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    Loss of Cajal bodies in motor neurons from patients with novel mutations in VRK1. El-Bazzal Lara,Rihan Khalil,Bernard-Marissal Nathalie,Castro Christel,Chouery-Khoury Eliane,Desvignes Jean-Pierre,Atkinson Alexandre,Bertaux Karine,Koussa Salam,Lévy Nicolas,Bartoli Marc,Mégarbané André,Jabbour Rosette,Delague Valérie Human molecular genetics 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'. 10.1093/hmg/ddz060
    Motor neuron diseases caused by a novel VRK1 variant - A genotype/phenotype study. Sedghi Maryam,Moslemi Ali-Reza,Olive Montse,Etemadifar Masoud,Ansari Behnaz,Nasiri Jafar,Emrahi Leila,Mianesaz Hamid-Reza,Laing Nigel G,Tajsharghi Homa Annals of clinical and translational neurology BACKGROUND:Motor neuron disorders involving upper and lower neurons are a genetically and clinically heterogenous group of rare neuromuscular disorders with overlap among spinal muscular atrophies (SMAs) and amyotrophic lateral sclerosis (ALS). Classical SMA caused by recessive mutations in SMN1 is one of the most common genetic causes of mortality in infants. It is characterized by degeneration of anterior horn cells in the spinal cord, leading to progressive muscle weakness and atrophy. Non-SMN1-related spinal muscular atrophies are caused by variants in a number of genes, including VRK1, encoding the vaccinia-related kinase 1 (VRK1). VRK1 variants have been segregated with motor neuron diseases including SMA phenotypes or hereditary complex motor and sensory axonal neuropathy (HMSN), with or without pontocerebellar hypoplasia or microcephaly. RESULTS:Here, we report an association of a novel homozygous splice variant in VRK1 (c.1159 + 1G>A) with childhood-onset SMA or juvenile lower motor disease with brisk tendon reflexes without pontocerebellar hypoplasia and normal intellectual ability in a family with five affected individuals. We show that the VRK1 splice variant in patients causes decreased splicing efficiency and a mRNA frameshift that escapes the nonsense-mediated decay machinery and results in a premature termination codon. CONCLUSIONS:Our findings unveil the impact of the variant on the VRK1 transcript and further support the implication of VRK1 in the pathogenesis of lower motor neuron diseases. 10.1002/acn3.50912