PD Genetics (AAN 2005)

Subject: PD Genetics (AAN 2005)

Date: 4/22/2005

E-MOVE reports from the 57th Annual Meeting of the American Academy of Neurology, 9-16 April 2005, Miami. Poster, session and page numbers are from Neurology 2005;64(suppl 1).

Four studies expand the understanding of the role of the LRRK2 gene in PD. The clinical features of PD caused by LRRK2 mutations are typical for late-onset PD, according to two reports from different populations. The G2019S mutation is especially common among North Africans. And the first molecular characterization of the lrrk2 protein suggests that two mutations in two different domains have two different effects on the function of the protein.

1. Parkinson's disease related to the Basque dardarin mutation
JF Marti Masso, C Paisan Ruiz, J Simon, I Marti, S Aparicio, J Ruiz, AM Gil, AB Singleton, JP Tur, A Lopez de Munain
S17.002

Clinical features were determined for 35 PD patients with LRRK2 mutations, including 22 from 4 previously identified families, 9 patients in 7 new families, and 4 sporadic patients. All had the R1396G mutation. Mean age at onset was years, with unilateral rest tremor of the lower leg the most common presenting symptom. Of 33 treated with levodopa, all had a good response with typical motor complications after several years of treatment.

2. The clinical features and frequency of LRRK2 associated Parkinson's disease in central Norway
JO Aasly, M Toft, I Fernandez-Mata, J Kachergus, M Hulihan, MF Farrer
S17.003, A148

Of 435 PD patients referred to a single hospital in central Norway, 9 (2%) were heterozygous for the G2019S mutation. The same mutation was found in 10/26 first-degree relatives, and in 0/724 unrelated, unaffected controls. In 2 cases, no family history was reported or found. Mean age of onset was 57, with tremor or bradykinesia as the most common presenting symptoms. All patients were levodopa-responsive, and dyskinesias were common.

3. The G2019S LRRK2 mutation in autosomal dominant European and North African Parkinson's disease is frequent and its penetrance is age-dependent
S Lesage, P Ibanez, E Lohmann, Y Agid, A Durr, A Brice
LBS.003

Analysis of 200 index cases of autosomal dominant PD revealed that among North Africans, 41% were associated with LRRK2 mutation, while among Europeans, the frequency was 2.8%.

4. Molecular characterization of LRRK2, the gene responsible for autosomal dominant PARK8
JP Taylor, S Lincoln, L Pielsticker, MJ Farrer
P02.037, A88

Two identified mutations in LRRK2 appear to have different effects on the lrrk2 protein, according to this report. LRRK2 was expressed in cell lines and localized by a fluorescent tag. Protein from the R1441C mutant formed cytoplasmic inclusions. Homology modeling of the Roc domain that bears this mutation suggested it is responsible for interacting with other proteins. Protein from the G2019S mutant formed no inclusions and appeared to be distributed normally. Homology modeling of the MAPKKK domain bearing this mutation suggests that the mutation may lead to overactivity of the kinase function.

5. Discordant sibling analysis confirms the association of UCHL1 with Parkinson's disease
DM Maraganore, M Facheris, TG Lesnick, KJ Strain, M de Andrade, JM Cunningham, WA Rocca
P01.102, A58

The S18Y variant of UCHL1 is inversely associated with risk of PD, according to this study. Genotyping was performed in 496 case-control pairs (496 PD cases, 434 unaffected sibling controls, 62 unaffected unrelated controls where no sibling was available). The S18Y variant was significantly less common in cases than in controls (OR=0.18, p=0.004), a relationship that remained significant even when previously published cases and unrelated controls were excluded. The authors note, "The UCHL1 S18Y variant encodes a UCHL1 protein that is unable to form dimers, thus favoring the degradation of alpha-synuclein via the ubiquitin-proteasome pathway."
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6. Mitochondrial ND5 mutations in idiopathic Parkinson's disease
WD Parker, JK Parks
P02.042, A89

A mitochondrial complex I mutation is more common in PD cases than in controls, according to this report. Mitochondrial DNA from 8 idiopathic PD cases and 8 age-matched controls was amplified and sequenced prospectively. Missense mutations in the gene for the ND5 subunit of complex I were found in all PD cases and only one control. The mutations were found in 1-8% of mitochondrial chromosomes in affected individuals. The authors note that very high abundance of two of the identified mutations has been previously associated with early-onset neurodegenerative diseases.
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7. Molecular study of parkin in 300 patients with early onset Parkinson's disease
B Garavaglia, D Ghezzi, E Marelli, C Barzaghi, P Barone, AR Bentivoglio, F Bracco, C Ferrarese, C Paccheti, G Pezzoli, P Stanzione, A Albanese, M Zeviane
P02.036, A88

Among 300 patients with early-onset PD (278 sporadic, 22 familial), 47 parkin-positive patients were identified: 22 homozygous, 15 compound heterozygous, and 10 with only one mutation (as confirmed by quantitative RT-PCR). Among sporadic cases, 38 (14%) had mutations, with greater frequency among younger patients. The authors state, "The frequency of a single heterozygous mutation in our cohort of positive patients (21.3%) reinforces the hypothesis of a haploinsufficiency and/or a dominant negative allele mechanism of certain mutations in the parkin gene.
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E-MOVE Editor: Richard Robinson, NASW, WE MOVE

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