Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology

Neuron. 2004 Nov 18;44(4):601-7. doi: 10.1016/j.neuron.2004.11.005.

Abstract

We have previously linked families with autosomal-dominant, late-onset parkinsonism to chromosome 12p11.2-q13.1 (PARK8). By high-resolution recombination mapping and candidate gene sequencing in 46 families, we have found six disease-segregating mutations (five missense and one putative splice site mutation) in a gene encoding a large, multifunctional protein, LRRK2 (leucine-rich repeat kinase 2). It belongs to the ROCO protein family and includes a protein kinase domain of the MAPKKK class and several other major functional domains. Within affected carriers of families A and D, six post mortem diagnoses reveal brainstem dopaminergic degeneration accompanied by strikingly diverse pathologies. These include abnormalities consistent with Lewy body Parkinson's disease, diffuse Lewy body disease, nigral degeneration without distinctive histopathology, and progressive supranuclear palsy-like pathology. Clinical diagnoses of Parkinsonism with dementia or amyotrophy or both, with their associated pathologies, are also noted. Hence, LRRK2 may be central to the pathogenesis of several major neurodegenerative disorders associated with parkinsonism.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Amino Acid Sequence
  • Blotting, Northern
  • Brain / pathology*
  • Chromosome Mapping
  • Female
  • Genetic Linkage
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Lewy Bodies / pathology
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Mutation
  • Nerve Degeneration / pathology
  • Parkinsonian Disorders / genetics*
  • Parkinsonian Disorders / pathology*
  • Pedigree
  • Protein Kinases / genetics*
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • Proteins / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Proteins
  • leucine-rich repeat proteins
  • Protein Kinases
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Lrrk2 protein, mouse
  • Protein-Serine-Threonine Kinases

Associated data

  • GENBANK/AY792511
  • GENBANK/AY792512