Evidence of an association of LRRK2 polymorphic variants with PD was reported in 2005 when a haplotype that increases disease risk when present in two copies was identified among sporadic
Trang 1LRRK2 in Parkinson’s disease: genetic and clinical
studies from patients
Udhaya Kumari1,2and E K Tan1,2
1 Department of Neurology, Singapore General Hospital, Singapore, Singapore
2 National Neuroscience Institute, Duke-NUS Graduate Medical School, Singapore, Singapore
Introduction
Parkinson’s disease (PD), a chronic progressive
neuro-degenerative movement disorder, is characterized
clini-cally by resting tremor, rigidity, bradykinesia and
postural instability This condition was first described
in 1817 by James Parkinson in his seminal paper ‘the shaking palsy’ Although PD predominantly affects older individuals, 10% of people with the disease are under the age of 40 years [1] The
neuropathologi-Keywords
LRRK2; mutations; Parkinson’s disease;
penetrance; polymorphisms
Correspondence
E.-K Tan, Department of Neurology,
Singapore General Hospital, Outram Road,
Singapore 169608, Singapore
Fax: +65 6220 3321
Tel: +65 6326 5003
E-mail: gnrtek@sgh.com.sg
(Received 30 May 2009, revised 27 July
2009, accepted 6 August 2009)
doi:10.1111/j.1742-4658.2009.07344.x
Mutations in leucine-rich repeat kinase 2 (LRRK2) (PARK8) are associ-ated with both familial and sporadic forms of Parkinson’s disease Most studies have shown that LRRK2 mutations may explain between 5% and 13% of familial and 1–5% of sporadic Parkinson’s disease Importantly,
a common recurrent mutation (G2019S) located in the kinase domain has been reported across most ethnic populations, with the highest prevalence among Ashkenazi Jews and North African Arabs A recent worldwide meta-analysis pooling data from 24 populations reported a higher occur-rence of G2019S in southern than in northern European countries and the penetrance is estimated to be 75% at the age of 79 years The R1441 ‘hotspot’ amino acid codon residue (G⁄ H ⁄ C) in the Ras of com-plex proteins domain is the second most common site of pathogenic LRRK2 substitutions after G2019S, with most carriers developing symp-toms by the age of 75 years Two polymorphic variants found almost exclusively among Asians (G2385R and R1628P) have been shown to increase the Parkinson’s disease risk by approximately two-fold The mutational event associated with R1628P is more recent, occurring
2500 years ago, compared to estimates of 4000 years for G2385R carri-ers LRRK2 mutation carriers generally simulate late onset Parkinson’s disease and present with the usual typical clinical features Genetic testing for G2019S in sporadic late-onset Parkinson’s disease can be considered
in some situations and may be useful in populations with high carrier sta-tus The identification of asymptomatic mutation and risk variant carriers provides a unique opportunity for recruiting these subjects in potential neuroprotective trials and longitudinal studies to identify biomarkers of neurodegeneration
Abbreviations
ANK, ankryn; ARM, armadillo; COR, C-terminal of ROC; LRRK2, leucine-rich repeat kinase 2; PD, Parkinson’s disease; PET, positron emission tomography; ROC, Ras of complex proteins.
