Novel motor phenotypes in patients with VRK1 mutations without pontocerebellar hypoplasia.
OBJECTIVE
To describe the phenotypes in 2 families with vaccinia-related kinase 1 (VRK1) mutations including one novel VRK1 mutation.


METHODS
VRK1 mutations were found by whole exome sequencing in patients presenting with motor neuron disorders.


RESULTS
We identified pathogenic mutations in the VRK1 gene in the affected members of 2 families. In family 1, compound heterozygous mutations were identified in VRK1, c.356A>G; p.H119R, and c.1072C>T; p.R358*, in 2 siblings with adult onset distal spinal muscular atrophy (SMA). In family 2, a novel VRK1 mutation, c.403G>A; p.G135R and c.583T>G; p.L195V, were identified in a child with motor neuron disease.


CONCLUSIONS
VRK1 mutations can produce adult-onset SMA and motor neuron disease in children without pontocerebellar hypoplasia.
From the Molecular Medicine Laboratory (M.S., G.N.), Neurology Department (J.L.), ANZAC Research Institute (G.N.), and NSW Health Pathology (G.N.), Concord Hospital (S.R.); Departments of Neurology (H.T., H.S., M.F.) and Genetics (T.R.), Sydney Children's Hospital; Discipline of Paediatrics, School of Women's and Children's Health, UNSW Medicine (H.T., H.S., M.F.), and St Vincent's Clinical School (T.R.), The University of New South Wales, Sydney; Kolling Institute (Y.Z.), Royal North Shore Hospital, Newcastle GOLD Service, Hunter Genetics, Waratah; SEALS Haematology and Genetics Laboratory (M.B.), Prince of Wales Hospital, Sydney; Kinghorn Centre for Clinical Genomics (T.R.); and Sydney Medical School (G.N.), University of Sydney, Australia.
Marion
M
Stoll
From the Molecular Medicine Laboratory (M.S., G.N.), Neurology Department (J.L.), ANZAC Research Institute (G.N.), and NSW Health Pathology (G.N.), Concord Hospital (S.R.); Departments of Neurology (H.T., H.S., M.F.) and Genetics (T.R.), Sydney Children's Hospital; Discipline of Paediatrics, School of Women's and Children's Health, UNSW Medicine (H.T., H.S., M.F.), and St Vincent's Clinical School (T.R.), The University of New South Wales, Sydney; Kolling Institute (Y.Z.), Royal North Shore Hospital, Newcastle GOLD Service, Hunter Genetics, Waratah; SEALS Haematology and Genetics Laboratory (M.B.), Prince of Wales Hospital, Sydney; Kinghorn Centre for Clinical Genomics (T.R.); and Sydney Medical School (G.N.), University of Sydney, Australia.
Hooiling
H
Teoh
From the Molecular Medicine Laboratory (M.S., G.N.), Neurology Department (J.L.), ANZAC Research Institute (G.N.), and NSW Health Pathology (G.N.), Concord Hospital (S.R.); Departments of Neurology (H.T., H.S., M.F.) and Genetics (T.R.), Sydney Children's Hospital; Discipline of Paediatrics, School of Women's and Children's Health, UNSW Medicine (H.T., H.S., M.F.), and St Vincent's Clinical School (T.R.), The University of New South Wales, Sydney; Kolling Institute (Y.Z.), Royal North Shore Hospital, Newcastle GOLD Service, Hunter Genetics, Waratah; SEALS Haematology and Genetics Laboratory (M.B.), Prince of Wales Hospital, Sydney; Kinghorn Centre for Clinical Genomics (T.R.); and Sydney Medical School (G.N.), University of Sydney, Australia.
James
J
Lee
From the Molecular Medicine Laboratory (M.S., G.N.), Neurology Department (J.L.), ANZAC Research Institute (G.N.), and NSW Health Pathology (G.N.), Concord Hospital (S.R.); Departments of Neurology (H.T., H.S., M.F.) and Genetics (T.R.), Sydney Children's Hospital; Discipline of Paediatrics, School of Women's and Children's Health, UNSW Medicine (H.T., H.S., M.F.), and St Vincent's Clinical School (T.R.), The University of New South Wales, Sydney; Kolling Institute (Y.Z.), Royal North Shore Hospital, Newcastle GOLD Service, Hunter Genetics, Waratah; SEALS Haematology and Genetics Laboratory (M.B.), Prince of Wales Hospital, Sydney; Kinghorn Centre for Clinical Genomics (T.R.); and Sydney Medical School (G.N.), University of Sydney, Australia.
Stephen
S
Reddel
From the Molecular Medicine Laboratory (M.S., G.N.), Neurology Department (J.L.), ANZAC Research Institute (G.N.), and NSW Health Pathology (G.N.), Concord Hospital (S.R.); Departments of Neurology (H.T., H.S., M.F.) and Genetics (T.R.), Sydney Children's Hospital; Discipline of Paediatrics, School of Women's and Children's Health, UNSW Medicine (H.T., H.S., M.F.), and St Vincent's Clinical School (T.R.), The University of New South Wales, Sydney; Kolling Institute (Y.Z.), Royal North Shore Hospital, Newcastle GOLD Service, Hunter Genetics, Waratah; SEALS Haematology and Genetics Laboratory (M.B.), Prince of Wales Hospital, Sydney; Kinghorn Centre for Clinical Genomics (T.R.); and Sydney Medical School (G.N.), University of Sydney, Australia.
