Introduction
Parkinson's disease (PD) is a common degenerative
disease of the central nervous system in the elderly, which is
primarily associated with environmental and genetic factors. There
are a number of genes that have been established to be associated
with PD, which include LRRK2. Mutations of LRRK2 are considered to
be the most prevalent in the pathogenesis of PD; in studies of
North American and European PD patients, 5% had a mutation of LRRK2
and a family history of PD, while 1–2% had sporadic PD (1–4). The
LRRK2 gene is the causative gene of the autosomal dominant
hereditary type 8 PD (5,6). It is composed of five structural
domains, namely, the ankyrin repeat (ANK), leucine-rich repeat
(LRR), Ras of complex proteins (Roc) C-terminal of Roc (COR),
mitogen activated kinase kinase kinase (MAPKKK) and WD40 regions
(7–9). Major mutations of LRRK2 include R1441C,
R1441G, R1441H, R1514Q, Y1699C, G2019S, I2020T, I2012T and G2385R
(10–12). Mutations of LRRK2 have been
associated with a number of diseases, in particular with familial
PD and sporadic PD, and the G2019S mutation is one of the most
common mutations in PD (13). Clear
racial and regional differences exist in the incidence of PD.
Xinjiang is an autonomous region located in Central
Asia, which has two predominant populations with different genetic
backgrounds, namely, the Uyghur and Han populations. The current
case-control study selected PD patients and healthy individuals
from the Uyghur and Han populations of the Xinjiang region for the
analysis of LRRK2 gene mutations. To the best of our knowledge,
this is the first time that the association between the G2019S and
R1441C mutations of the LRRK2 gene and PD susceptibility has been
investigated in different ethnicities and regions.
Subjects and methods
Diagnostic criteria and study
subjects
From June 2010 to April 2013, 312 patients with PD
(all sporadic) visiting the specialist neurology clinic of the
First Affiliated Hospital of Xinjiang Medical University (Urumqi,
China) were enrolled in the study. The diagnosis was in line with
the UK Brain Bank diagnostic criteria for PD. Cerebrovascular
disease, encephalitis, trauma, drug-induced Parkinson's syndrome,
Parkinson's plus syndrome and other severe systemic diseases were
excluded. The control group consisted of 359 volunteers from the
same region, who had no family history or clinical manifestations
of PD. Gender, age and ethnicity were matched between the two
groups. The study was approved by the Ethics Committee of the First
Affiliated Hospital of Xinjiang Medical University, and all
subjects provided informed consent.
DNA extraction
A sample of blood (2 ml) was collected from each
subject, subsequent to the provision of informed consent. Following
EDTA anticoagulation, a non-centrifugal-type DNA Extraction kit
(Shanghai Tiangen Biotech Co., Ltd., Shanghai, China) was used to
extract the genomic DNA Tris-borate buffer (Sangon Biotech Co.,
Ltd., Shanghai, China) was added and the DNA was maintained at
−80°C.
Design of primers and amplification of
the gene
The primers used for G2019S were based on those used
in a previous study by Thaler et al (14) and the sequences were as follows:
upstream, 5′-CCTGTGCATTTTCTGGCAGATA-3′ and downstream,
5′-CCTCTGATGTTTTTATCCCCATTC-3′. According to the study by
Paisán-Rauíz et al (7), the
primer sequences for R1441C were as follows: upstream,
5′-TCAACAGGAATGTGAGCAGG-3′ and downstream
5′-CCCACAATTTTAAGTGAGTTGC-3′. DNA amplification was carried out as
follows: The total volume of the quantitative polymerase chain
reaction (qPCR) was 20 µl, including 100 ng/µl upstream and
downstream primers (0.5 µl), 2X Power Taqman Master Mix (10 µl;
Beijing Baitaike Biotechnology Co., Ltd., Beijing, China), 50 ng/µl
DNA (3.0 µl) and ddH2O (11 µl). Primers were synthesized
by Sangon Biotech Co., Ltd (Shanghai, China). A GeneAmp System 9700
thermal cycler (Applied Biosystems Corporation, Foster City, CA,
USA) was used. PCR was performed after the first denaturation at
95°C for 2 min; each cycle consisted of denaturation at 95°C for 20
sec, annealing at 62°C for 20 sec and extension at 72°C for 30 sec.
The number of total PCR cycles was 35.
qPCR product detection
Equal volumes of PCR products (7 µl) were taken,
sample buffer [2X bromophenol blue; Sangon Biotech (Shanghai) Co.,
Ltd.] was added and the solution was mixed. The sample was placed
on a 4% agarose gel for nucleic acid staining and 4 V/cm
electrophoresis was performed for one hour.