Trang 2cal hallmarks are characterized by a progressive and
profound loss of neuromelanin-containing
dopaminer-gic neurons in the substantia nigra pars compacta with
the presence of eosinophillic, intracytoplasmic and
pro-teinaceous inclusions termed as Lewy bodies and
dys-trophic Lewy neurites in surviving neurons [2] For
many decades, the relative influence of genes and
envi-ronmental agents on the pathophysiology of PD has
been debated However, subsequent to the discovery of
a-synuclein as a causative gene in 1997, there is
increas-ing recognition that genes play an important role in
the disease, particularly in familial cases At present,
many causative genes and susceptibility loci have been
identified (Table 1) Many of these PD-associated
genes affect both familial and sporadic forms and are
found in a number of different ethnic populations The
discovery and subsequent identification of the gene for
leucine-rich repeat kinase 2 (LRRK2) (PARK8) as a
causative PD gene has significantly contributed to our
understanding of not only the eitopathology of the
condition, but also provides information that could
potentially influence clinical management
LRRK2 is a large (280 kDa) multidomain protein,
with pathogenic mutations distributed throughout its
length, although there is a degree of clustering within
the enzymatic domains The gene encompasses 144 kb,
with an ORF consisting of 7581 bp (in 51 exons) and its encoded protein is unusually large (2527 amino acids) It is a multidomain protein comprising (from N-terminal to C-terminal), armadillo (ARM), ankryn (ANK), LRR, Ras of complex proteins (ROC), C-ter-minal of ROC (COR), mitogen-activated protein kinase kinase kinase and WD40 domains The presence
of the four protein–protein interaction domains (ARM, ANK, LRR and WD40) strongly suggests a role of LRRK2 in protein complex formation
Discovery of LRRK2 as a cause of PD
In 2002, Funayama et al [3] identified a novel locus
on chromosome 12p11.2–q13.1 that co-segregates with autosomal dominant parkinsonism in a family from Sagamihara (a region in Japan) consisting of 31 indi-viduals from four generations Two large families with autosomal-dominant late-onset parkinsonism, family A (German–Canadian) and family D (Western Nebraska) are also linked to this PARK8 locus In 2004, missense LRRK2 mutations were identified in family A (Y1699C) and in family D (R1441C) Sixteen individu-als (eight unaffected and eight affected) in family A were genotyped and all affected were heterozygous for the mutation and all the unaffected aged over 60 years
Table 1 Genes and loci linked with PD.
No causative gene identified
Reported in a PD sibling pair
Pathogenicity uncertain
No causative gene identified
Pathogenicity uncertain
Awaiting more data
Awaiting more data
AD, Autosomal dominant; AR, autosomal recessive; UCHL1, ubiquitin carboxy-terminal hydrolase L1; PINK1, PTEN-induced kinase 1; ATP13A2, ATPase type 13A2; GIGYF2, GRB10-interacting GYF protein 2; HTRA2, HtrA serine peptidase 2; PLA2G6, group VI phospholipase A2; FBX07, F-box protein 7.
Trang 3did not have the mutation In family D, 34 individuals
were genotyped (ten affected and 24 unaffected) All
affected were heterozygous for R1441C mutation and
24 clinically unaffected were genotyped; only two older
than 60 years of age were mutation carriers These
individuals are considered to be at risk [4] At the same
time, another study revealed missense mutations
segre-gates with PARK8-linked PD in five families from
England and Spain The authors named the protein
dardarin because dardar is derived from the Basque
(i.e where families of LRRK2 are found) word for
tremor, and it was a common symptom [5]
Identification of a common LRRK2
mutation (G2019S)
In 2005, three concurrent reports identified a LRRK2
mutation (G2019S, which produces a glycine to serine
amino acid substitution at codon 2019) to be common
in both familial and sporadic PD [6–8] Nichols et al
[6] analyzed 767 affected individuals from 358
multi-plex families and revealed that 5% were either
hetero-zygotes or homohetero-zygotes for the mutation Di Fonzo
et al [7] found 6.6% of unrelated families from Italy,
Portugal and Brazil with PD and with autosomal
dom-inant inheritance harbor the mutation Gilks et al [8]
analyzed 482 sporadic PD patients and reported 1.6%
of them as having the mutation These three reports
highlighted, for the first time, that a common recurrent
mutation can be a cause of both sporadic and familial
PD and consequently set the stage for numerous genetic
screening studies for this mutation worldwide [9]
Prevalence of LRRK2 G2019S mutation
Most studies have shown that LRRK2 mutations may
explain between 5% and 13% of familial and 1–5% of
sporadic PD [4–9] (Fig 1) The variability depends on the ethnic population and the extent of genetic screening
Of greater interest is the prevalence of G2019S, which has been found to be very rare in Asia, South Africa and in some European countries, such as Poland, Greece and Germany However, that appears as a predilection for some ethnic races This mutation accounts for 13.3% of sporadic and 29.7% of familial PD among Ashkenazi Jews and 40.8% of sporadic and 37.0% of familial PD in North African Arabs [10,11] The muta-tion accounts for 1–7% of familial patients from European and US origin and for 1–3% of sporadic
PD from most Caucasian populations This mutation
is located in the kinase domain of the protein and may
be associated with increased kinase activity [12,13] The estimation of the penetrance of autosomal domi-nant mutations is a challenging task but it is essential for genetic counseling Penetrance estimates are usually high when they are based on high-risk families and might not apply to the general population The pene-trance of G2019S-associated disease increased from 17% at age 50 years to 85% at age 70 years in an initial family-based study, but varied in subsequent reports, depending on sample size, study design, inclu-sion of probands in the analysis and methods of calcu-lation To address some of these issues, Healy et al [14], in a recent worldwide meta-analysis, pooled data from 24 populations, involving 1045 individuals with LRRK2 mutations from 133 families Interestingly, they found a higher occurrence of G2019S in southern than in northern European countries The authors esti-mated the penetrance to be 28%, 51% and 74% at 59,
69 and 79 years of age, respectively The over-riding message is that, although the penetrance clearly increases with age, it is not complete because some very elderly carriers remain free of disease Ethnic dif-ferences for LRRK2 mutations have been reported
Fig 1 Genomic and protein structures of
LRRK2 LRRK2 has 2527 amino acids and
contains ARM, ANK, LRR, ROC, COR,
MAP-KKK and WD40 domains Proven pathogenic
mutations are shown in red Potentially
pathogenic mutations, for which
co-segrega-tion analyses were reported, are highlighted
in blue Variants of unknown significance,
found in single PD patients, are highlighted
in black Risk factors are shown in red and
in a yellow box.
