Abstract for presentation at The Australian and New Zealand Association of Neurologists Annual Scientific Meeting 2007

Autosomal dominant late-onset Parkinson’s disease due to a novel A1442P mutation in the LRRK2 gene

  • Dr Yue Huang, Prince of Wales Medical Research Institute and University of New South Wales, Australia
  • Prof Glenda Halliday, Prince of Wales Medical Research Institute and University of New South Wales, Australia
  • Prof Frank Mastaglia, Centre for Neuromuscular and Neurological Disorders, Queen Elizabeth II Medical Centre, Australia
  • Dr Dominic Rowe, Department of Neurology, Royal North Shore Hospital and University of Sydney, Australia
  • Carolyn Sue, Departments of Neurology and Neurogenetics, Kolling Institute, Royal North Shore Hospital and University of Sydney, Australia

    • Objective: To report a novel mutation in the Roc domain of LRRK2 in a 3-generation family with LOPD.
    Background: Over 20 mutations in LRRK2 have been reported to cause familial or sporadic Parkinson’s disease (PD). The commonest mutations are in the kinase domain in exon 41 (at G2019S) and in the Roc domain in exon 31 (at R1441G/C/H).
    Methods: We performed PCR-RFLP analysis to screen for mutations in exon 31 and 41 in a large Western Australian PD cohort (n= 109). We subsequently identified mutations by direct sequencing of the PCR product.
    Results: We found an A1442P (4324 G>C) mutation in a 65yr old male proband, with clinical features typical of PD. One of his 3 sisters, aged 69yrs, who on clinical examination had mild unilateral limb rigidity also had the A1442P mutation. Five other affected family members, at least three of who were thought to have PD, were not available for clinical or genetic study.
    Conclusions: We conclude that the A1442P mutation is pathogenic because: a) the A1442 residue is highly conserved; b) the substitution of proline for alanine is likely to alter the secondary structure of the protein; c) it may alter the binding properties of the “RabSF3” motif on the surface of Rab GTPase in a similar way to mutations at residue 1441 and d) it has not been identified in any other member of our Australian cohort or in large numbers of patients or controls in previous studies. Similar to other mutations in LRRK2, the A1442P mutation may express variable penetrance. Functional studies to assess pathogenic mechanisms are warranted.

    Conference Organiser - ICMS Pty Ltd