GCH1 variants contribute to the risk and earlier age-at-onset of Parkinson's disease: a two-cohort case-control study.

BACKGROUND: Common and rare variants of guanosine triphosphate cyclohydrolase 1 (GCH1) gene may play important roles in Parkinson's disease (PD). However, there is a lack of comprehensive analysis of GCH1 genotypes, especially in non-coding regions. The aim of this study was to explore the genetic characteristics of GCH1, including rare and common variants in coding and non-coding regions, in a large population of PD patients in Chinese mainland, as well as the phenotypic characteristics of GCH1 variant carriers. METHODS: In the first cohort of this case-control study, we performed whole-exome sequencing in 1555 patients with early-onset or familial PD and 2234 healthy controls; then in the second cohort, whole-genome sequencing was performed in sporadic late-onset PD samples (1962 patients), as well as 1279 controls. Variants at target GCH1 regions were extracted, and then genetic and detailed phenotypic data were analyzed using regression models and the sequence kernel association test. We also performed a meta-analysis to correlate deleterious GCH1 variants with age at onset (AAO) in PD patients. RESULTS: For coding variants, we identified a significant burden of GCH1 deleterious variants in early-onset or familial PD cases compared to controls (1.2% vs 0.1%, P < 0.0001). In the analysis of possible regulatory variants in GCH1 non-coding regions, rs12323905 (P = 0.001, odds ratio = 1.19, 95%CI 1.07-1.32) was significantly associated with PD, and variant sets in untranslated regions and intron regions, GCH1 brain-specific expression quantitative trait loci, and two possible promoter/enhancer (GH14J054857 and GH14J054880) were suggestively associated with PD. Genotype-phenotype correlation analysis revealed that the carriers of GCH1 deleterious variants manifested younger AAO (P < 0.0001), and had milder motor symptoms, milder fatigue symptoms and more autonomic nervous dysfunctions. Meta-analysis of six studies demonstrated 6.4-year earlier onset in GCH1 deleterious variant carriers (P = 0.0009). CONCLUSIONS: The results highlight the importance of deleterious variants and non-coding variants of GCH1 in PD in Chinese mainland and suggest that GCH1 mutation can influence the PD phenotype, which may help design experimental studies to elucidate the mechanisms of GCH1 in the pathogenesis of PD.

Identification of novel SPG11 mutations in a cohort of Chinese families with hereditary spastic paraplegia.

AIM OF THE STUDY: To investigate the mutation frequency of SPG11, SPG15, SPG5 and SPG7 in China. MATERIALS AND METHODS: We have scanned the whole exons of KIAA1840, ZFYVE26, SPG7 and CYP7B1 genes in a group of 36 unrelated Chinese ARHSP families. RESULTS: SPG11 mutations were found in 33.33% (12/36) of ARHSP patients in our study, and no mutation was identified in SPG15, SPG5 or SPG7 genes. Among the SPG11 mutations detected, c.1755_1758delAGCA/p. P585PfsX623, c.29832984delTA/p.L934LfsX1010, c.1845_1848delGTCT/p.F617Lfs*5, c.6478+1G>T and c.3662_3665delTCAA/p.I1221RfsX1230 were novel mutations, they all introduced premature termination codons which were predicted to leading to the absence of the spastacsin protein in the patients' cells. All the SPG11 patients in our study presented with spastic paraparesis and/or mental impairment at initial time, and most patients showed thin corpus callosum (TCC) and white matter abnormalities (WMA) in brain MRI. After years' duration, they gradually manifested with dysarthria, dysphagia, peripheral neuropathy, amyotrophy, skeletal deformity, cerebellar signs, ophthalmoplegia, decreased vision, sphincter disturbance and tremor. CONCLUSIONS: SPG11 was suspected to be the most common subtype of ARHSP in China, whereas SPG15, SPG5 or SPG7 are rare. The core symptoms of Chinese SPG11 patients showed no difference when compared to SPG11 in western countries, and clinical heterogeneity also existed in our SPG11 patients. We suggested that ARHSP patients with mental impairment, especially combined with TCC, should be excluded SPG11 first in China.

