Three new studies show that a single mutation in dardarin accounts for approximately 6% of familial Parkinson’s disease cases, and a smaller fraction of sporadic cases. The mutation is inherited as an autosomal dominant with reduced penetration. Dardarin, also called leucine-rich repeat kinase 2, is the protein product of PARK 8. The reported mutation is in the highly conserved kinase domain of the protein.
A previous E-MOVE report on the PARK 8 gene is archived at http://www.mdvu.org/emove/article.asp?ID=769
1. Genetic screening for a single common LRRK2 mutation in familial Parkinson’s disease
WC Nichols, N Pankratz, D Hernandez, C Paisán-Ruíz, S Jain, CA Halter, VE Michaels, T Reed, A Rudolph, CW Shults, A Singleton, T Foroud, Parkinson Study Group-PROGENI Investigators.
Lancet 2005;356:410-412
Of 769 patients in 358 families with PD, 35 individuals (5%) were either heterozygous (34) or homozygous (1) for a Gly2019Ser mutation in exon 41 of the dardarin gene. Patients had typical PD, with median age of onset 63 years old (range 18-87), but less severe clinical symptoms than non-carrier patients. Despite the apparent autosomal dominance of the mutation, only 37% of affected families reported a parent with PD, suggesting reduced penetrance. No mutation was found in over 1200 unaffected individuals, median age 71 (range 42-93).
The authors note that other mutations in this gene have already been identified, suggesting the fraction of cases due to dardarin mutation is likely to be higher.
2. A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson’s disease
A Di Fonzo, CF Rohé, J Ferreira, HF Chien, L Vacca, F Stocchi, L Guedes, E Fabrizio, M Manfredi, N Vanacore, S Goldwurm, G Breedveld, C Sampaio, G Meco, E Barbosa, BA Oostra, V Bonifati, Italian Parkinson Genetics Network.
Lancet 2005;356:412-415.
Of 61 consecutive families with autosomal dominant PD, 4 (6.6%) were heterozygous for the Gly2019Ser mutation. In 10 patients for whom accurate clinical information was available, age of onset ranged from 38-68 years, and clinical features were similar to patients without mutation. Several unaffected families member carry the mutation, but their ages are still below the latest age of onset, suggesting they may still be at risk.
A common LRRK2 mutation in idiopathic Parkinson’s disease
WP Gilks, PM Abou-Sleiman, S Gandhi, S Jain, A Singleton, AJ Lees, K Shaw, KP Bhatia, V Bonifati, NP Quinn, J Lynch, DG Healy, JL Holton, T Revesz, NW Wood.
Lancet 2005;356:415-416
Of 482 patients with sporadic PD, including 263 pathologically confirmed cases, 8 (1.6%) were heterozygous for the Gly2019Ser mutation. Of these 8, 3 were in pathologically confirmed cases. Five of the 8 had no family history of PD. No mutation was found in 345 controls, including 102 unaffected relatives of Huntington’s disease patients.