A novel <i>VRK1</i> mutation associated with recessive distal hereditary motor neuropathy

Feng, Shuyan; Li, Liuyi; Feng, Shuman; Zou, Zhang‐Yu

doi:10.1002/acn3.701

Cited by 17 publications

(17 citation statements)

References 13 publications

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“…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.…”

Section: Discussioncontrasting

confidence: 52%

“…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…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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Background Adult‐onset hereditary motor neuropathies are caused by mutations in multiple genes. Mutations within the vaccinia‐related kinase 1 (VRK1) gene were associated with a wide spectrum of recessively inherited motor neuropathies, characterized by childhood to early adulthood age of onset and an occasionally non‐lower motor neuron involvement. Methods We describe two patients with adult‐onset (aged 48 and 40 years) length‐dependent motor neuropathy from unrelated consanguineous families of Moroccan Jewish descent. One also demonstrated mild nocturnal respiratory difficulty and sensory symptoms. Whole‐exome sequencing (WES) was performed. Results A homozygous mutation in VRK1 (c.1160G>A (p.Arg387His)), shared by both patients, was identified. This rare mutation segregated with the disease in the two families, and was absent in 120 controls of Jewish Moroccan origin. Conclusions Our findings support VRK1 as a causative gene for adult‐onset distal hereditary motor neuropathy, and indicate its relevance for evaluation of individuals with similar motor impairment.

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Section: Discussioncontrasting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…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) …”

Section: Discussionmentioning

confidence: 52%

“…36 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). 38,39 P150 Glued is essential in maintaining microtubule stability by acting as an anticatastrophe factor in neuronal cultures. 40 However, we did not observe any substantial loss of axons in peripheral nerve biopsy for Patient 1.…”

Section: Discussionmentioning

confidence: 99%

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

Tian

Liu

Zhou

et al. 2020

Ann Clin Transl Neurol

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Objective To describe the clinical and genetic features of two patients with different phenotypes due to various Dynactin 1 (DCTN1) gene mutations and further explore the phenotype–genotype relationship. Methods Patient 1 is a 23‐year‐old man with congenital foot deformity and life‐long distal muscle weakness and atrophy. Patient 2 is a 48‐year‐old woman with adult‐onset progressive weakness, lower limbs atrophy, and pyramid bundle signs. Electrophysiology test showed normal nerve conduction velocity of both patients and neurogenic changes in needle electromyography. Open sural nerve biopsy for Patient 1 showed slight loss of myelinated nerve fibers. Both patients were performed with whole‐exome sequencing followed by functional study of identified variants. Results Two mutations in DCTN1 gene were identified in Patient 1 (c.626dupC) and Patient 2 (c.3823C>T), respectively. In vitro, the wild type mostly located in cytoplasm and colocalized with α‐tubulin. However, c.626dupC tended to be trapped into nuclear and the c.3823C>T formed cytoplasmic aggregates, both losing colocalization with α‐tubulin. Western blotting showed a truncated mutant with less molecular weight of c.626dupC was expressed. Interpretation We identify two novel DCTN1 mutations causing different phenotypes: (1) early‐onset distal hereditary motor neuropathy plus congenital foot malformation and (2) amyotrophic lateral sclerosis, respectively. We provide the initial evidence that foot developmental deficiency probably arises from subcellular localizing abnormality of Dynactin 1, revealing DCTN1‐related spectrum is still expanding.

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

Sedghi

Moslemi

Olivé

et al. 2019

Ann Clin Transl Neurol

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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.

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A novel VRK1 mutation associated with recessive distal hereditary motor neuropathy

Cited by 17 publications

References 13 publications

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

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

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

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

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