Occurrence of GCH1 gene mutations in a group of Indian dystonia patients
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The aim of this study is to examine the role of GCH1 among Indians affected with dopa responsive dystonia (DRD) and early onset Parkinson’s disease (EOPD). The patients (n = 76 including 19 DRD and 36 EOPD) and controls (n = 138) were screened for variants in GCH1 by PCR amplification of exons, splice junctions and 1 kb upstream region followed by SSCP and DNA sequencing. Four novel variants (p.Met1Val, p.Val204_205del, IVS3+68A>G, and IVS5−6T>G) were identified in 10 patients but not in the controls. In addition to two nonsynonymous changes, identified in four DRD patients in heterozygous condition, one intronic variant (IVS5−6T>G) could be linked to pathogenesis of the disease since it has the potential of altering the splice site as assessed by in silico analysis. Patients carrying different nonsynonymous variants had remarkable variation in clinical phenotype. Consistent with earlier reports, severity of clinical phenotype and the age of onset varied among family members harboring the same mutation. No mutation was detected in the EOPD patients. Three novel mutations in GCH1 gene have been found and are shown to be associated with variable clinical phenotypes mostly within the spectrum of DRD. The mutations identified represent 15.79% (3/19) of east Indian DRD patient cohort.
KeywordsDopa responsive dystonia (DRD) Dystonia EOPD GCH1
The authors are thankful to the patients for participating in the study. The study was supported partially by grants from University Grant Commission [Grant no. F.14-38/2007(Inno./ASIST)] and Council of Scientific and Industrial Research (CSIR) (Grant no. MLP-0016 and SIP-007). TN is supported by a fellowship from CSIR, India. AB is supported by a fellowship from ICMR, India.
- Brain MF, Jankovic J, Comella C, Blitzer A, Tsui J, Pullman SL (1995) Treatment of dystonia using botulinum toxin. In: Kurlan Roger (ed) Treatment of movement disorders. JB Lippincott, NewYork, pp 183–246Google Scholar
- Bressman SB (2003) Dystonia: phenotypes and genotypes. Rev Neurol (Paris) 159:849–856Google Scholar
- Clot F, Grabli D, Cazeneuve C, Roze E, Castelnau P, Chabrol B, Landrieu P, Nguyen K, Ponsot G, Abada M, Doummar D, Damier P, Gil R, Thobois S, Ward AJ, Hutchinson M, Toutain A, Picard F, Camuzat A, Fedirko E, San C, Bouteiller D, LeGuern E, Durr A, Vidailhet M, Brice A (2009) Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with dopa-responsive dystonia. Brain 132:1753–1763PubMedCrossRefGoogle Scholar
- Garavaglia B, Invernizzi F, Carbone ML, Viscardi V, Saracino F, Ghezzi D, Zeviani M, Zorzi G, Nardocci N (2004) GTP-cyclohydrolase I gene mutations in patients with autosomal dominant and recessive GTP-CH1 deficiency: identification and functional characterization of four novel mutations. J Inherit Metab Dis 27:455–463PubMedCrossRefGoogle Scholar
- Tassin J, Durr A, Bonnet AM, Gil R, Vidailhet M, Lucking CB, Goas JY, Durif F, Abada M, Echenne B, Motte J, Lagueny A, Lacomblez L, Jedynak P, Bartholome B, Agid Y, Brice A (2000) Levodopa-responsive dystonia GTP cyclohydrolase I or parkin mutations? Brain 123(Pt 6):1112–1121PubMedCrossRefGoogle Scholar