Parkinsons disease caused by mutations in the gene for Leucinerich repeat kinase 2 LRRK2 PARK8

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Recently, a locus for a dominant form of PD has been mapped in a large Japanese family to the pericentromeric region of chromosome 12. Affected in this family showed typical l-dopa responsive parkinsonism with onset in their fifties. Pathologically, nigral degeneration was found, but no Lewy bodies or other distinctive inclusions (Funayama et al., 2002).

We have confirmed linkage to this region in two families of European ancestry and refined the disease gene containing interval to about 3 cM (Zimprich et al., 2004b). Following a positional cloning approach, we and others have identified the disease gene in this region as the gene for leucine-rich repeat kinase 2 (LRRK2) (Paisan-Ruiz et al., 2004; Zimprich et al., 2004a). The encoded protein has also been called ''dardarin'' (Paisan-Ruiz et al., 2004). The gene spans a genomic region of 144 Kb, with 51 exons encoding 2527 amino acids (Fig. 1). The gene is expressed in all brain regions and also in all peripheral tissues examined so far, although at low levels.

12q12 (144 kb)

12q12 (144 kb)

1000

2000

1000

2000

2527

LRR JUU.

R793M" Ex19

Q930R' Ex21

S1096C" Ex24

3342A>G° Ex24

11122V8 S1228T® R1441C"'bY1699Ca Ex25 Ex27 Ex31 Y1699G"

Ex35

G2019S0 Ex41

l2020Ta,d Ex41

Fig. 1. Genomic structure and functional domains of LRRK2. The gene spans a genomic distance of 144 kb and contains 51 exons. LRR leucine rich repeat; Roc Ras of complex proteins: COR C-terminal of Roc; MAPKKK mitogen activated kinase kinase kinase; WD Beta-Propeller. Mutations as published in: a: Zimprich et al. (2004a); b: Paisan-Ruiz et al. (2004); c: Kachergus et al. (2005), Di Fonzo et al. (2005), Gilks et al. (2005), Nichols et al.

(2005); d: Funayama et al. (2005); e: Berg et al. (2005)

LRRK2-associated PD is remarkable for several reasons. First, mutations in the LRRK2 gene appear to be the most common cause of autosomal-dominantly inherited par-kinsonism discovered so far. Four different mutations were detected in five of 34 dominant families studied by Zimprich et al. (in two of the families, the same mutation, R1441C, arose independently, based on the analysis of polymorphisms closely surrounding the gene). The same codon was affected in the group of Basque families studied by Paisan-Ruiz et al. (Paisan-Ruiz et al., 2004), but this mutation resulted in a different amino-acid exchange. These cases and other series show that LRRK2 mutations account for approximately 10 to 20% of dominantly inherited PD.

One particularly common mutation, Gly2019Ser, was detected on a founder hap-lotype across several European populations (Kachergus et al., 2005) and in up to 5 to 6% of several large cohorts of families with dominant parkinsonism (Di Fonzo et al., 2005; Nichols et al., 2005), and even in 1 to 2% of patients with sporadic late-onset disease (Gilks et al., 2005). Penetrance of this mutation is age-dependent, being about 20% with the age of 50 and rising to 80% at the age of 80. This reduced penetrance probably accounts for the finding of a negative family history in a significant proportion of cases.

Second, clinical signs and symptoms resemble typical sporadic PD in most families. This is true also for age of onset, which is on average in the late fifties and sixties in the families described so far. Therefore, of the PD-genes identified, LRRK2 mutations are by far the most common genetic cause of inherited PD and are likely to play a role also in the setting of typical sporadic late-onset disease.

Third, although the clinical picture appears to resemble typical PD, the associated pathology is remarkably variable. Pathologic changes include abnormalities consistent with Lewy body Parkinson's disease (this is found in the vast majority of cases), diffuse Lewy body disease, nigral degeneration without distinctive histopathology and progressive supranuclear palsy-like tau aggregation. LRRK2 mutations may therefore be an upstream event in the cascade leading to neurodegeneration with different pathologies.

By sequence homology, LRRK2 can be assigned to the group of recently identified ROCO-proteins (Bosgraaf and Van Haastert, 2003) and contains a protein kinase domaine of the MAPKKK class, suggesting a role in intracellular signaling pathways, but its precise function remains to be determined. Mutations appear to be clustered in functionally important regions, which are highly conserved through the species.

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