LRRK2 Gene

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This entry is adapted from the peer-reviewed paper https://medlineplus.gov/genetics/gene/lrrk2

Leucine rich repeat kinase 2

genes

1. Introduction

The LRRK2 gene provides instructions for making a protein called dardarin. The LRRK2 gene is active in the brain and other tissues throughout the body.

One segment of the dardarin protein is called a leucine-rich region because it contains a large amount of a protein building block (amino acid) known as leucine. Proteins with leucine-rich regions appear to play a role in activities that require interactions with other proteins, such as transmitting signals or helping to assemble the cell's structural framework (cytoskeleton). Other parts of the dardarin protein are also thought to be involved in protein-protein interactions.

Additional studies indicate that dardarin has an enzyme function known as kinase activity. Proteins with kinase activity assist in the transfer of a phosphate group (a cluster of oxygen and phosphorus atoms) from the energy molecule ATP to amino acids in certain proteins. This phosphate transfer is called phosphorylation, and it is an essential step in turning on and off many cell activities. Dardarin also has a second enzyme function referred to as a GTPase activity. This activity is associated with a region of the protein called the ROC domain. The ROC domain may help control the overall shape of the dardarin protein.

2. Health Conditions Related to Genetic Changes

2.1. Parkinson Disease

Researchers have identified more than 100 LRRK2 gene mutations in families with late-onset Parkinson disease (the most common form of the disorder, which appears after age 50). These mutations replace single amino acids in the dardarin protein, which affects the protein's structure and function. It is unclear how LRRK2 gene mutations lead to the movement and balance problems characteristic of Parkinson disease.

A mutation that replaces the amino acid arginine with the amino acid glycine at protein position 1441 (written as Arg1441Gly or R1441G) is a relatively common cause of Parkinson disease in the Basque region between France and Spain. The protein name dardarin comes from the Basque word "dardara," which means tremor, a characteristic feature of Parkinson disease.

Studies of several different populations from around the world revealed a common LRRK2 gene mutation in 3 to 7 percent of familial Parkinson disease cases. This mutation replaces the amino acid glycine with the amino acid serine at protein position 2019 (written as Gly2019Ser or G2019S). The incidence of the Gly2019Ser mutation in familial cases is highest among Arabs from North Africa and people of Ashkenazi (eastern and central European) Jewish ancestry, and it is lowest in Asian and northern European populations. This particular mutation has also been reported in 1 to 3 percent of sporadic Parkinson disease cases, in which there is no family history of the disease.

Studies in Chinese and Japanese populations have identified an LRRK2 gene mutation that occurs more frequently in people with Parkinson disease than in people without the disease. This mutation replaces the amino acid glycine with the amino acid arginine at protein position 2385 (written as Gly2385Arg or G2385R). This mutation appears to increase the risk of Parkinson disease among people in these populations.

3. Other Names for This Gene

DRDN
leucine-rich repeat kinase 2
LRRK2_HUMAN
PARK8
RIPK7
ROCO2

References

Bonifati V. LRRK2 low-penetrance mutations (Gly2019Ser) and risk alleles(Gly2385Arg)-linking familial and sporadic Parkinson's disease. Neurochem Res.2007 Oct;32(10):1700-8.
Cookson MR. The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson'sdisease. Nat Rev Neurosci. 2010 Dec;11(12):791-7. doi: 10.1038/nrn2935.
Di Fonzo A, Rohé 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; Italian Parkinson Genetics Network. A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease.Lancet. 2005 Jan 29-Feb 4;365(9457):412-5.
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.A common LRRK2 mutation in idiopathic Parkinson's disease. Lancet. 2005 Jan29-Feb 4;365(9457):415-6.
Guo L, Wang W, Chen SG. Leucine-rich repeat kinase 2: relevance to Parkinson'sdisease. Int J Biochem Cell Biol. 2006;38(9):1469-75.
Kumar A, Cookson MR. Role of LRRK2 kinase dysfunction in Parkinson disease.Expert Rev Mol Med. 2011 Jun 13;13:e20. doi: 10.1017/S146239941100192X. Review.
Lesage S, Dürr A, Tazir M, Lohmann E, Leutenegger AL, Janin S, Pollak P, BriceA; French Parkinson's Disease Genetics Study Group. LRRK2 G2019S as a cause ofParkinson's disease in North African Arabs. N Engl J Med. 2006 Jan26;354(4):422-3.
Mata IF, Wedemeyer WJ, Farrer MJ, Taylor JP, Gallo KA. LRRK2 in Parkinson'sdisease: protein domains and functional insights. Trends Neurosci. 2006May;29(5):286-93.
Ozelius LJ, Senthil G, Saunders-Pullman R, Ohmann E, Deligtisch A, Tagliati M,Hunt AL, Klein C, Henick B, Hailpern SM, Lipton RB, Soto-Valencia J, Risch N,Bressman SB. LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews. N Engl J Med. 2006 Jan 26;354(4):424-5.
Ross OA, Soto-Ortolaza AI, Heckman MG, Aasly JO, Abahuni N, Annesi G, BaconJA, Bardien S, Bozi M, Brice A, Brighina L, Van Broeckhoven C, Carr J,Chartier-Harlin MC, Dardiotis E, Dickson DW, Diehl NN, Elbaz A, Ferrarese C,Ferraris A, Fiske B, Gibson JM, Gibson R, Hadjigeorgiou GM, Hattori N, Ioannidis JP, Jasinska-Myga B, Jeon BS, Kim YJ, Klein C, Kruger R, Kyratzi E, Lesage S, LinCH, Lynch T, Maraganore DM, Mellick GD, Mutez E, Nilsson C, Opala G, Park SS,Puschmann A, Quattrone A, Sharma M, Silburn PA, Sohn YH, Stefanis L, Tadic V,Theuns J, Tomiyama H, Uitti RJ, Valente EM, van de Loo S, Vassilatis DK,Vilariño-Güell C, White LR, Wirdefeldt K, Wszolek ZK, Wu RM, Farrer MJ; GeneticEpidemiology Of Parkinson's Disease (GEO-PD) Consortium. Association of LRRK2exonic variants with susceptibility to Parkinson's disease: a case-control study.Lancet Neurol. 2011 Oct;10(10):898-908. doi: 10.1016/S1474-4422(11)70175-2.
Smith WW, Pei Z, Jiang H, Moore DJ, Liang Y, West AB, Dawson VL, Dawson TM,Ross CA. Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutantLRRK2 induces neuronal degeneration. Proc Natl Acad Sci U S A. 2005 Dec20;102(51):18676-81.
Tan EK, Zhao Y, Skipper L, Tan MG, Di Fonzo A, Sun L, Fook-Chong S, Tang S,Chua E, Yuen Y, Tan L, Pavanni R, Wong MC, Kolatkar P, Lu CS, Bonifati V, Liu JJ.The LRRK2 Gly2385Arg variant is associated with Parkinson's disease: genetic and functional evidence. Hum Genet. 2007 Feb;120(6):857-63.
West AB, Moore DJ, Biskup S, Bugayenko A, Smith WW, Ross CA, Dawson VL, DawsonTM. Parkinson's disease-associated mutations in leucine-rich repeat kinase 2augment kinase activity. Proc Natl Acad Sci U S A. 2005 Nov 15;102(46):16842-7.
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, Müller-Myhsok B, Dickson DW, Meitinger T, Strom TM, Wszolek ZK, Gasser T. Mutations in LRRK2 cause autosomal-dominant parkinsonism withpleomorphic pathology. Neuron. 2004 Nov 18;44(4):601-7.

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Dean Liu

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Update Date: 23 Dec 2020

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