Original Article

Neurogenetics

, Volume 6, Issue 4, pp 171-177

Lrrk2 pathogenic substitutions in Parkinson's disease

  • Ignacio F. MataAffiliated withDepartments of Neurology and Neuroscience, Mayo Clinic
  • , Jennifer M. KachergusAffiliated withDepartments of Neurology and Neuroscience, Mayo Clinic
  • , Julie P. TaylorAffiliated withDepartments of Neurology and Neuroscience, Mayo Clinic
  • , Sarah LincolnAffiliated withDepartments of Neurology and Neuroscience, Mayo Clinic
  • , Jan AaslyAffiliated withDepartment of Neurology, St. Olav's Hospital
  • , Timothy LynchAffiliated withDepartment of Neurology, Mater Misericordiae University HospitalConway Institute of Biomolecular and Biomedical Research
  • , Mary M. HulihanAffiliated withDepartments of Neurology and Neuroscience, Mayo Clinic
  • , Stephanie A. CobbAffiliated withDepartments of Neurology and Neuroscience, Mayo Clinic
  • , Ruey-Meei WuAffiliated withDepartment of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University
    • , Chin-Song LuAffiliated withDepartment of Neurology, Chang Gung Memorial Hospital
    • , Carlos LahozAffiliated withServicio de Neurología, Hospital Universitario Central de Asturias
    • , Zbigniew K. WszolekAffiliated withDepartments of Neurology and Neuroscience, Mayo Clinic
    • , Matthew J. FarrerAffiliated withDepartments of Neurology and Neuroscience, Mayo ClinicDepartment of Neuroscience, Molecular Genetics Laboratory and Core, Morris K. Udall Parkinson's Disease Research Center of Excellence Email author 

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Abstract

Leucine-rich repeat kinase 2 (LRRK2) mutations have been implicated in autosomal dominant parkinsonism, consistent with typical levodopa-responsive Parkinson's disease. The gene maps to chromosome 12q12 and encodes a large, multifunctional protein. To identify novel LRRK2 mutations, we have sequenced 100 affected probands with family history of parkinsonism. Semiquantitative analysis was also performed in all probands to identify LRRK2 genomic multiplication or deletion. In these kindreds, referred from movement disorder clinics in many parts of Europe, Asia, and North America, parkinsonism segregates as an autosomal dominant trait. All 51 exons of the LRRK2 gene were analyzed and the frequency of all novel sequence variants was assessed within controls. The segregation of mutations with disease has been examined in larger, multiplex families. Our study identified 26 coding variants, including 15 nonsynonymous amino acid substitutions of which three affect the same codon (R1441C, R1441G, and R1441H). Seven of these coding changes seem to be pathogenic, as they segregate with disease and were not identified within controls. No multiplications or deletions were identified.

Keywords

LRRK2 Kinase Idiopathic Parkinson's disease Mutation Polymorphism