Enzyme digestion genotyping
PCR products (8 µl), 10X endonuclease buffer (2 µl;
New England Biolabs, Inc., Ipswich, MA, USA) and restriction
endonucleases ScfI and BstUl (5 units; New England
Biolabs Inc., Ipswich, MA, USA) were added to 20 µl sterile double
distilled water and incubated at 37°C overnight (16 h). The
digestion products (9 µl) were placed on a 4% agarose gel for
ethidium bromide staining, and underwent electrophoresis at 110 V
for 1.5 h. A Gel Doc 1000 gel imaging analysis system (Bio-Rad,
Hercules, CA, USA) was used to detect the electrophoretic bands
(Fig. 1).
Direct sequencing
To determine the accuracy of the results, 10% of the
samples were randomly selected (31 from the patient group and 36
from the control group) for direct sequencing, which was performed
by Shanghai Invitrogen Biotechnology Co., Ltd. (Shanghai,
China).
Statistical methods
The age difference between the two groups was
compared using an independent samples t-test; the differences in
gender, allele and genotype frequencies between the two groups were
compared using a χ2 test. P<0.05 was considered to
indicate a statistically significant difference.
Results
qPCR
Using the template DNA, qPCR amplification products
of 329 bp were obtained from Uyghur (n=186) and Han (n=127)
patients with PD. All the products were digested with ScfI
overnight and 228 and 101 bp fragments were obtained as presented
in Fig. 1 (left). Following
amplification, PCR products of 386 bp were obtained, the resulting
products were digested overnight using BstU1, and two
fragments of 314 and 72 bp were obtained as presented in Fig. 1 (right).
Sequence analysis
Following random sequencing comparison, no G2019S
(Fig. 2) and R1441C (Fig. 3) mutations or novel heterozygotes
were found. For G2019S, only the GG genotype and no mutant
genotypes were identified in all subjects of the Han and Uygur
populations. For R1441C, only one genotype (CC) was identified in
the Han and Uygur populations. There were no differences between PD
patients and the control group in these two single nucleotide
polymorphisms (Tables I and II).
 | Table I.G2019S genotype and allele frequency
comparison/cases (%) of Parkinson's disease and control groups of
Uyghur and Han individuals from Xinjiang. |
Table I.
G2019S genotype and allele frequency
comparison/cases (%) of Parkinson's disease and control groups of
Uyghur and Han individuals from Xinjiang.
|
|
| Genotype
frequency | Allele frequency |
| Control group | Allele frequency |
|---|
|
|
|
|
|
|
|
|
|---|
| Ethnic group | PD group | GG | GA | AA | G | A | Control group | GG | GA | AA | G | A |
|---|
| Uyghur | 130 | 130 (100) | 0 (0) | 0 (0) | 260 (100) | 0 (0) | 179 | 179 (100) | 0 (0) | 0 (0) | 358 (100) | 0 (0) |
| Male | 76 | 76
(100) | 0 (0) | 0 (0) | 152 (100) | 0 (0) | 104 | 104 (100) | 0 (0) | 0 (0) | 208 (100) | 0 (0) |
|
Female | 54 | 54 (100) | 0 (0) | 0 (0) | 108 (100) | 0 (0) | 75 | 75
(100) | 0 (0) | 0 (0) | 150 (100) | 0 (0) |
| Han | 182 | 182 (100) | 0 (0) | 0 (0) | 364 (100) | 0 (0) | 181 | 181 (100) | 0 (0) | 0 (0) | 362 (100) | 0 (0) |
|
Male | 109 | 109 (100) | 0 (0) | 0 (0) | 218 (100) | 0 (0) | 109 | 109 (100) | 0 (0) | 0 (0) | 218 (100) | 0 (0) |
|
Female | 73 | 73
(100) | 0 (0) | 0 (0) | 146 (100) | 0 (0) | 72 | 72
(100) | 0 (0) | 0 (0) | 144 (100) | 0 (0) |
| Table II.R441C genotype and allele frequency
comparison/cases (%) of Parkinson's disease and control groups of
Uyghur and Han individuals from Xinjiang. |
Table II.
