Glucocerebrosidase mutations in subjects with parkinsonism

Recent studies showing an association between glucocerebrosidase deficiency and parkinsonism in Gaucher disease prompted an examination of the glucocerebrosidase gene sequence (GBA) and enzyme activity in brain samples from 57 subjects carrying the diagnosis of Parkinson disease. Alterations in GBA were identified in 12 samples (21%) and were more frequent among the younger subjects. These included eight with mutations (N370S, L444P, K198T, and R329C) and four with probable polymorphisms (T369M and E326K). Our findings suggest that mutations in glucocerebrosidase may be a risk factor for the development of parkinsonism.     

LRRK2 mutations are not common in Alzheimer's disease

The development of common age-related neurodegenerative disorders as Parkinson's disease and Alzheimer's disease (AD) are influenced by genetic factors. Recently, pathogenic mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified in familial Parkinsonism. Individuals in some of these families developed symptoms of dementia with Lewy-bodies and AD. The LRRK2 gene is also located within a locus on chromosome 12 reported in late-onset AD, and is therefore a good candidate gene for dementia. A series of 242 patients from Norway diagnosed clinically with dementia were included in the study, the majority were diagnosed with AD. Individuals were screened for the presence of seven known pathogenic mutations previously reported in the LRRK2 gene. We did not identify LRRK2 mutations in our series of dementia patients, indicating that known pathogenic mutations are not common in patients clinically diagnosed with AD. However, these results do not exclude a possible role of other genetic variants within the LRRK2 gene in AD or other forms of dementia.     

Analysis of LRRK 2 G 2019 S and I 2020 T mutations in Parkinson's disease

Mutations in the leucine-rich repeat kinase 2 (LRRK 2), encoding dardarin protein, have been demonstrated to be linked to autosomal dominant Parkinson's disease (PD). In the present study the entire exon 41 of LRRK 2 gene was evaluated in a series of 174 PD patients recruited from Polish population, aged at the time of diagnosis 54.0+/-39.1 years, 21 of them had positive family history of PD with mean onset of the disease of 51.9+/-11.7 years as well as in 190 healthy controls aged 73.7+/-6.0 years. The mutations were evaluated by direct sequencing for mutations in exon 41 of LRRK 2 gene. In the studied patients no known mutations in exon 41 of LRRK 2 gene, including G 2019 S and I 2020 T were found, both in PD patients as well as in the controls. It can be concluded that the G 2019 S and I 2020 T mutations in exon 41 of LRRK 2 gene are rare causes of Parkinson disease in a Polish population.     

LRRK2 G2019S is a common mutation in Spanish patients with late-onset Parkinson's disease

Mutations in the leucine-rich repat kinase 2 (LRRK2) gene have been shown to cause both autosomal dominant and sporadic Parkinson's disease (PD). The common G2019S mutation shows wide geographical distribution while R1441G has been only reported in Northern Spain. The overall frequency of these mutations remains to be established. To determine the prevalence of G2019S and R1441G mutations in our population of Cantabria (Northern Spain), we recruited 105 consecutive PD patients and 310 controls and conducted genetic analysis of these mutations. G2019S was detected in eight late-onset patients (7.6%). Five of them had no relevant family history. R1441G was not detected in any of our study subjects. The prevalence of G2019S mutation in unselected late-onset PD patients might be higher than previously reported: 3/16 (18.7%) of familial PD and 5/82 (6.1%) of sporadic PD.     