Trang 4among Asian races For example, the LRRK2 G2019S
substitution has not been found in three independent
Chinese populations involving more than 2000 study
subjects, whereas it has been detected among Japanese
and rarely among Indians [15–17] Different founder
haplotypes have been described in G2019S carriers A
common 193 kb genomic region, so-called haplotype 1,
is shared by 95% of G2019S carriers of European,
North and South African and Ashkenazi Jewish origin
[18,19] The mutation possibly arose in Ashkenazi Jews
much earlier than in North African Arabs and
Euro-peans several thousand years ago [20] The frequency
of this haplotype in non-G2019S Chinese carriers in
both PD and controls is 30–33%, which is similar
to the frequency in European noncarriers [21] The
sec-ond rare haplotype is found in a total of five families
of European ancestry The third, found primarily in
Japanese carriers, has also been reported in a Turkish
family [22,23] Distinct G2019S haplotypes in different
races suggest that the mutation originates from
different founders in Europe and Asia
Mutational hotspot at position R1441
The R1441 ‘hotspot’ amino acid codon residues
gly-cine⁄ histidine ⁄ cysteine (G ⁄ H ⁄ C) in the ROC domain is
the second most common site of pathogenic LRRK2
substitutions, after G2019S [24] The R1441C mutation
was initially found in two autosomal-dominant PD
families [4] Affected individuals reported typical PD
symptoms and the mean age at onset in the first family
was 65 years Two asymptomatic mutation carriers
were more than 60 years old The phenotype of
carri-ers in the second family was similar, with mean age at
onset of 56 years Interestingly, Zabetian et al [25]
reported a R1441C patient with sporadic PD with
onset at age 61 years and all nine siblings were
asymp-tomatic even though they were more than 60 years
old These initial observations suggest that the
pene-trance of R1441C can be highly variable Recently,
in a worldwide pooled analysis involving 33 affected
and 15 unaffected R1441C mutation carriers, the
demographics and clinical features of LRRK2 carriers
were found to be generally similar to idiopathic PD
[14] More than 90% had developed symptoms by
75 years of age Four independent founders for the
R1441C mutation have also been reported [26] The
apparent high penetrance in this pooled analysis
needs to be interpretated with caution because this
is not a population-based study Although R1441C
is found in different ethnic races, R1441G is most
common in the Basque Country ( 20%) and is rare
outside of Northern Spain [27–29] A common
founder for R1441G carriers was found to date back
to the 7th Century in Northern Spain [29] R1441H has been described in four probands of diverse ethni-cities [30]
Polymorphic variants G2385R variant
The discovery of polymorphic risk variants is unex-pected because few of genetic variants linked to PD have been consistently replicated [31] Evidence of an association of LRRK2 polymorphic variants with PD was reported in 2005 when a haplotype that increases disease risk when present in two copies was identified among sporadic Chinese PD population in Singapore [32] However, other studies did not reveal association with any LRRK2 haplotypes in Caucasians, suggesting the existence of ethnic-specific differences [33–35] In
2005, Mata et al [24,36] reported a G2835R variant a
PD family from Taiwan and it was thought that it could be a pathogenic mutation However, Tan et al [37] and Di Fonzo et al [38] subsequently found that the G2385R variant is a common polymorphism and increases the risk of PD in Singaporean and Taiwan populations This association has been consistently replicated among Chinese and Japanese populations with an average carrier rate of 9% in PD and 4% in controls [37,39–41] The population attributable risk for the heterozygous genotype is 4% It has been sug-gested that the G2385R variant possibly originates from one common ancestor in China 4000 years ago [40] Thus far, LRRK2 G2385R appears absent in Caucasian subjects [41] Interestingly, the G2385R var-iant has not been shown to be a risk factor for PD among Indians and Malays in Singapore or to be asso-ciated with other neurodegenerative conditions such as Alzheimer’s disease [42] The LRRK2 G2385R is located in the WD40 domain, and the base substitu-tion alters the net positive charge of the WD40 domain Because WD40 domain is involved in mediat-ing protein–protein interactions, the LRRK2 G2385R variant may impact on interactions with substrates and⁄ or regulatory proteins Preliminary studies suggest that it may lead to decreased kinase activity and be pro-apoptoptic under cellular stresses [12,41] The clin-ical features of G2385R carriers are similar to noncar-riers, although those individuals with familial PD appear to have a higher carrier rate [43] Recently, a large-scale pooled analysis involving multiple Asian centers revealed that the G2385R variant lowers the age of onset of PD [44] However, because almost all the G2385R carriers are heterozygotes, the additive