Polygenic determinants of Parkinson's disease in a Chinese population.

It has been reported that some single-nucleotide polymorphisms (SNPs) are associated with the risk of Parkinson's disease (PD), but whether a combination of these SNPs would have a stronger association with PD than any individual SNP is unknown. Sixteen SNPs located in the 8 genes and/or loci (SNCA, LRRK2, MAPT, GBA, HLA-DR, BST1, PARK16, and PARK17) were analyzed in a Chinese cohort consisting of 1061 well-characterized PD patients and 1066 control subjects from Central South of Mainland China. We found that Rep1, rs356165, and rs11931074 in SNCA gene; G2385R in LRRK2 gene; rs4698412 in BST1 gene; rs1564282 in PARK17; and L444P in GBA gene were associated with PD with adjustment of sex and age (p < 0.05) in the analysis of 16 variants. PD risk increased when Rep1 and rs11931074, G2385R, rs1564282, rs4698412; rs11931074 and G2385R, rs1564282, rs4698412; G2385R and rs1564282, rs4698412; and rs1564282 and rs4698412 were combined for the association analysis. In addition, PD risk increased cumulatively with the increasing number of variants (odds ratio for carrying 3 variants, 3.494). In summary, we confirmed that Rep1, rs356165, and rs11931074 in SNCA gene, G2385R in LRRK2 gene, rs4698412 in BST1 gene, rs1564282 in PARK17, and L444P in GBA gene have an independent and combined significant association with PD. SNPs in these 4 genes have a cumulative effect with PD.

Involvement of Bcl-2-associated athanogene (BAG)-family proteins in the neuroprotection by rasagiline.

Rasagiline, a novel monoamine oxidase (MAO)-B inhibitor, has a mild to moderate effect in relieving Parkinson's disease (PD) symptoms as well as unique neuroprotective effects. Previous studies demonstrated rasagiline protect neurons by regulating Bcl-2 family proteins. Our study aimed to study whether Bcl-2-associated athanogene (BAG)-family proteins, which were reported closely associated with neurodegenerative disease, were involved in the neuroprotective effect of rasagiline. We found that after the administration of 1-methy1-4-phenvl-1,2,3,6-tetrahvdropvridine (MPTP), BAG2 and BAG5 proteins were up-regulated in the substantia nigra dopaminergic neurons of PD mouse model. A further increase of BAG2 and BAG5 was detected after intragastric administration of rasagiline to post-MPTP lesioned mice. Thus, the current study proved the association of BAG family proteins with PD, and suggested the involvement and a positive role of BAG2, BAG5 in the neuroprotection of rasagiline. These preliminary results implicate a novel pathway for further study on neuroprotection of rasagiline.

Hypomethylation of SNCA in blood of patients with sporadic Parkinson's disease.

SNCA is a pathogenic gene identified in rare familial PD, and over-expression of SNCA was suggested in the pathogenesis of familial and sporadic PD. Rep1 polymorphism of SNCA was associated with susceptibility to sporadic PD and SNCA expression in intro and in vivo. Hypomethylation in SNCA intron-1 was associated with increased SNCA expression and was observed in postmortem brains of patients with sporadic PD. We studied the methylation status of SNCA intron-1, SNCA mRNA levels and Rep1 genotypes in PBMCs of 100 sporadic PD patients and 95 controls and explored the relationship between DNA methylation, mRNA expression and Rep1 genotypes. Hypomethylation of SNCA intron-1 was detected in PBMCs of PD patients, and DNA methylation levels were associated with Rep1 polymorphism. The shorter allele was associated with higher level of SNCA intron-1 methylation, and genotypes carrying the shorter allele showed significantly higher methylation level of SNCA intron-1 than genotypes carrying the longer allele. However, SNCA mRNA levels were not associated with disease status, Rep1 polymorphism or DNA methylation of SNCA intron-1 in our study.

