Brain Advance Access originally published online on October 26, 2005
Brain 2005 128(12):3000-3011; doi:10.1093/brain/awh666
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Type and frequency of mutations in the LRRK2 gene in familial and sporadic Parkinson's disease*
1 Hertie Institute of Clinical Brain Research, 2 Department of Medical Genetics and 3 Department of Neuroradiology, University of Tübingen, Tübingen, 4 Institute of Human Genetics, GSF National Research Institute, Neuherberg, 5 Institute of Epidemiology, GSF-National Research Center for Environment and Health, Neuherberg, 6 Department of Neurology, University of Munich, Munich, Germany, 7 Department of Neurology, Medical University of Vienna, Vienna, Austria and 8 Department of Neurology, Mayo Clinic, Jacksonville, FL, USA
Correspondence to: Daniela Berg, MD, Hertie Institute of Clinical Brain Research, Hoppe-Seyler-Strasse 3, D-72076 Tübingen, Germany E-mail: daniela.berg{at}uni-tuebingen.de
There is increasing evidence of genetic contribution to the pathogenesis of Parkinson's disease. The identification of mutations in the leucine-rich repeat kinase 2 (LRRK2) gene has shed new light on genetic variations responsible for autosomal dominantly inherited Parkinson's disease. In this analysis, the most comprehensive published so far, we screened a second large series comprising 53 families with Parkinson's disease for mutations in the LRRK2 gene by direct sequencing to further determine the frequency of the mutation and evaluate the clinical phenotype to establish a genotype/phenotype relation. For comparison, all novel and known mutations were investigated in a cohort of 337 patients with apparently sporadic Parkinson's disease and a cohort of 1200 control subjects using an ABI 7900 Allelic Detection system. We identified 7 more families with LRRK2 variations in the 53 families with Parkinson's disease. Four of these are novel amino acid substitutions (R793M, Q930R, S1096C, S1228T). Because of incomplete penetrance and possible phenocopies pathogenic relevance of the Q930R and S1096C mutations as well as for the previously described A3342G splice site mutation could not be established with certainty. The so far most common mutation (G2019) was not detected in our large cohort. Late onset and typical L-dopa responsive parkinsonian features were generally observed, often accompanied by impairment of executive functions and high interference values in neuropsychological testing, as well as sleeping disturbances but rare hallucinations. There were no abnormalities in electrophysiological investigations. Distinct intrafamily and interfamily differences could be observed, including the clinical presentation of diffuse Lewy body disease in one patient. The frequent finding of cerebral atrophy on MRI and less substantia nigra hyperechogenicity compared with idiopathic Parkinson's disease on transcranial ultrasound needs to be confirmed in further studies. Together with the findings obtained in 46 families in our first study, LRRK2 mutations, therefore, account for 13% of apparently autosomal dominant families in our population with varying but still generally typical clinical presentation of Parkinson's disease.
Key Words: leucine-rich repeat kinase 2 (LRRK2) gene; PARK 8; frequency of mutations; genotype/phenotype relation
Abbreviations: LRRK2 = leucine-rich repeat kinase 2
.
Received July 20, 2005. Revised September 12, 2005. Accepted September 19, 2005.