LRRK2 Parkinson disease mutations enhance its microtubule association

Dominant missense mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic causes of Parkinson disease (PD) and genome-wide association studies identify LRRK2 sequence variants as risk factors for sporadic PD. Intact kinase function appears critical for the toxicity of LRRK2 PD mutants, yet our understanding of how LRRK2 causes neurodegeneration remains limited. We find that most LRRK2 PD mutants abnormally enhance LRRK2 oligomerization, causing it to form filamentous structures in transfections of cell lines or primary neuronal cultures. Strikingly, ultrastructural analyses, including immuno-electron microscopy and electron microscopic tomography, demonstrate that these filaments consist of LRRK2 recruited onto part of the cellular microtubule network in a well-ordered, periodic fashion. Like LRRK2-related neurodegeneration, microtubule association requires intact kinase function and the WD40 domain, potentially linking microtubule binding and neurodegeneration. Our observations identify a novel effect of LRRK2 PD mutations and highlight a potential role for microtubules in the pathogenesis of LRRK2-related neurodegeneration.     

Glucocerebrosidase mutations in Chinese subjects from Taiwan with sporadic Parkinson disease

BACKGROUND: An association between glucocerebrosidase, the enzyme deficient in Gaucher disease, and the synucleinopathies has been suggested both by the development of parkinsonism in Gaucher probands and carriers, as well as by the presence of mutations in the gene for glucocerebrosidase (GBA) in different series of subjects with synucleinopathies. In this study, an open access Parkinson repository was used to establish the incidence of GBA alterations in a different ethnic cohort with sporadic Parkinson disease (PD). METHODS: The glucocerebrosidase gene was sequenced in samples collected from 92 Chinese Parkinson disease patients from Taiwan along with 92 clinically screened controls, matched for age and ethnicity. FINDINGS: The frequency of GBA mutations among the Chinese PD probands was 4.3%, in contrast to 1.1% in Chinese controls. Mutant alleles identified included two known mutations, L444P and D409H, and two novel mutations, L174P and Q497R. INTERPRETATION: These results, ascertained in subjects from Taiwan collected in a standardized and clinically rigorous open access Parkinson disease repository and screened by direct sequencing of GBA, demonstrate that GBA mutations are also encountered in Chinese subjects with sporadic PD at a higher frequency than many other known PD genes. The study demonstrates that the association of GBA mutations with the development of parkinsonian pathology is not related to ethnic origin.     

LRRK2基因G2019S突变帕金森病相关基因的生物信息学分析

目的 从分子水平揭示富亮氨酸重复激酶2（LRRK2)基因G2019S突变帕金森病的发病机制,为临床诊断及治疗提供新思路。 方法 在公共基因芯片数据库（GEO）中下载LRRK2基因G2019S突变帕金森病的相关基因芯片数据（GSE22491）,其中LRRK2(G2019S)突变帕金森病样本10 例,正常控制组样本8 例,利用Qlucore Omics Explorer（QOE）3.0 软件、DAVID、STRING等在线分析软件对LRRK2基因G2019S突变帕金森病差异基因进行生物信息学分析。结果 QOE3.0分析筛选出1752个LRRK2基因G2019S突变帕金森病差异基因,其中上调191个,下调1561个。对其进行生物信息学分析发现,SKP2、RBX1、SKP1、CUL1、CUL4A 等基因以及核糖体信号通路、氧化磷酸化信号通路、蛋白酶体信号通路、白细胞跨内皮迁移信号通路、磷酸戊糖途径信号通路、枸橼酸信号通路、Fcγ受体（FcγR）介导的吞噬通路等在LRRK2基因G2019S突变帕金森病的发生发展中可能起着重要作用。 结论 通过生物信息学分析LRRK2基因G2019S突变帕金森病相关基因芯片数据,提示LRRK2基因G2019S突变帕金森病发病是多种基因、多种分子机制相互作用的结果,对相关分子机制的进一步分析有利于揭示LRRK2基因G2019S突变帕金森病的发病机制。     

Glucocerebrosidase mutations are not a common risk factor for Parkinson disease in North Africa