Ying
Y
Zhu
From the Molecular Medicine Laboratory (M.S., G.N.), Neurology Department (J.L.), ANZAC Research Institute (G.N.), and NSW Health Pathology (G.N.), Concord Hospital (S.R.); Departments of Neurology (H.T., H.S., M.F.) and Genetics (T.R.), Sydney Children's Hospital; Discipline of Paediatrics, School of Women's and Children's Health, UNSW Medicine (H.T., H.S., M.F.), and St Vincent's Clinical School (T.R.), The University of New South Wales, Sydney; Kolling Institute (Y.Z.), Royal North Shore Hospital, Newcastle GOLD Service, Hunter Genetics, Waratah; SEALS Haematology and Genetics Laboratory (M.B.), Prince of Wales Hospital, Sydney; Kinghorn Centre for Clinical Genomics (T.R.); and Sydney Medical School (G.N.), University of Sydney, Australia.
Michael
M
Buckley
From the Molecular Medicine Laboratory (M.S., G.N.), Neurology Department (J.L.), ANZAC Research Institute (G.N.), and NSW Health Pathology (G.N.), Concord Hospital (S.R.); Departments of Neurology (H.T., H.S., M.F.) and Genetics (T.R.), Sydney Children's Hospital; Discipline of Paediatrics, School of Women's and Children's Health, UNSW Medicine (H.T., H.S., M.F.), and St Vincent's Clinical School (T.R.), The University of New South Wales, Sydney; Kolling Institute (Y.Z.), Royal North Shore Hospital, Newcastle GOLD Service, Hunter Genetics, Waratah; SEALS Haematology and Genetics Laboratory (M.B.), Prince of Wales Hospital, Sydney; Kinghorn Centre for Clinical Genomics (T.R.); and Sydney Medical School (G.N.), University of Sydney, Australia.
Hugo
H
Sampaio
From the Molecular Medicine Laboratory (M.S., G.N.), Neurology Department (J.L.), ANZAC Research Institute (G.N.), and NSW Health Pathology (G.N.), Concord Hospital (S.R.); Departments of Neurology (H.T., H.S., M.F.) and Genetics (T.R.), Sydney Children's Hospital; Discipline of Paediatrics, School of Women's and Children's Health, UNSW Medicine (H.T., H.S., M.F.), and St Vincent's Clinical School (T.R.), The University of New South Wales, Sydney; Kolling Institute (Y.Z.), Royal North Shore Hospital, Newcastle GOLD Service, Hunter Genetics, Waratah; SEALS Haematology and Genetics Laboratory (M.B.), Prince of Wales Hospital, Sydney; Kinghorn Centre for Clinical Genomics (T.R.); and Sydney Medical School (G.N.), University of Sydney, Australia.
Tony
T
Roscioli
From the Molecular Medicine Laboratory (M.S., G.N.), Neurology Department (J.L.), ANZAC Research Institute (G.N.), and NSW Health Pathology (G.N.), Concord Hospital (S.R.); Departments of Neurology (H.T., H.S., M.F.) and Genetics (T.R.), Sydney Children's Hospital; Discipline of Paediatrics, School of Women's and Children's Health, UNSW Medicine (H.T., H.S., M.F.), and St Vincent's Clinical School (T.R.), The University of New South Wales, Sydney; Kolling Institute (Y.Z.), Royal North Shore Hospital, Newcastle GOLD Service, Hunter Genetics, Waratah; SEALS Haematology and Genetics Laboratory (M.B.), Prince of Wales Hospital, Sydney; Kinghorn Centre for Clinical Genomics (T.R.); and Sydney Medical School (G.N.), University of Sydney, Australia.
Michelle
M
Farrar
From the Molecular Medicine Laboratory (M.S., G.N.), Neurology Department (J.L.), ANZAC Research Institute (G.N.), and NSW Health Pathology (G.N.), Concord Hospital (S.R.); Departments of Neurology (H.T., H.S., M.F.) and Genetics (T.R.), Sydney Children's Hospital; Discipline of Paediatrics, School of Women's and Children's Health, UNSW Medicine (H.T., H.S., M.F.), and St Vincent's Clinical School (T.R.), The University of New South Wales, Sydney; Kolling Institute (Y.Z.), Royal North Shore Hospital, Newcastle GOLD Service, Hunter Genetics, Waratah; SEALS Haematology and Genetics Laboratory (M.B.), Prince of Wales Hospital, Sydney; Kinghorn Centre for Clinical Genomics (T.R.); and Sydney Medical School (G.N.), University of Sydney, Australia. garth.nicholson@sydney.edu.au.
Garth
G
Nicholson
D000328:Adult; D017668:Age of Onset; D002675:Child, Preschool; D005190:Family; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D016472:Motor Neuron Disease / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*
D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; C109890:VRK1 protein, human