Trang 5effect of carrying two copies of the variant could not
be meaningfully determined
R1628P variant
R1628P is the second risk factor to be identified in the
Han Chinese population after the G2385R because
investigators found that it increased the risk of PD
among Chinese in Taiwan and Singapore [45,46]
LRRK2 R1628P is located in the COR domain and is
evolutionarily conserved across species, highlighting
the importance of the residue (arginine) to protein
function The LRRK2 R1628P variant has not been
detected in Indian subjects and does not appear to be
associated with risk among individuals of Malay
eth-nicity [47] It is possibly rare or absent among whites
and, interestingly, has not been detected in Japanese
patients The phenotype of carriers appears similar to
idiopathic PD [45,48] It would appear that the
muta-tional event associated with LRRK2 R1628P is more
recent, occurring 2500 years ago, compared to
estimates of 4000 years for carriers of the LRRK2
G2385R variant [46] Very few subjects carry both
G2385R and R1628P risk alleles However, the
esti-mated population attributable risk of R1628P and
G2385R variants is 10% [48] The functional
activi-ties of R1628P have yet to be determined
Phenotype–genotype correlation
On the basis of findings of a multicenter pooled
analy-sis, it is quite clear that R1441C, G2019S and other
mutational carriers share a common phenotype with
idiopathic PD [14,26] Thus, LRRK2 carriers simulate
late onset PD and present with the usual typical PD
clinical features These observations challenge the
clas-sification of ‘idiopathic PD’ Although long-term
longi-tudinal data are not available, Healy et al [14], in
their worldwide pooled analysis, reported that both
motor symptoms and nonmotor symptoms (e.g
cogni-tion) of LRRK2 carriers appear to be milder than
those of idiopathic PD
Phenotype studies
Positron emission tomography (PET), by providing
quantitative information on dopaminergic function, is
useful for the in vivo investigation of PD [18
F]6-fluoro-l-dopa uptake correlates with the number of nigral
dopamine neurons in humans and in animal models of
PD [49] Thus, PET and other functional imaging
modalities provide a useful means to monitor nigral
integrity in LRRK2 asymptomatic and symptomatic
carriers In one of the earliest functional imaging stud-ies on LRRK2 carriers, Adams et al [50] reported that abnormalities on functional imaging studies are quite similar between LRRK2 carriers and sporadic PD More recently, a multitracer PET study was carried out in asymptomatic members of the kindred from family D (R1441C) with some of them rescanned 2–3 years apart [49] Worsening of PET markers over time was greater compared to healthy controls for some of the carriers This suggests that progressive dopaminergic dysfunction occurs in pre-symptomatic members of the LRRK2 kindred The identification of these individuals could provide an opportunity for potential early neuroprotective interventions
Interestingly, transcranial sonography studies in LRRK2 carriers revealed that substantia nigra echoge-nicity was greater compared to controls but smaller than in idiopathic PD [51] However, it remains specu-lative as to whether iron has a different pathophysio-logical role in LRRK2 carriers than in idiopathic PD Hyposmia is a common finding in majority of PD patients Using the University of Pennsylvania Smell Test, one study showed that the mean test score in G2019S parkinsonian carriers was lower than that in healthy controls, but no different in patients with PD [52] Two asymptomatic G2019S carriers had a normal smell test This test cannot differentiate LRRK2 carriers from idiopathic PD Myocardial 123 I-metaiod-obenzylguanidine (which assesses postganglionic sym-pathetic cardiac innervation) uptake is decreased in most PD patients Quattrone et al [53] showed that 50% of G2019S carriers compared to all the patients with idiopathic PD had impaired 123 I-metaiodobenzyl-guanidine uptake This suggests that G2019S carriers may not be a homogenous entity Taken together, the current limited clinical studies of LRRK2 mutation carriers appear to suggest that, although clinically inseparable, there may be subtle differences between these carriers with respect to idiopathic PD and further investigations should be considered It is unclear how the variable pathology associated with G2019S muta-tions influences the phenotypic features
