Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations

Abstract

Autosomal dominant parkinsonism has been attributed to pathogenic amino acid substitutions in leucine-rich repeat kinase 2 (LRRK2). By sequencing multiplex families consistent with a PARK8 assignment, we identified a novel heterozygous LRRK2 mutation. A referral sample of 248 affected probands from families with autosomal dominant parkinsonism was subsequently assessed; 7 (2.8%) were found to carry a heterozygous LRRK2 6055G-->A transition (G2019S). These seven patients originate from the United States, Norway, Ireland, and Poland. In samples of patients with idiopathic Parkinson disease (PD) from the same populations, further screening identified six more patients with LRRK2 G2019S; no mutations were found in matched control individuals. Subsequently, 42 family members of the 13 probands were examined; 22 have an LRRK2 G2019S substitution, 7 with a diagnosis of PD. Of note, all patients share an ancestral haplotype indicative of a common founder, and, within families, LRRK2 G2019S segregates with disease (multipoint LOD score 2.41). Penetrance is age dependent, increasing from 17% at age 50 years to 85% at age 70 years. In summary, our study demonstrates that LRRK2 G2019S accounts for parkinsonism in several families within Europe and North America. Our work highlights the fact that a proportion of clinically typical, late-onset PD cases have a genetic basis.

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.

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.

Figure 3

Penetrance of LRRK2-associated disease, showing the probability of becoming affected by parkinsonism, in LRRK2 G2019S carriers, as a function of age.

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).

Figure 5

Aligned amino acid sequences of the activation segment of different human kinases. In most kinases, the activation segment starts and ends with the conserved residues DFG and APE, respectively. In LRRK2 and LRRK1, phenylalanine is changed to tyrosine, an amino acid with a similar structure. LRRK2 = leucine-rich repeat kinase 2; LRRK1 = leucine-rich repeat kinase 1; MATK = megakaryocyte-associated tyrosine kinase; PDGFRA = platelet-derived growth factor receptor alpha; MAP3K10 = mitogen-activated protein kinase kinase kinase 10; DAPK1 = death-associated protein kinase 1; BRAF = v-raf murine sarcoma viral oncogene homolog B1.