Mutations in the glucocerebrosidase gene (GBA) have recently been associated with an increased risk of Parkinson disease (PD). GBA mutations have been observed to be particularly prevalent in the Ashkenazi Jewish population. Interestingly, this population also has a high incidence of the Lrrk2 p.G2019S mutation which is similar in North African Arab-Berber populations. Herein, our sequencing of the GBA gene, in 33 North African Arab-Berber familial parkinsonism probands, identified two novel mutations in three individuals (p.K-26R and p.K186R). Segregation analysis of these two variants did not support a pathogenic role. Genotyping of p.K-26R, p.K186R and the common p.N370S in an ethnically matched series consisting of 395 patients with PD and 372 control subjects did not show a statistically significant association (P > 0.05). The p.N370S mutation was only identified in 1 sporadic patient with PD and 3 control subjects indicating that the frequency of this mutation in the North African Arab-Berber population is much lower than that observed in Ashkenazi Jews, and therefore arose in the latter after expansion of the Lrrk2 p.G2019S variant in North Africa.     

Mechanistic insight into the dominant mode of the Parkinson's disease-associated G2019S LRRK2 mutation

Pathogenic mutations in the leucine-rich repeat kinase-2 (LRRK2) gene cause autosomal-dominant and certain cases of sporadic Parkinson's disease (PD). The G2019S substitution in LRRK2 is the most common genetic determinant of PD identified so far, and maps to a specific region of the kinase domain called the activation segment. Here, we show that autophosphorylation of LRRK2 is an intermolecular reaction and targets two residues within the activation segment. The prominent pathogenic G2019S mutation in LRRK2 results in altered autophosphorylation, and increased autophosphorylation and substrate phosphorylation, through a process that seems to involve reorganization of the activation segment. Our results suggest a molecular mechanistic explanation for how the G2019S mutation enhances the catalytic activity of LRRK2, thereby leading to pathogenicity. These findings have important implications for therapeutic strategies in PD.     

The G2019S LRRK2 mutation is uncommon in an Asian cohort of Parkinson's disease patients

A common heterozygous leucine-rich repeat kinase 2 (LRRK2) mutation 6055G > A transition (G2019S) accounts for about 3-7% of familial Parkinson's disease (PD) and 1-1.6% sporadic PD in a number of European populations. To determine the prevalence of the G1019S mutation in our Asian population, we conducted genetic analysis of this mutation in 1000 PD and healthy controls. The G2019S mutation was not detected in any of our study subjects. The prevalence of G2019S mutation is rare (< 0.1%) in our population, suggesting that occurrence of this mutation may vary amongst different ethnic races. This has important clinical implication when implementing guidelines for genetic testing.     

Glucocerebrosidase gene mutations in patients with type 2 Gaucher disease

Gaucher disease, the most common lysosomal storage disorder, results from the inherited deficiency of the enzyme glucocerebrosidase. Three clinical types are recognized: type 1, non-neuronopathic; type 2, acute neuronopathic; and type 3, subacute neuronopathic. Type 2 Gaucher disease, the rarest type, is progressive and fatal. We have performed molecular analyses of a cohort of 31 patients with type 2 Gaucher disease. The cases studied included fetuses presenting prenatally with hydrops fetalis, infants with the collodion baby phenotype, and infants diagnosed after several months of life. All 62 mutant glucocerebrosidase (GBA) alleles were identified. Thirty-three different mutant alleles were found, including point mutations, splice junction mutations, deletions, fusion alleles and recombinant alleles. Eleven novel mutations were identified in these patients: R131L, H255Q, R285H, S196P, H311R, c.330delA, V398F, F259L, c.533delC, Y304C and A190E. Mutation L444P was found on 25 patient alleles. Southern blots and direct sequencing demonstrated that mutation L444P occurred alone on 9 alleles, with E326K on one allele and as part of a recombinant allele on 15 alleles. There were no homozygotes for point mutation L444P. The recombinant alleles that included L444P resulted from either reciprocal recombination or gene conversion with the nearby glucocerebrosidase pseudogene, and seven different sites of recombination were identified. Homozygosity for a recombinant allele was associated with early lethality. We have also summarized the literature describing mutations associated with type 2 disease, and list 50 different mutations. This report constitutes the most comprehensive molecular study to date of type 2 Gaucher disease, and it demonstrates that there is significant phenotypic and genotypic heterogeneity among patients with type 2 Gaucher disease. Hum Mutat 15:181-188, 2000. Published 2000 Wiley-Liss, Inc.     