R441C genotype and allele frequency
comparison/cases (%) of Parkinson's disease and control groups of
Uyghur and Han individuals from Xinjiang.
|
|
| Genotype
frequency | Allele
frequency |
| Control group | Allele
frequency |
|---|
|
|
|
|
|
|
|
|
|---|
| Ethnic group | PD group | CC | CT | CG | GT | TT | GG | C | T | Control group | CC | CT | CG | GT | TT | GG | C | T |
|---|
| Uyghur | 130 | 130 (100) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 260 (100) | 0 (0) | 179 | 179 (100) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 358 (100) | 0 (0) |
|
Male | 76 | 76 (100) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 152 (100) | 0 (0) | 104 | 104 (100) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 208 (100) | 0 (0) |
|
Female | 54 | 54
(100) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 108 (100) | 0 (0) | 75 | 75
(100) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 150 (100) | 0 (0) |
| Han | 182 | 182 (100) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 364 (100) | 0 (0) | 181 | 181 (100) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 362 (100) | 0 (0) |
|
Male | 109 | 109 (100) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 218 (100) | 0 (0) | 109 | 109 (100) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 218 (100) | 0 (0) |
|
Female | 73 | 73
(100) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 146 (100) | 0 (0) | 72 | 72
(100) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 144 (100) | 0 (0) |
Discussion
In recent years, an increasing number of studies
have focused on PD, and in particular on the genes associated with
PD. By far, the LRRK2 gene is the most frequently mutated gene in
autosomal dominant hereditary PD patients, and its incidence
gradually increases with age (1,15–17). The
LRRK2 gene is located on chromosome 12p11.2-q13.1 and has a total
length of 1,441 nucleotides, containing 51 exons and encoding 2,527
amino acids, with a relative molecular weight of 286,000. The
product protein LRRK2/dardarin is rich in leucine (18). In the study of the molecular activity
of LRRK2, two regions associated with GTP enzymes and kinases have
been found. The most common LRRK2 mutations in the two regions
affect the enzymatic activity, suggesting that their functionality
is important (19). Different LRRK2
mutations have been reported in patients with familial and sporadic
PD. Genome-wide association studies (GWAS) have found that common
mutations in SNCA, LRRK2, MAPT and HLA are risk factors for PD, and
have demonstrated that a loss of chromosome 18 can significantly
increase the development of PD (20–33).
G2019S is the most common causative mutation of PD, and ~2% of PD
cases are caused by the G2019S mutation (34). G2019S is located in exon 41 of the
LRRK2 gene; it increases LRRK2 kinase activity and accelerates the
phosphorylation of ezrin/radixin/moesin protein (11); however, while it induces neuronal
apoptosis it has no effect on the GTP carrier or GTP activity.
G2019S reduces the interaction of LRRK2 with the 14-3-3 proteins
and increases the aggregation of and interaction with FADD
(35). Healy et al (17) found that in 19,376 PD patients across
21 regions, the G2019S mutation was highest in North African
populations, and that it accounted for 39% of sporadic PD and 36%
of familial PD. In the Jewish population of Northern Europe, G2019S
accounted for 10% of cases of sporadic and 28% of cases of familial
PD. However, in Asia this locus mutation is very rare, only
accounting for 0.1% of LRRK2 mutations. In Japan, India, Singapore,
China, Taiwan and the mainland, Gly2019Ser and Arg1441Cys/Gly
mutations were not found in PD patients during LRRK2 gene
detection.
R1441C is another common mutation locus in LRRK2, it
is located in exon 31 of the LRRK2 gene, and it induces neuronal
apoptosis. It has no kinase activity, or at least the effect is
negligible; however, it stabilizes the LRRK2 dimer, reduces GTP
activity and participates in FADD aggregation (35). R1441G, found in northern Spain, has
the same codon as R1441H, which primarily occurs in the Caucasian
population (36). Of 304 patients
with PD in Belgium, 18.1% had familial PD, and the R1441C mutation
accounted for 10.7% (37). R1441C is
in the Roc functional domain, with GTP enzyme sequences to
participate in regulatory activities, including signal
transduction, cell differentiation and cell growth (38). R1441C impairs dopamine
neurotransmission and D2 receptor function, leading to degeneration
of the dopaminergic nervous system in patients with PD (38,39). To
the best of our knowledge, there has been no relevant report of the
mutation in Han PD patients.
In the current study, the G2019S and RL441C
mutations of the LRRK2 gene, or any novel variant of these, were
not found to be present in PD patients from the Han and Uyghur
populations. This is consistent with previous studies concerning
the Chinese population (40,41). These mutations may not be hot spot
mutations in PD; or the small sample size of this study may explain
why the mutations were not found. Future studies of these
populations may investigate recent-onset PD patients, larger sample
sizes and other mutations of the LRRK2 gene.
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