Motor neuron diseases caused by a novel VRK1 variant – A genotype/phenotype study

Abstract

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 nonsensemediated 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.

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.…”

“…The currently identified mutation is located in the first nucleotide of the last (13th) exon of the gene, changing amino acid number 387 of 396 in the protein (Figure ). Of interest, a homozygous splice variant (c.1159 + 1G>A) in the 5′ junction of intron 12 (bordering exon 12), causing decreased splicing efficiency and RNA frameshift, was found in a family with childhood‐onset SMA or juvenlie lower motor disease with hyperreflexia . The differences in the mutation types and positions across the gene may explain the wide clinical spectrum of VRK1 ‐related neuropathies.…”

“…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…”

“…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.…”

New phenotype of DCTN1‐related spectrum: early‐onset dHMN plus congenital foot deformity

“…The depletion of p150 Glued induces severe cell‐cycle block before mitosis, due to the lack of NEBD . Similar phenotypes have also been observed in another cell‐cycle regulation gene, VRK1 (vaccinia‐related kinase 1), including dHMN, ALS, and spinal muscular atrophy (SMA) …”