream of APP (amyloid precursor protein). This role is at least partly independent of VRK1’s kinase activity.
Diagnostic testing is based on sequencing. Currently, this is largely preformed in the context of multi-gene panel testing in patients with neuropathy/motor neuron disease, or by whole exome sequencing in patients with relevant phenotypes.
VRK1