Abstract
Leucine-rich repeat kinase 2 (LRRK2) mutations have been implicated in autosomal dominant parkinsonism, consistent with typical levodopa-responsive Parkinson's disease. The gene maps to chromosome 12q12 and encodes a large, multifunctional protein. To identify novel LRRK2 mutations, we have sequenced 100 affected probands with family history of parkinsonism. Semiquantitative analysis was also performed in all probands to identify LRRK2 genomic multiplication or deletion. In these kindreds, referred from movement disorder clinics in many parts of Europe, Asia, and North America, parkinsonism segregates as an autosomal dominant trait. All 51 exons of the LRRK2 gene were analyzed and the frequency of all novel sequence variants was assessed within controls. The segregation of mutations with disease has been examined in larger, multiplex families. Our study identified 26 coding variants, including 15 nonsynonymous amino acid substitutions of which three affect the same codon (R1441C, R1441G, and R1441H). Seven of these coding changes seem to be pathogenic, as they segregate with disease and were not identified within controls. No multiplications or deletions were identified.
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References
Fahn S (2003) Description of Parkinson's disease as a clinical syndrome. Ann N Y Acad Sci 991:1–14
Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K (2004) Stages in the development of Parkinson's disease-related pathology. Cell Tissue Res 318:121–134
Tanner CM (2003) Is the cause of Parkinson's disease environmental or hereditary? Evidence from twin studies. Adv Neurol 91:133–142
Wirdefeldt K, Gatz M, Schalling M, Pedersen NL (2004) No evidence for heritability of Parkinson disease in Swedish twins. Neurology 63:305–311
Di Monte DA (2003) The environment and Parkinson's disease: is the nigrostriatal system preferentially targeted by neurotoxins? Lancet Neurol 2:531–538
Vila M, Przedborski S (2004) Genetic clues to the pathogenesis of Parkinson's disease. Nat Med 10(Suppl):S58–S62
Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, Kachergus J, Hulihan M, Uitti RJ, Calne DB, Stoessl AJ, Pfeiffer RF, Patenge N, Carbajal IC, Vieregge P, Asmus F, Muller-Myhsok B, Dickson DW, Meitinger T, Strom TM, Wszolek ZK, Gasser T (2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44:601–607
Paisan-Ruiz C, Jain S, Evans EW, Gilks WP, Simon J, van der Brug M, de Munain AL, Aparicio S, Gil AM, Khan N, Johnson J, Martinez JR, Nicholl D, Carrera IM, Pena AS, de Silva R, Lees A, Marti-Masso JF, Perez-Tur J, Wood NW, Singleton AB (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 44:595–600
Di Fonzo A, Rohe CF, Ferreira J, Chien HF, Vacca L, Stocchi F, Guedes L, Fabrizio E, Manfredi M, Vanacore N, Goldwurm S, Breedveld G, Sampaio C, Meco G, Barbosa E, Oostra BA, Bonifati V (2005) A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease. Lancet 365:412–415
Gilks WP, Abou-Sleiman PM, Gandhi S, Jain S, Singleton A, Lees AJ, Shaw K, Bhatia KP, Bonifati V, Quinn NP, Lynch J, Healy DG, Holton JL, Revesz T, Wood NW (2005) A common LRRK2 mutation in idiopathic Parkinson's disease. Lancet 365:415–416
Kachergus J, Mata IF, Hulihan M, Taylor JP, Lincoln S, Aasly J, Gibson JM, Ross OA, Lynch T, Wiley J, Payami H, Nutt J, Maraganore DM, Czyzewski K, Styczynska M, Wszolek ZK, Farrer MJ, Toft M (2005) Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations. Am J Hum Genet 76:672–680
Nichols WC, Pankratz N, Hernandez D, Paisan-Ruiz C, Jain S, Halter CA, Michaels VE, Reed T, Rudolph A, Shults CW, Singleton A, Foroud T (2005) Genetic screening for a single common LRRK2 mutation in familial Parkinson's disease. Lancet 365:410–412
Funayama M, Hasegawa K, Kowa H, Saito M, Tsuji S, Obata F (2002) A new locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2–q13.1. Ann Neurol 51:296–301
Bosgraaf L, Van Haastert PJ (2003) Roc, a Ras/GTPase domain in complex proteins. Biochim Biophys Acta 1643:5–10
Li Y, Tomiyama H, Sato K, Yoshino H, Funayama M, Hattori N, Mizumo Y (2005) The hot spot for LRRK2 mutations in Parkinson's disease is located within the exon 41. Parkinsonism Relat Disord 11:252–253
Mata IF, Taylor JP, Kachergus J, Hulihan M, Huerta C, Lahoz C, Blazquez M, Guisasola LM, Salvador C, Ribacoba R, Martinez C, Farrer M, Alvarez V (2005) LRRK2 R1441G in Spanish patients with Parkinson's disease. Neurosci Lett 382:309–311
Paisan-Ruiz C, Saenz A, de Munain AL, Marti I, Martinez Gil A, Marti-Masso JF, Perez-Tur J (2005) Familial Parkinson's disease: clinical and genetic analysis of four Basque families. Ann Neurol 57:365–372
Funayama M, Hasegawa K, Ohta E, Kawashima N, Komiyama M, Kowa H, Tsuji S, Obata F (2005) An LRRK2 mutation as a cause for the parkinsonism in the original PARK8 family. Ann Neurol 57:918–921
Stenmark H, Olkkonen VM (2001) The Rab GTPase family. Genome Biol 2:REVIEWS3007
Nolen B, Taylor S, Ghosh G (2004) Regulation of protein kinases; controlling activity through activation segment conformation. Mol Cell 15:661–675
Ali BR, Wasmeier C, Lamoreux L, Strom M, Seabra MC (2004) Multiple regions contribute to membrane targeting of Rab GTPases. J Cell Sci 117:6401–6412
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954
Gelb DJ, Oliver E, Gilman S (1999) Diagnostic criteria for Parkinson disease. Arch Neurol 56:33–39
Acknowledgements
We would like to acknowledge patients and family members for their participation. In addition, we thank all collaborating investigators and physicians of the Udall Center, Mayo Clinic (Jacksonville, FL) for their continued effort. Minnie Schreiber is thanked for laboratory support. NINDS P01 NS40256 funded the Udall Clinical and Genetic Cores. The Asociacion Parkinson Asturias helped fund I.F.M.
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Mata, I.F., Kachergus, J.M., Taylor, J.P. et al. Lrrk2 pathogenic substitutions in Parkinson's disease. Neurogenetics 6, 171–177 (2005). https://doi.org/10.1007/s10048-005-0005-1
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DOI: https://doi.org/10.1007/s10048-005-0005-1