PRKAR1B mutation associated with a new neurodegenerative disorder with unique pathology

Tsz Hang Wong, Wang Zheng Chiu, Guido J Breedveld, Ka Wan Li, Annemieke J M H Verkerk, David Hondius, Renate K Hukema, Harro Seelaar, Petra Frick, Lies-Anne Severijnen, Gert-Jan Lammers, Joyce H G Lebbink, Sjoerd G van Duinen, Wouter Kamphorst, Annemieke J Rozemuller, E Bert Bakker, Manuela Neumann, Rob Willemsen, Vincenzo Bonifati, August B SmitJohn van Swieten,

Research output: Contribution to journal/periodicalArticleScientificpeer-review

237 Downloads (Pure)


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.

Original languageEnglish
Pages (from-to)1361-73
Number of pages13
JournalBrain: a journal of neurology
Issue numberPt 5
Publication statusPublished - 2014


  • Aged
  • Amyloid beta-Peptides
  • Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
  • Cyclic AMP-Dependent Protein Kinase RIbeta Subunit
  • DNA-Binding Proteins
  • Electron Microscope Tomography
  • Family Health
  • Female
  • Frontal Lobe
  • Genetic Association Studies
  • Humans
  • Male
  • Middle Aged
  • Models, Molecular
  • Nerve Tissue Proteins
  • Neurodegenerative Diseases
  • Polymorphism, Single Nucleotide
  • alpha-Synuclein
  • tau Proteins

Fingerprint Dive into the research topics of 'PRKAR1B mutation associated with a new neurodegenerative disorder with unique pathology'. Together they form a unique fingerprint.

Cite this