F.-Y. Hu

Association of the glucocerebrosidase N370S allele with Parkinson’s disease in two separate Chinese Han populations of mainland China

Background and purpose:  Mutations in the glucocerebrosidase (GBA) gene have been implicated in the development of Parkinson’s disease (PD). However, recent screenings for GBA mutations in PD subjects from different ethnic populations have yielded contradictory results.

H63D polymorphism in the hemochromatosis gene is associated with sporadic amyotrophic lateral sclerosis in China.

Background and purpose:  The H63D polymorphism in the hemochromatosis (HFE) gene has been reported as a risk factor for amyotrophic lateral sclerosis (ALS) in Europe and America, but no data have been reported for Asia. Here, we investigated the possible association between H63D and sporadic ALS (sALS) in a Chinese Han population.

Anti-NMDA receptor encephalitis: clinical characteristics, predictors of outcome and the knowledge gap in southwest China.

The aim was to analyse the clinical profiles and outcomes of patients with anti‐ N‐methyl‐d‐aspartate receptor (anti‐NMDAR) encephalitis in China.

SNP rs7684318 of the α-synuclein gene is associated with Parkinson's disease in the Han Chinese population

Mutations in the alpha-synuclein (SNCA) gene have been shown to be responsible for a rare familial form of Parkinsons disease (PD). Furthermore, polymorphic variants in multiple regions of the gene have been associated with susceptibility to idiopathic PD in different populations. Previous studies in Japanese have found a strong association between idiopathic PD and the single-nucleotide polymorphism (SNP) rs7684318, which is located within an intron of the SNCA gene. Our aim was to verify these findings and to further explore the nature of the association in a subset of Han Chinese PD patients. A case-control study of the SNP rs7684318, comprising 332 PD patients and 300 healthy controls, was carried out in Han Chinese populations from two centers in mainland China. The rs7684318 polymorphism was determined by PCR-restriction fragment length polymorphism (PCR-RFLP) analysis. The SNP rs7684318 of the SNCA gene showed a strong association with PD (P<0.01). Among our PD patients, mean age at disease onset and gender did not differ significantly between rs7684318 carriers and non-carriers. Our findings suggested that the SNP rs7684318 (T>C) transition of the SNCA gene contributes to PD susceptibility in Chinese Han population, which is consistent with the earlier study form Japan.

LRRK2 R1628P contributes to Parkinson's disease susceptibility in Chinese Han populations from mainland China

Common genetic variants that increase the risk for Parkinsons disease (PD) may differentiate patient subgroups and influence future individual therapeutic strategies. Previous studies have found associations between PD and polymorphisms located within the leucine-rich repeat kinase 2 (LRRK2) gene in ethnic Han Chinese from Taiwan and Singapore. Herein, we performed a case-control study and provide evidence supporting the LRRK2 R1628P variant as a risk factor for PD in 2 separate Chinese Han populations from mainland China. A total of 328 PD patients and 300 control individuals were genotyped using PCR-restriction fragment length polymorphism analysis. Differences in genotype frequencies between groups were assessed by the chi-square test. In the PD group, 17 patients (5.2%) were heterozygous for the R1628P variant. This was significantly higher than for the control group [2.0%, P<0.05].No one carrier of the LRRK2 G2385R variant was detected in all the carriers of the R1628P variant. Our results confirm that the LRRK2 R1628P variant contributes to the pathogenesis of PD in Chinese Han populations.

The transcription factor Pitx3 is a risk modifier for Parkinson’s disease in a Chinese Han population

Background and purpose:  The transcription factor Pitx3 plays a crucial role in the development and survival of midbrain dopaminergic (mDA) neurons, especially the mDA neurons in the substantia nigra pars compacta. The degeneration of these neurons is the pathological hallmark in Parkinson’s disease (PD). Several polymorphisms of the Pitx3 gene have been linked with sporadic and early‐onset forms of PD, but different studies have given conflicting or inconsistent findings. Amongst the polymorphisms studied, the single‐nucleotide polymorphism (SNP) rs3758549, located in the promoter region of Pitx3 gene, is one of the most well‐studied but also one of the most controversial. In order to explore the nature of this association in greater detail and in a new ethnic group, we carried out a case–control study of the SNP rs3758549.

Two novel mutations of the GTP cyclohydrolase 1 gene and genotype-phenotype correlation in Chinese Dopa-responsive dystonia patients.

