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Subject: PD Genetics Update Date: 10/26/2004 PD GeneticsE-MOVE presents a round-up of new genetic findings in Parkinson’s disease: --Cloning of the PARK8 gene has led to the discovery of the dardarin protein, a putative cytoplasmic protein kinase (Paisan-Ruiz, Neuron). --Fibroblast growth factor polymorphisms strongly influence the risk for PD (van der Walt, Am J Hum Genetics). --Analysis of concordance in the Swedish Twin Registry shows that genes play little role in the large majority of PD cases. --Seven new reports rule out multiplication of the alpha-synuclein gene (Johnson, Neurology; Chartier-Harlin, Lancet; Ibanez, Lancet), DJ1 mutations (Maraganore, Neurology), PINK1 mutations (Healy, Neurology; Hatano, Neurology) and FMR1 premutations (Deng, JAMA) as common causes of PD. 1. Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease C Paisan-Ruiz, S Jain, EW Evans, WP Gilks, J Simon, M van der Brug, A Lopez de Munain, A Aparicio, AM Gil, N Khan, J Johnson, JR Martinez, D Nicholl, IM Carrera, AS Pena, R de Silva, A Lees, JF Marti-Masso, J Perez-Tur, NW Wood, AB Singleton Neuron 2004, published online 22 October 2004 PARK8 codes for a protein of unknown function, whose structure suggests it may be a cytoplasmic protein kinase, according to this report. The authors have named the protein dardarin, from the Basque word for tremor, in recognition of the Basque families who were the subject of the study. Genetic analysis of four Basque families indicated the PARK8 gene was within a 2.6 Mb region on chromosome 12 which contained only 11 genes. Cosegregating mutations were identified within a gene that codes for a predicted 2482 amino acid protein homologous to protein kinases found in mice, rats, and pufferfish. No mutations were found in 30 other non-PARK8 Basque PD patients with familial PD, 107 Basque sporadic PD patients, or 94 North American PD patients with familial PD. Identified mutations were missense mutations outside of the kinase domain of the protein. The authors note that this mutation, while rare generally, appears to be implicated in as many as 8% of PD cases among the Basque, due to a founder effect. Patients have late onset, levodopa responsiveness, and a benign course. The protein is expressed throughout the adult brain, and at higher levels in other tissues. They write, “Because phosphorylation of proteins has been implicated in the pathogenesis of neurodegenerative disease, it is particularly tempting to hypothesize a role for dardarin in the phosphorylation of proteins central to PD, such as alpha-synuclein and tau.” 2. Fibroblast growth factor 20 polymorphisms and haplotypes strongly influence risk of Parkinson disease JM van der Walt, MA Noureddine, A Kittappa, MA Hauser, WK Scott, R McKay, F Zhang, JM Stajich, K Fujiwara, BL Scott, MA Pericak-Vance, JM Vance, ER Martin Am J Hum Genet 2004;74:1121-1127 Variations in fibroblast growth factor 20 are strongly associated with risk of Parkinson’s disease, according to this study. FGF20 is a neurotrophic factor important for survival of dopaminergic neurons. Individuals from 355 families with only one affected member, and 289 families with at least two affected members, were genotyped for variations in the FGF20 gene. Strong evidence of association with PD was found for three SNPs within the gene, one in an intron and two in the 3’ untranslated region. The authors suggest these variations may disrupt regulatory binding sequences within the gene, reducing its transcription and thus reducing production of FGF20. Molecular studies are underway to assess this hypothesis. 