RESUMEN
Dopa-responsive dystonia (DRD) comprises a heterogeneous group of movement disorders. A limited number of studies of Chinese patients with DRD have been reported. In the present study, we investigated the clinical and genetic features of 12 Chinese DRD families. Point mutation analysis of the GTP-cyclohydrolase I (GCH1), tyrosine hydroxylase (TH) and sepiapterin reductase (SPR) genes was conducted by direct sequencing. In addition, multiplex ligation-dependent probe amplification targeting GCH1 and TH was performed in "mutation-free" patients. Three reported mutations (IVS2-2A>G, c.293C>T, c.550C>T) were detected in GCH1, whereas two compound heterozygous variants were identified in TH, one of which was novel (c.1083C>A). Furthermore, this novel variant was not detected in any of the 250 ethnicity-matched, healthy controls. No exon deletions or duplicate mutations in the two genes were found in patients with DRD. No mutation in SPR was found. In addition, one patient with the IVS2-2A>G mutation in GCH1 showed signs of Parkinsonism. In conclusion, we here identified a novel heterozygous variant in TH (c.1083C>A). It is important to perform routine screening of GCH1 and TH for patients with DRD. While for patients with Parkinsonism, GCH1 mutation analysis should be performed after screening of genes like PARKIN, PARK7 (DJ-1) and PINK1.
Asunto(s)
Pueblo Asiatico/genética , Trastornos Distónicos/genética , GTP Ciclohidrolasa/genética , Variación Genética/genética , Tirosina 3-Monooxigenasa/genética , Adolescente , Adulto , Secuencia de Aminoácidos , Niño , Preescolar , Trastornos Distónicos/diagnóstico , Trastornos Distónicos/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Linaje , Mutación Puntual/genética , Adulto JovenRESUMEN
Whole-exome sequencing of Parkinson's disease (PD) patients has revealed that the frequency of GTP-cyclohydrolase I (GCH1) variants was signiï¬cantly higher in patients than in controls. GCH1 rs11158026 was also found to increase the risk of PD. To investigate genetic contribution of dopa-responsive dystonia-related genes to PD, GCH1, and tyrosine hydroxylase (TH) were tested in PD patients. A total of 859 study subjects comprising 421 patients with PD and 438 controls were recruited. For GCH1 gene, one known variant (c.239G > A, p.S80N) was detected in a patient who was diagnosed with PD clinically. In TH, 3 heterozygous variants, c.1495G > A (p. V499M, rs1800033), c.334 A > G (p.V112M, rs6356), and c.813 G > A (p. K271K, rs6357), were identified. After stratiï¬cation by age, the frequency of rs6356G allele was signiï¬cantly lower (p = 0.041) for the late-onset PD group than controls. Our results indicate that to analyze the relationship between dopa-responsive dystonia-related genes and PD, it is important to screen GCH1 and test rs6356 of TH in a larger sample.
Asunto(s)
GTP Ciclohidrolasa/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Enfermedad de Parkinson/genética , Tirosina 3-Monooxigenasa/genética , Pueblo Asiatico/genética , Trastornos Distónicos/congénito , Trastornos Distónicos/genética , Frecuencia de los Genes/genética , HumanosRESUMEN
CD33 and MS4A cluster variants have been identified to modulate the risk of Alzheimer's disease (AD) in several recent genome-wide association studies (GWAS) in Caucasians. In the present study, we first conducted a case-control study to investigate the CD33 single nucleotide polymorphisms (SNPs) rs3865444 and rs3826656 and the MS4A cluster SNPs rs610932 and rs670139 in a cohort from eastern China that comprised 126 late-onset Alzheimer's disease (LOAD) patients and 129 healthy controls. The results revealed that the frequency of rs3826656 major (G) allele carriers was higher among the LOAD patients than among the controls [P=0.005; odds ratio (OR), 1.760; 95% confidence interval (CI), 1.185-2.615]. In apolipoprotein E (APOE) ε4 allele carriers, the G allele of the SNP rs3865444 was found to be associated with an increased risk of LOAD (P=0.002; OR, 3.391; 95% CI, 1.512-7.605). Next, we re-evaluated the association between these variants and LOAD by conducting a meta-analysis using data from studies of East Asian populations, including the present case-control study, and confirmed that rs3826656 increased the risk of LOAD. In addition, we identified a significant association between rs610932 and LOAD (P=0.035; OR, 0.79; 95% CI, 0.63-0.98). Note that heterogeneity should be considered during the interpretation of these results; significant heterogeneity was identified among studies on rs3865444, even in a subgroup analysis based on stratification of studies by the country of origin. In summary, our results suggest that CD33 and MS4A cluster variants are associated with LOAD susceptibility in East Asian populations.