The most common form of Dopa-responsive dystonia (DRD) is caused by heterozygous mutations in the GTP cyclohydrolase I (GCH1) gene. We screened two unrelated, DRD-symptomatic Chinese Han individuals, for GCH1 gene mutations by direct sequencing. As the clinical manifestations of DRD are highly variable, we also explored the association between genotype and phenotype in all Chinese DRD patients reported so far in the literature, comprising 62 DRD-affected patients from 36 Chinese families. Two novel missense mutations (T94M, L145F) and a novel variant (c. 453+6 G>T) were identified in our two new patients. None of these variants was detected in 200 healthy controls. On the basis of this and other reports, heterozygous mutations were detected in 90.3% of Chinese Han subjects with DRD. Seeming the age of onset for males and females, the mean age was 13 years older in males than in females (P=0.006). Different mutation types did not show any significant differences in age of onset, gender composition, initial symptoms, or the L-dopa dose that abolished the symptoms. Among DRD patients lacking missense or exon–intron boundary mutations, 68.4% were found to possess a large deletion in GCH1, which were detected by multiplex ligation-dependent probe amplification. Most GCH1 mutations were found to cluster in two regions of the coding sequence, suggesting the probable existence of mutation hotspot for the first time. The genotype–phenotype correlation described here may improve our understanding of DRD in Chinese individuals.

A novel missense mutation in GTP cyclohydrolase I (GCH1) gene causes Dopa-responsive dystonia in Chinese Han population.

Background:  Dopa‐responsive dystonia has been shown to be caused by a number of different mutations in the GCH1 gene. Up to now, only several genetic studies of Chinese patients with Dopa‐responsive dystonia (DRD) have been reported.

ACTA2 is not a major genetic risk gene for Chinese patients with moyamoya disease

In 2009, Guo et al. (1) first reported that mutation carriers of the vascular smooth muscle cell-specific isoform of a-actin (ACTA2) gene can have a diversity of vascular diseases, including thoracic aortic aneurysms and dissections, coronary artery disease, premature ischemic stroke, and moyamoya disease (MMD). These results indicate that heterozygous ACTA2 mutations can increase the risk for MMD and ACTA2 may be a genetic susceptibility gene to MMD. However, subsequent studies in two ethnic populations demonstrated that ACTA2 was not a major disease-causing gene for MMD. One study did not detect the ACTA2 mutation in 53 Japanese MMD patients (2). Another study found only one missense mutation of ACTA2 in one of the 39 European patients with MMD (3). These conflicting results suggest that it is premature to conclude an association between ACTA2 and MMD. MMD is an uncommon cerebrovascular disease characterized by progressive occlusion of terminal portions of the internal carotid arteries causing cerebral ischemia and haemorrhage. The previously reported cases were mainly from Asian populations, especially in Japan. To date, the etiology of MMD remains unclear. In order to clarify the currently uncertain association of ACTA2 with MMD, we conducted a replication study in a Chinese Han population. Fifty-five patients with MMD (male/ female = 24/31, mean age 33·4 12·1 years) were recruited to our study. All nine exons and exon-intron boundaries of ACTA2 were sequenced directly. However, genomic sequencing did not find any ACTA2 mutation. Our findings further confirmed that ACTA2 did not play an important role in the pathogenesis of MMD. Owing to some limitations of the sample size, however, larger studies are warranted to further evaluate the possible association of ACTA2 or other genes and MMD in varied populations.

ACTA2 is not a major responsible gene for spontaneous cerebral artery dissection

Recent study revealed that missense mutations in the vascular smooth muscle cell-specific isoform of a-actin (ACTA2) gene cause a variety of vascular diseases, including thoracic aortic aneurysms and dissections, premature coronary artery disease, stroke, and moyamoya disease (1). In addition, a novel missense mutation of ACTA2 was also found in sporadic patients with spontaneous cervical artery dissection (2). These observations raised the possibility that ACTA2 mutations may be involved in the development of spontaneous cerebral artery dissection (SCAD). SCAD is one of the most common reasons for young stroke. However, the etiology of SCAD is still poorly understood. Genetic factors may play an important role in the pathogenesis of SCAD (3). In the present study, we tested the hypothesis that ACTA2 is also a potential diseasecausing gene for SCAD. We performed a mutational analysis of the ACTA2 gene in 103 digital subtraction angiography (DSA)-confirmed Chinese SCAD patients, including 72 subjects with cervical artery dissection (male/ female = 48/24, mean age 48·4 10·6 years) and 31 subjects with vertebral artery dissection (male/female = 23/8, mean age 43·8 7·9 years). The nine exons and flanking intronic regions of ACTA2 were sequenced directly. However, we did not find any mutation in the coding region of the ACTA2 gene. Our data suggest that ACTA2 is not a major disease-causing gene for SCAD, especially for Chinese SCAD patients. Further studies are required to identify a responsible gene for SCAD.