Identification of a Novel LRRK2 Mutation Linked to Autosomal Dominant Parkinsonism: Evidence of a Common Founder across European Populations Jennifer.

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Identification of a Novel LRRK2 Mutation Linked to Autosomal Dominant Parkinsonism: Evidence of a Common Founder across European Populations Jennifer Kachergus, Ignacio F. Mata, Mary Hulihan, Julie P. Taylor, Sarah Lincoln, Jan Aasly, J. Mark Gibson, Owen A. Ross, Timothy Lynch, Joseph Wiley, Haydeh Payami, John Nutt, Demetrius M. Maraganore, Krzysztof Czyzewski, Maria Styczynska, Zbigniew K. Wszolek, Matthew J. Farrer, Mathias Toft The American Journal of Human Genetics Volume 76, Issue 4, Pages 672-680 (April 2005) DOI: 10.1086/429256 Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 1 Chromosome 12q12 markers on the disease haplotype (PARK8). Genotypes for mutation carriers from 13 families with LRRK2 G2019S are shown; those shared are highlighted in gray. For families whose phase could not be determined with certainty, both alleles are shown. The American Journal of Human Genetics 2005 76, 672-680DOI: (10.1086/429256) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 2 Pedigrees of families with LRRK2 G2019S. Blackened symbols denote family members affected with parkinsonism. An asterisk (*) denotes a genotyped individual, with “m” for mutation carriers and “wt” for wild-type LRRK2. To protect confidentiality, the genotypes and sexes of some unaffected individuals are not shown, and some family members for whom no information was available have been removed from the pedigrees. The American Journal of Human Genetics 2005 76, 672-680DOI: (10.1086/429256) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 3 Penetrance of LRRK2-associated disease, showing the probability of becoming affected by parkinsonism, in LRRK2 G2019S carriers, as a function of age. The American Journal of Human Genetics 2005 76, 672-680DOI: (10.1086/429256) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 4 LRRK2 with the novel G2019S substitution. A, Schematic drawing of LRRK2 with predicted protein domains. LRR = leucine-rich repeat; Roc = Ras in complex proteins; COR = C-terminal domain of Roc; MAPKKK = mitogen-activated protein kinase kinase kinase; WD40 = WD40 repeats. B, The human LRRK2 protein sequence in the region of the G2019S mutation, aligned with orthologs from rat (GenBank accession number XP_235581), mouse (GenBank accession number AAH34074), frog (GenBank accession number AAH76853), and puffer fish (GenBank accession number CAG05593). The mutation is indicated by a blackened arrowhead. C, Chromatogram showing the 6055G→A transition (G2019S). The American Journal of Human Genetics 2005 76, 672-680DOI: (10.1086/429256) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 5 Aligned amino acid sequences of the activation segment of different human kinases. The American Journal of Human Genetics 2005 76, 672-680DOI: (10.1086/429256) Copyright © 2005 The American Society of Human Genetics Terms and Conditions