Genetic testing for G2019S
A genetic test can help confirm or exclude a suspected genetic disease The test can also help determine the risk of developing the disorder for an individual The recent discovery of the common LRRK2 G2019S mutation provides an opportunity for testing in fami-lies with autosomal-dominant pattern inheritance, as well as in some cases of sporadic PD However, the clinical utility of such testing would require careful
Trang 6evaluation of the potential risks and benefits of testing
and the availability of treatment options to manage
those at risk However, the feasibility of diagnostic
and predictive testing of PD is not as simple as it
appears to be Many questions have been raised,
including the sensitivity and specificity of the test and
reliability of the laboratory carrying the test [54]
Spe-cific to G2019S testing, its incomplete penetrance
com-plicates pre-symptomatic genetic testing For other
LRRK2 mutations, there are questions regarding its
actual pathogenicity Some investigators have argued
that such testing should be carried out under a
research setting rather than as part of a clinical service
because it will help remove concerns regarding
insur-ability and other social issues Genetic testing should
preferably be supported by a multidisciplinary team
with expertise in handling pre-testing and post-testing
related problems A recent study has demonstrated
that the relationship between the level of genetic
knowledge and the attitude towards the potential risks
and benefits of predictive genetic testing in PD may be
influenced by racial and cultural differences and, thus,
this has to be taken into consideration in counseling
programs [55]
For LRRK2 testing, there is a lack of available
sci-entific information with respect to advising subjects on
their prognosis and the result will not alter the
man-agement of the disease The large size of the LRRK2
makes it impractical to provide comprehensive
screen-ing Furthermore, the pathogenicity of many of the
putative heterozygous LRRK2 mutations is unclear
because many of them have been described in single
patients and no segregation data in affected families
are available Nevertheless, testing for G2019S in
spo-radic late-onset PD can be considered in some
situa-tions and may be useful in populasitua-tions with high
carrier status [56] It will be useful if professional
bodies come together to set up guidelines and help
provide advice to both patients and the public
Future directions
The discovery of the gene for LRRK2 as a causative
gene in PD is both extremely important and exciting
because LRRK2 mutations are the most common
cause of familial PD and a common mutation and two
common polymorphic risk variants have been
identi-fied Furthermore, the varied prevalence of causative
mutations and risk variants across different ethnic
populations suggest that, besides a common founder
effect, epigenetic or other factors such as
environmen-tal or lifestyle factors may be important Multicenter
studies to determine the prevalence, penetrance and
phenotype–genotype correlation for the various reported LRRK2 mutations, and gene–environmental interaction would be needed As the the gene for LRRK2 is large, studies that report direct sequence analysis of the entire gene and copy number analysis are still limited Thus, familial segregation analysis and functional studies to determine which ones are truly pathogenic are needed Additional studies to determine haplotype structure, population and ethnic differences and identification of new risk variants will also be use-ful The identification of asymptomatic mutation and risk variant carriers provides a unique opportunity in the field because these subjects are ideal candidates for potential neuroprotective trials and longitudinal studies
to identify biomarkers of neurodegeneration Clinical, genetic and biological information gathered from genetic underpinnings of PD will hopefully be trans-lated into better treatment for patients
Acknowledgement Supported by Singapore Millennium Foundation, National Medical Research Council, Biomedical Research Council, Duke-NUS Graduate Medical School and SingHealth Services
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