Loss of Cajal bodies in motor neurons from patients with novel mutations in VRK1

Abstract

Distal hereditary motor neuropathies (dHMNs) are a heterogeneous group of diseases, resembling Charcot–Marie–Tooth syndromes, but characterized by an exclusive involvement of the motor part of the peripheral nervous system. Here, we describe two new compound heterozygous mutations in VRK1, the vaccinia-related kinase 1 gene, in two siblings from a Lebanese family, affected with dHMN associated with upper motor neurons (MNs) signs. The mutations lead to severely reduced levels of VRK1 by impairing its stability, and to a shift of nuclear VRK1 to cytoplasm. Depletion of VRK1 from the nucleus alters the dynamics of coilin, a phosphorylation target of VRK1, by reducing its stability through increased proteasomal degradation. In human-induced pluripotent stem cell-derived MNs from patients, we demonstrate that this drop in VRK1 levels leads to Cajal bodies (CBs) disassembly and to defects in neurite outgrowth and branching. Mutations in VRK1 have been previously reported in several neurological diseases affecting lower or both upper and lower MNs. Here, we describe a new phenotype linked to VRK1 mutations, presenting as a classical slowly progressive motor neuropathy, beginning in the second decade of life, with associated upper MN signs. We provide, for the first time, evidence for a role of VRK1 in regulating CB assembly in MNs. The observed MN defects are consistent with a length dependent axonopathy affecting lower and upper MNs, and we propose that diseases due to mutations in VRK1 should be grouped under a unique entity named `VRK1-related motor neuron disease’.

Identification of a homozygous VRK1 mutation in two patients with adult‐onset distal hereditary motor neuropathy

“…The clinical presentation was characterized by an older onset age compared with previously reported VRK1 neuropathy patients, who usually manifest in childhood through early adulthood, but not later than the end of the third decade . No upper motor neuron signs, cognitive impairment, abnormal brain imaging findings, or microcephaly were noted in our patients, in contrast to other reported cases of VRK1 mutations . However, mild sensory symptoms (probably related to small fiber loss) and respiratory insufficiency were present in one.…”

“…Schematic illustration of the VRK1 protein and the mutations identified within it (wide arrow denotes the currently reported mutation) . Protein domains and their positions are shown below…”

“…VRK1 also plays a role in neuronal proliferation and cortical neuron migration . In a human‐induced pluripotent stem model, VRK1 mutation caused disassembly of Cajal bodies and defects in neurite outgrowth and branching …”

“…Mutations in the vaccinia‐related kinase 1 ( VRK1 ) gene cause a wide spectrum of recessive phenotypes with variable age of onset, usually characterized by motor neuropathy, and occasionally also non‐lower motor neuron involvement or structural brain changes. Among these are motor neuron disease (including SMA) in children with or without pontocerebellar hypoplasia, motor and sensory axonal neuropathy plus microcephaly, dHMN and dHMN associated with upper motor neuron signs, early onset amyotrophic lateral sclerosis, and adult‐onset dSMA . In other cases, pontocerebellar hypoplasia with intellectual disability, primary micocephaly or brain abnormalities in the prenatal setting were reported.…”

Examination of the human motor endplate after brachial plexus injury with two‐photon microscopy

“…3,5 Mutations in the vaccinia-related kinase 1 (VRK1) gene cause a wide spectrum of recessive phenotypes with variable age of onset, usually characterized by motor neuropathy, and occasionally also non-lower motor neuron involvement or structural brain changes. Among these are motor neuron disease (including SMA) in children with or without pontocerebellar hypoplasia, [6][7][8][9] motor and sensory axonal neuropathy plus microcephaly, 10 dHMN 11,12 and dHMN associated with upper motor neuron signs, 13 early onset amyotrophic lateral sclerosis, 14 and adult-onset dSMA. 7,15 In other cases, pontocerebellar hypoplasia with intellectual disability, 16 primary micocephaly 17 or brain abnormalities in the prenatal setting 18 were reported.…”