Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson's disease: clinical, pathological, olfactory and functional imaging and genetic data

Abstract

We have established that the frequency of LRRK2 mutations in a series of 118 cases of familial Parkinson's disease is 5.1%. In the largest family with autosomal dominant, late-onset Parkinson's disease where affected subjects share a Y1699C missense mutation we provide a detailed clinical, pathological and imaging report. The phenotype in this large British kindred included asymmetrical, levodopa-responsive parkinsonism where unilateral leg tremor at onset and foot dystonia were prominent features. There was no significant abnormality of cognition but there was prominent behavioural disorder. We observed a lower age of onset in successive generations. Histopathology in one patient showed substantia nigra cell loss and Lewy body formation, with small numbers of cortical Lewy bodies. 18F-dopa positron emission tomography (PET) in another patient showed a pattern of nigrostriatal dysfunction typical of idiopathic Parkinson's disease. 18F-dopa-PET scans in unaffected family members prior to identifying the disease locus did not detect subclinical nigrostriatal dysfunction. Olfaction was assessed in affected subjects and Lewy bodies were identified in the olfactory bulb as well as cortex and brainstem of one deceased patient. In order to assess the role of mutations in this gene in other familial cases we undertook a mutation screen of all 51 exons of LRRK2 in 117 other smaller British kindreds with familial Parkinson's disease. The commonest mutation was G2019S and we also identified two novel mutations, R1941H and T2356I, in the coding sequence. These data suggest that parkinsonism caused by mutations in LRRK2 is likely to represent the commonest locus for autosomal dominant Parkinson's disease with a phenotype, pathology and in vivo imaging similar to idiopathic, late-onset Parkinson's disease.

Cellular processes associated with LRRK2 function and dysfunction

“…Finally, the Y1699C mutation lies within the spacer domain, between the GTPase and kinase domains, and is responsible for one of the largest PD pedigrees in the UK with 25 affected subjects over four generations 32. The R1441C/G/H mutations showed decreased GTP hydrolysis 33, 34, as did the Y1699C mutation 35.…”

The olfactory vector hypothesis of neurodegenerative disease: Is it viable?

“…59 Fifth, not all familial cases of PD exhibit smell loss, including some with LRRK2-associated PD. 60 Sixth, aside from interactions between environmental factors and genetic determinants, the heterogeneity of smell loss observed in AD and PD could reflect the following circumstances:…”

Roco kinase structures give insights into the mechanism of Parkinson disease-related leucine-rich-repeat kinase 2 mutations

“…The identification of missense mutations in LRRK2 has redefined the role of genetic variation in PD susceptibility. LRRK2 mutations initiate a penetrant phenotype with complete clinical and neurochemical overlap with idiopathic disease (4)(5)(6). The various mutations that have been identified in PD are concentrated in the central region of the protein; one residue mutated in the LRR region, one in the Roc domain (with multiple substitutions), one in the COR domain, and two in the kinase domain (7).…”