PRKAR1B mutation associated with a new neurodegenerative disorder with unique pathology.
Pathological accumulation of intermediate filaments can be observed in neurodegenerative disorders, such as Alzheimer's disease, frontotemporal dementia and Parkinson's disease, and is also characteristic of neuronal intermediate filament inclusion disease. Intermediate filaments type IV include three neurofilament proteins (light, medium and heavy molecular weight neurofilament subunits) and α-internexin. The phosphorylation of intermediate filament proteins contributes to axonal growth, and is regulated by protein kinase A. Here we describe a family with a novel late-onset neurodegenerative disorder presenting with dementia and/or parkinsonism in 12 affected individuals. The disorder is characterized by a unique neuropathological phenotype displaying abundant neuronal inclusions by haematoxylin and eosin staining throughout the brain with immunoreactivity for intermediate filaments. Combining linkage analysis, exome sequencing and proteomics analysis, we identified a heterozygous c.149T>G (p.Leu50Arg) missense mutation in the gene encoding the protein kinase A type I-beta regulatory subunit (PRKAR1B). The pathogenicity of the mutation is supported by segregation in the family, absence in variant databases, and the specific accumulation of PRKAR1B in the inclusions in our cases associated with a specific biochemical pattern of PRKAR1B. Screening of PRKAR1B in 138 patients with Parkinson's disease and 56 patients with frontotemporal dementia did not identify additional novel pathogenic mutations. Our findings link a pathogenic PRKAR1B mutation to a novel hereditary neurodegenerative disorder and suggest an altered protein kinase A function through a reduced binding of the regulatory subunit to the A-kinase anchoring protein and the catalytic subunit of protein kinase A, which might result in subcellular dislocalization of the catalytic subunit and hyperphosphorylation of intermediate filaments.
1 Department of Neurology, Erasmus Medical Centre, 3015 CE Rotterdam, The Netherlands.
Tsz Hang
TH
Wong
Wang Zheng
WZ
Chiu
Guido J
GJ
Breedveld
Ka Wan
KW
Li
Annemieke J M H
AJ
Verkerk
David
D
Hondius
Renate K
RK
Hukema
Harro
H
Seelaar
Petra
P
Frick
Lies-Anne
LA
Severijnen
Gert-Jan
GJ
Lammers
Joyce H G
JH
Lebbink
Sjoerd G
SG
van Duinen
Wouter
W
Kamphorst
Annemieke J
AJ
Rozemuller
E Bert
EB
Bakker
Manuela
M
Neumann
Rob
R
Willemsen
Vincenzo
V
Bonifati
August B
AB
Smit
John
J
van Swieten
D000368:Aged; D016229:Amyloid beta-Peptides / Q000378:metabolism; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000737:chemistry / Q000378:metabolism; D054753:Cyclic AMP-Dependent Protein Kinase RIbeta Subunit / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D055032:Electron Microscope Tomography; D005192:Family Health; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000473:pathology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D051844:alpha-Synuclein / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D054753:Cyclic AMP-Dependent Protein Kinase RIbeta Subunit; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; C517766:PRKAR1B protein, human; D051844:alpha-Synuclein; D016875:tau Proteins; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; C463959:protein kinase A Calpha
PRKAR1B; intermediate filament; neurodegenerative disorders; neurofilament; protein kinase A