* This article is positioned according to subject, however due to an unfortunate error in the production process this has resulted in the non-sequential pagination of this article. The publisher apologizes for any inconvenience caused.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  Y. Tong, A. Pisani, G. Martella, M. Karouani, H. Yamaguchi, E. N. Pothos, and J. Shen R1441C mutation in LRRK2 impairs dopaminergic neurotransmission in mice PNAS, August 25, 2009; 106(34): 14622 - 14627. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S Lesage, C Condroyer, A Lannuzel, E Lohmann, A Troiano, F Tison, P Damier, S Thobois, A-M Ouvrard-Hernandez, S Rivaud-Pechoux, et al. Molecular analyses of the LRRK2 gene in European and North African autosomal dominant Parkinson's disease J. Med. Genet., July 1, 2009; 46(7): 458 - 464. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Lesage and A. Brice Parkinson's disease: from monogenic forms to genetic susceptibility factors Hum. Mol. Genet., April 15, 2009; 18(R1): R48 - R59. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Gasser Genomic and proteomic biomarkers for Parkinson disease Neurology, February 17, 2009; 72(7_Supplement_2): S27 - S31. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Silveira-Moriyama, L. C. Guedes, A. Kingsbury, H. Ayling, K. Shaw, E. R. Barbosa, V. Bonifati, N. P. Quinn, P. Abou-Sleiman, N. W. Wood, et al. Hyposmia in G2019S LRRK2-related parkinsonism: Clinical and pathologic data Neurology, September 23, 2008; 71(13): 1021 - 1026. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J M Hagenah, B Becker, N Bruggemann, A Djarmati, K Lohmann, A Sprenger, C Klein, and G Seidel Transcranial sonography findings in a large family with homozygous and heterozygous PINK1 mutations J. Neurol. Neurosurg. Psychiatry, September 1, 2008; 79(9): 1071 - 1074. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Marin, W. N. van Egmond, and P. J. M. van Haastert The Roco protein family: a functional perspective FASEB J, September 1, 2008; 22(9): 3103 - 3110. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. A. Ross, M. Toft, K. Haugarvoll, A. Chen-Plotkin, W. Yuan, C. Anderson, E. M. Wood, H.I. Hurtig, C. Clark, B.L. Miller, et al. CORTICOBASAL SYNDROME AND PRIMARY PROGRESSIVE APHASIA AS MANIFESTATIONS OF LRRK2 GENE MUTATIONS Neurology, July 22, 2008; 71(4): 303 - 304. [Full Text] [PDF]
|
|
|
|
|
|
A. S. Chen-Plotkin, W. Yuan, C. Anderson, E. M. Wood, H. I. Hurtig, C. M. Clark, B. L. Miller, V. M.-Y. Lee, J. Q. Trojanowski, M. Grossman, et al. Corticobasal syndrome and primary progressive aphasia as manifestations of LRRK2 gene mutations Neurology, February 12, 2008; 70(7): 521 - 527. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Klein and M. G. Schlossmacher Parkinson disease, 10 years after its genetic revolution: Multiple clues to a complex disorder Neurology, November 27, 2007; 69(22): 2093 - 2104. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. C. Nichols, V. E. Elsaesser, N. Pankratz, M. W. Pauciulo, D. K. Marek, C. A. Halter, A. Rudolph, C. W. Shults, T. Foroud, and For the Parkinson Study Group PROGENI Investigato LRRK2 mutation analysis in Parkinson disease families with evidence of linkage to PARK8 Neurology, October 30, 2007; 69(18): 1737 - 1744. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. B. West, D. J. Moore, C. Choi, S. A. Andrabi, X. Li, D. Dikeman, S. Biskup, Z. Zhang, K.-L. Lim, V. L. Dawson, et al. Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity Hum. Mol. Genet., January 15, 2007; 16(2): 223 - 232. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Marin The Parkinson Disease Gene LRRK2: Evolutionary and Structural Insights Mol. Biol. Evol., December 1, 2006; 23(12): 2423 - 2433. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Ishihara, L. Warren, R. Gibson, R. Amouri, S. Lesage, A. Durr, M. Tazir, Z. K. Wszolek, R. J. Uitti, W. C. Nichols, et al. Clinical Features of Parkinson Disease Patients With Homozygous Leucine-Rich Repeat Kinase 2 G2019S Mutations. Arch Neurol, September 1, 2006; 63(9): 1250 - 1254. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C H Williams-Gray, A Goris, T Foltynie, J Brown, M Maranian, A Walton, D A S Compston, S J Sawcer, and R A Barker Prevalence of the LRRK2 G2019S mutation in a UK community based idiopathic Parkinson's disease cohort J. Neurol. Neurosurg. Psychiatry, May 1, 2006; 77(5): 665 - 667. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Brice Genetics of Parkinson's disease: LRRK2 on the rise Brain, December 1, 2005; 128(12): 2760 - 2762. [Full Text] [PDF]
|
|