Pathogenic Effects of Novel Mutations in ATP13A2 (PARK9) Causing Kufor-Rakeb Syndrome, an Autosomal Recessive Form of Early-onset Parkinsonism

  • Dr Jin-Sung Park, Department of Neurogenetics, Kolling Intitute of Medical Research, University of Sydney, Royal North Shore Hospital, NSW, Australia
  • Dr Neil Manwaring, Department of Neurogenetics, Kolling Intitute of Medical Research, University of Sydney, Royal North Shore Hospital, NSW, Australia
  • Dr Victor Fung, Department of Neurology, Westmead Hospital, NSW, Australia
  • A/Prof Carolyn Sue, Department of Neurogenetics, Kolling Intitute of Medical Research, University of Sydney, Royal North Shore Hospital, NSW, Australia

    • Objective
    Recently, loss-of-function mutations in a lysosomal type 5 P-type ATPase, ATP13A2 (or PARK9) were reported to cause Kufor-Rakeb syndrome (KFS), an autosomal recessive form of early-onset parkinsonism. Pathogenic effects of this gene are currently unknown. The aim of this study was to assess the changes in expression of relevant genes in individuals with KFS using semi-quantitative RT-PCR.

    Methods
    We synthesised cDNA using total RNA extracted from the whole blood of affected and unaffected individuals within a family who had been identified with novel mutations (3176T>G and 3253delC) in the ATP13A2 gene. We then performed semi-quantitative RT-PCR followed by densitometry to compare the expression level of ATP13A2, lysosomal membrane-associated protein 2 (LAMP2) and alpha-synuclein (SNCA).

    Results
    LAMP2 expression was significantly increased in the affected (compound heterozygotes; 3176T>G / 3253delC, p<0.05) compared to wild type controls. In contrast, no change in the expression level of ATP13A2 or SNCA was observed.

    Conclusions
    LAMP2 expression is increased in our patients with compound heterozygous mutations in ATP13A2. ATP13A2 and SNCA expression remained unchanged when compared to controls. Given that LAMP2 is localised in the lysosome, our findings indicate a compensatory increase in lysosomal function in affected individuals. Further investigations to assess lysosomal function in patients with KFS are warranted.