Mutation analysis of LRRK2, SCNA, UCHL1, HtrA2 and GIGYF2 genes in Chinese patients with autosomal dorminant Parkinson's disease.

Autosomal dorminant Parkinson's disease (ADPD) has been associated with mutations in the SCNA, LRRK2, UCHL1, HtrA2 and GIGYF2 genes. We studied the prevalence of variants in all five genes in 12 Chinese unrelated families with ADPD and 4 families with both essential tremor (ET) and Parkinson's disease (PD) phenotypes using direct sequencing analysis. We found 27 variants in the LRRK2 gene, eight in GIGYF2 gene, three in the SCNA and UCHL1 gene respectively, in which five variants were novel. However, no pathogenic mutations in the five genes were found in these families. Our result indicated that SCNA, LRRK2, UCHL1, HtrA2 and GIGYF2 genes' mutations might not be a main reason for Chinese ADPD.

Follow-up study of variants of the GIGYF2 gene in Chinese patients with Parkinson's disease.

The Grb10-interacting GYF protein-2 gene (GIGYF2) is a PARK11 gene that reportedly has a causal role in familial Parkinson's disease (PD) among populations from Italy and France. However, no comprehensive study of the GIGYF2 gene has been conducted among PD patients from mainland China. In our previous study, the GIGYF2 gene was directly sequenced, and nine missense variants and 14 polymorphisms were identified. For these 14 polymorphisms, in the present study we performed a case­control analysis for 300 PD patients and 200 healthy controls from mainland China. The c.297T>C p.Ala99Ala polymorphism was associated with increased risk with respect to the pathogenesis of sporadic PD. In conclusion, within the Chinese population, the c.297T>C p.Ala99Ala polymorphism of the GIGYF2 gene may be associated with an increased risk of developing PD.

Expansion of the phenotypic spectrum of SPG6 caused by mutation in NIPA1.

BACKGROUND: Hereditary spastic paraplegia type 6 (SPG6) is caused by mutations in the NIPA1 gene, this is a rare cause of HSP, until now, all the affected individuals reported displayed "pure" spastic paraplegia. OBJECTIVES: To analyze the genotype/phenotype correlation of mutations so far described in NIPA1. METHODS: Eighty-six Chinese Han HSP patients were investigated for SPG6 mutations by direct sequencing of the NIPA1 gene. RESULTS: One heterozygous missense mutation c.316G>C/p.G106R was identified in a complicated form of ADHSP family with peripheral nerves disease, and SPG6 mutation in our sample accounted for 3.6% (1/28) of ADHSP families and 1.1% (1/86) of non-ARHSP patients who were negative for SPG4, SPG3A and SPG31 mutations. CONCLUSIONS: We report the first complicated case of SPG6 in the world by the presence of peripheral neuropathy, which extends the phenotype initially described.

Novel GIGYF2 gene variants in patients with Parkinson's disease in Chinese population.

The Grb10-Interacting GYF Protein-2 gene (GIGYF2), located in the chromosomal region 2q36-q37, has been reported as a PARK11 gene with a causal role in familial Parkinson's disease (PD) in Italian and French populations. However, there is no comprehensive study of GIGYF2 gene conducted in Chinese patients with PD from mainland China. The 27 coding exons and intron/exon boundaries of the GIGYF2 gene were sequenced in 300 sporadic patients with Parkinson's disease. Eight heterozygous and one homozygous novel missense variants were identified in nine patients with PD, and not in 300 controls. p.Leu580Phe locates in the GYF domain and might interrupt the potentially function of GIGYF2 protein. Another variant Gln979stop encodes a truncated protein. In conclusion, we identified nine novel variants in GIGYF2 gene, which might be associated with PD in the Chinese population.