Analysis of the LRRK2 p.G2019S mutation in Colombian Parkinson's Disease Patients

Introduction:

Mutations in the leucine-rich repeat kinase 2 gene (LRRK2 or Dardarin) are considered to be a common cause of autosomal dominant and sporadic Parkinson´s disease, but the prevalence of these mutations varies among populations.

Objective:

to analyzed the frequency of the LRRK2 p.G2019S mutation (c.6055 G>A transition) in a sample of Colombian patients.

Methods:

In the present study we have analyzed the frequency of the LRRK2 p.G2019S mutation in 154 patients with familial or sporadic Parkinson Disease, including early and late onset patients, and 162 normal controls.

Results:

Our results show occurrence of this mutation in two cases (2/154, 1.3%) with classical Parkinson´s signs, and one completely asymptomatic control (1/162, 0.6%).

Conclusion:

The p.G2019S mutation is not an important causal factor of Parkinson Disease in Colombia having similar frequencies to those reported in other Latin American populations.     

A comparative study of Parkinson's disease and leucine-rich repeat kinase 2 p.G2019S parkinsonism

Parkinson disease is a progressive neurodegenerative disease for which leucine-rich repeat kinase 2 (LRRK2 carriers) p.G2019S confers substantial genotypic and population attributable risk. With informed consent, we have recruited clinical data from 778 patients from Tunisia (of which 266 have LRRK2 parkinsonism) and 580 unaffected subjects. Motor, autonomic, and cognitive assessments in idiopathic Parkinson disease and LRRK2 patients were compared with regression models. The age-associated cumulative incidence of LRRK2 parkinsonism was also estimated using case-control and family-based designs. LRRK2 parkinsonism patients had slightly less gastrointestinal dysfunction and rapid eye movement sleep disorder. Overall, disease penetrance in LRRK2 carriers was 80% by 70 years but women become affected a median 5 years younger than men. Idiopathic Parkinson disease patients with younger age at diagnosis have slower disease progression. However, age at diagnoses does not predict progression in LRRK2 parkinsonism. LRRK2 p.G2019S mutation is a useful aid to diagnosis and modifiers of disease in LRRK2 parkinsonism may aid in developing therapeutic targets.     

Glucocerebrosidase mutations do not cause increased Lewy body pathology in Parkinson's disease

Mutations in the glucocerebrosidase (GBA) gene have been implicated in increased formation of Lewy bodies (LBs) in Parkinson's disease (PD). We found GBA mutation status not to be significantly associated with the density of cortical LBs, after adjusting for sex, age at death, duration of PD and presence of dementia. Comparison of GBA carriers to PD controls found no difference in Alzheimer's disease pathological findings. Our results do not support GBA carriers to have a more advanced neuropathologic disease i.e. increased density of protein aggregates.     

LRRK2 R1441G in Spanish patients with Parkinson's disease

Pathogenic mutations in leucine-rich repeat kinase 2 (LRRK2; PARK8) have been implicated in autosomal dominant, late-onset Parkinson's disease (PD). The LRRK2 4321C>G (R1441G) mutation was originally identified in Spanish families originating from the Basque region. Within this ethnicity, Lrrk2 R1441G substitutions have been suggested as a frequent cause of disease. Herein we have assessed another referral-based series of 225 patients with PD from the neighboring region of Asturias, Northern Spain. The LRRK2 4321C>G mutation was found in 5 (2.7%) of sporadic, late-onset patients and was not present in control subjects. Although patients with a Lrrk2 R1441G substitution are apparently unrelated, they share a chromosome 12q12 haplotype not found in controls and indicative of a common founder.