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

Abstract

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 þ 6 G4T) 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 ¼ 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.

Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies

“…For PCDD, AR-GTPCHD, DHPRD, and PTPSD, there are no consistent reports on genotype-phenotype correlation. For AD-GTPCHD, there is certain heterogeneity: Some publications discuss and exclude genotypephenotype correlation [35,36]. Others describe different large heterozygous GCH1 deletions with high penetrance and association with multifocal dystonia and adult onset in a Taiwanese DRD population [37].…”

Atypical presentation of dopa‐responsive dystonia in Taiwan

“…We reviewed a previous report and found that Arg249Ser, Ser81Pro, Ser76X, Gly203Arg, 249del A, and IVS5+3insT have been reported in Taiwan (Hwu, Chiou, Lai, & Lee, 2000;Wu-Chou et al, 2010). In a group of Chinese Han patients, the locus included Gly155Ser in exon 3 (Hu et al, 2011); Met137Arg in exon 2 (Hu et al, 2011); Gly203Arg in exon 5 (Hu et al, 2011;Liu et al, 2010;Yu, Zhou, Hu, & Xu, 2013); Cases within each family had either pure parkinsonism or dystonia with or without parkinsonism. Patients with uncertain sign or onset age were excluded.…”

“…Ala98Val (Cai et al, 2013); Ile135Thr (Cai et al, 2013); Leu91Val (Wu et al, 2008); Pro95Leu (Wu et al, 2008); Val204Gly (Wu et al, 2008) and 628delC (Wu et al, 2008); Met1Ile (Li et al, 2007); Thre94Met (Yu et al, 2013); Leu145Phe (Yu et al, 2013); and c. 453+6G>T (Yu et al, 2013). A study of 40 patients with Segawa disease suggested that most mutations in Chinese patients with Segawa disease are clustered in two regions-the 210-360 and 550-650 base pair (Yu et al, 2013).…”

A Genome-Wide mRNA Screen and Functional Analysis Reveal FOXO3 as a Candidate Gene for Chicken Growth

“…Therefore, the G66715314C mutation may have important effects on economic traits, and its association with chicken growth traits needs further study. Conversely, four SNPs found in this study were located near the exon-intron boundaries, which are special regions that usually had important functional roles in protein [ 50 ]. Three of these four SNPs were associated with growth traits.…”