3. No evidence for heritability of Parkinson disease in Swedish twins K Wirdefeldt, M Gatz, M Schalling, NL Pedersen Neurology 2004;63:305-311 Phone interviews of 14,082 twin pairs revealed 247 twins with self-reported PD or PD diagnosis (“possible PD”), as well as 517 with parkinsonian symptoms or use of antiparkinson medications (“suspected parkinsonism or movement disorder”). Only two twin pairs, both dizygotic female pairs, were concordant for possible PD. An additional five pairs (three dizygotic, two monozygotic) were found among those twins whose sibling had died. Concordance remained low even when defined as possible PD plus suspected parkinsonism or movement disorder. The authors conclude, “Our findings indicate that genetic effects are of little importance for liability to broad-definition PD.” Results of a similar study of US twin pairs is archived at http://www.mdvu.org/emove/article.asp?ID=37 4. Seven studies report on the limited roles played by four different genes in PD. Alpha-synuclein: --Johnson et al. found no alpha-synuclein multiplications in 101 familial PD probands, 325 sporadic PD cases, 65 patients with dementia with Lewy bodies, and 366 neurologically normal controls. --Chartier-Harlin et al. found alpha-synuclein duplication in 1 of 9 kindreds with autosomal dominant PD. --Ibanez et al. found alpha-synuclein duplication in 2 of 119 index patients with autosomal dominant PD. DJ1: --Maraganore et al., who studied 691 PD patients and 957 unaffected siblings, found no overall difference in frequency of 4 haplotype-tagging SNPs within the DJ1 gene between patients and siblings. They did find that two SNPs were associated with disease risk, one directly and one inversely, in women. Their results “suggest that the DJ1 gene is not a major susceptibility or modifying gene for PD.” PINK1: --Healy et al. found 1 PINK1 mutation in 290 unrelated early- and late-onset PD patients in Ireland. --Hatano et al. studied 39 families with autosomal recessive early-onset PD who were negative for parkin and DJ1 mutations. They found 8 families, from Japan, Taiwan, Turkey, and Israel, with evidence of linkage to the PINK1 locus. “The results indicate worldwide distribution of PARK6-linked parkinsonism,” they conclude. FMR1: --Deng et al. found no FMR1 CGG expansion (premutation) in 216 men with PD and 196 men with essential tremor. Four PD patients and 3 ET patients had “gray-zone” expansions of 45-54 repeats. “Premutation of FMR1 probably plays little or no role in the pathogenesis of idiopathic PD or essential tremor,” they conclude. SNCA multiplication is not a common cause of Parkinson disease or dementia with Lewy bodies J Johnson, SM Hague, M Hanson, A Gibson, KE Wilson, EW Evans, AA Singleton, A McInerney-Leo, RL Nussbaum, DG Hernandez, M Gallardo, IG McKeith, DJ Burn, M Ryu, O Hellstrom, B Ravina, J Eerola, RH Perry, E Jaros, P Tienari, R Weiser, K Gwinn-Hardy, CM Morris, J Hardy, AB Singleton Neurology 2004;63:554-556 Alpha-synuclein locus duplication as a cause of familial Parkinson’s disease MC Chartier-Harlin, J Kachergus, V Mouroux, X Douay, S Lincoln, C Levecque, L Larvor, J Andrieux, M Hulihan, N Waucquier, L Defebvre, P Amouyel, M Farrer, A Destee Lancet 2004;364:1167-1168 Causal relation between alpha-synuclein gene duplication and familial Parkinson’s disease P Ibanez, AM Bonnet, B Debarges, E Lohmann, F Tison, P Pollak, Y Agid, A Durr, A Brice, French Parkinson’s Disease Study Group Lancet 2004;364:1169-1171 A limited role for DJ1 in Parkinson disease susceptibility DM Maraganore, K Wilkes, TG Lesnick, KJ Strain, M de Andrade, WA Rocca, JH Bower, JE Ahlskog, S Lincoln, MJ Farrer Neurology 2004;63:550-553 PINK1 (PARK6) associated parkinsonism disease in Ireland DG Healy, PM Abou-Sleiman, JM Gibson, OA Ross, S Jain, S Gandhi, D Gosal, MMK Muqit, NW Wood, T Lynch Neurology 2004;63:1486-1488 PARK6-linked autosomal recessive early-onset parkinsonism in Asian populations Y Hatano, K Sato, B Elibol, H Yoshino, Y Yamamura, V Bonifati, H Shinotoh, M Asahina, S Kobayashi, AR Ng, RL Rosales, S Hassin-Baer, Y Shinar, CS Lu, HC Chang, YH Wu-Chou, FB Atac, T Kobayashi, T Toda, Y Mizuno, N Hattori Neurology 2004;63:1482-1485 Premutation alleles associated with Parkinson disease and essential tremor H Deng, W Le, J Jankovic JAMA 2004;292:1685-1686 E-MOVE Editor: Richard Robinson, NASW, WE MOVE
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