A novel missense mutation pattern of the GCH1 gene in dopa-responsive dystonia

Scola, Rosana Hermínia; Carducci, Carla; Amaral, Vanise G.; Lorenzoni, Paulo José; Teive, Hélio Afonso Ghizoni; Giovanniello, Teresa; Werneck, Lineü Cesar

doi:10.1590/s0004-282x2007000700026

Cited by 7 publications

(3 citation statements)

References 18 publications

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“…The two patients with compound heterozygous mutations carried a common missense variant (c.68C4T, p.Pro23Leu) located in exon 1. This substitution was previously described as a mutation or a variant in 8 different families (Jarman et al, 1997;de la Fuente-Fernandez 1997;Steinberger et al, 2000;Scola et al, 2007;Zirn et al, 2008) and it was found in 1/210 control chromosomes by Jarman et al (1997). We found the p.Pro23Leu variant in 1/174 control chromosomes.…”

Section: Gch1 Mutation Carriers and Their Clinical Characteristicssupporting

confidence: 65%

Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with Dopa-responsive dystonia

Clot

Grabli

Cazeneuve

et al. 2009

Brain

124

113

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Dopa-responsive dystonia is a childhood-onset dystonic disorder, characterized by a dramatic response to low dose of L-Dopa. Dopa-responsive dystonia is mostly caused by autosomal dominant mutations in the GCH1 gene (GTP cyclohydrolase1) and more rarely by autosomal recessive mutations in the TH (tyrosine hydroxylase) or SPR (sepiapterin reductase) genes. In addition, mutations in the PARK2 gene (parkin) which causes autosomal recessive juvenile parkinsonism may present as Dopa-responsive dystonia. In order to evaluate the relative frequency of the mutations in these genes, but also in the genes involved in the biosynthesis and recycling of BH4, and to evaluate the associated clinical spectrum, we have studied a large series of index patients (n = 64) with Dopa-responsive dystonia, in whom dystonia improved by at least 50% after L-Dopa treatment. Fifty seven of these patients were classified as pure Dopa-responsive dystonia and seven as Dopa-responsive dystonia-plus syndromes. All patients were screened for point mutations and large rearrangements in the GCH1 gene, followed by sequencing of the TH and SPR genes, then PTS (pyruvoyl tetrahydropterin synthase), PCBD (pterin-4a-carbinolamine dehydratase), QDPR (dihydropteridin reductase) and PARK2 (parkin) genes. We identified 34 different heterozygous point mutations in 40 patients, and six different large deletions in seven patients in the GCH1 gene. Except for one patient with mental retardation and a large deletion of 2.3 Mb encompassing 10 genes, all patients had stereotyped clinical features, characterized by pure Dopa-responsive dystonia with onset in the lower limbs and an excellent response to low doses of L-Dopa. Dystonia started in the first decade of life in 40 patients (85%) and before the age of 1 year in one patient (2.2%). Three of the 17 negative GCH1 patients had mutations in the TH gene, two in the SPR gene and one in the PARK2 gene. No mutations in the three genes involved in the biosynthesis and recycling of BH4 were identified. The clinical presentations of patients with mutations in TH and SPR genes were strikingly more complex, characterized by mental retardation, oculogyric crises and parkinsonism and they were all classified as Dopa-responsive dystonia-plus syndromes. Patient with mutation in the PARK2 gene had Dopa-responsive dystonia with a good improvement with L-Dopa, similar to Dopa-responsive dystonia secondary to GCH1 mutations. Although the yield of mutations exceeds 80% in pure Dopa-responsive dystonia and Dopa-responsive dystonia-plus syndromes groups, the genes involved are clearly different: GCH1 in the former and TH and SPR in the later.

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Section: Gch1 Mutation Carriers and Their Clinical Characteristicssupporting

confidence: 65%

Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with Dopa-responsive dystonia

Clot

Grabli

Cazeneuve

et al. 2009

Brain

124

113

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“…Ova promena je prvobitno prijavljena kao patogena mutacija u 8 različitih porodica (Jarman et al, 1997a;de la Fuente-Fernandez, 1997;Steinberger et al, 2000;Scola et al, 2007;Zirn et al, 2008b). Međutim, opisana su dva slučaja gde se promena Pro23Leu javila zajedno sa malom delecijom, odnosno missense mutacijom, takođe u egzonu 1.…”

Section: Molekularno Genetička Osnova Dyt5aunclassified

“…Bolesnik kod koga je detektovana ova promena ima generalizovanu distoniju sa početkom prvih simptoma u 30. godini. Ova promena je do sada u literaturi opisana u deset porodica (Jarman et al, 1997a;de la Fuente-Fernandez 1997;Steinberger et al, 2000;Scola et al, 2007;Zirn et al, 2008b;Clot et al, 2009), od toga su u 7 slučajeva bolesnici imali status kombinovanog heterozigota, odnosno pored p.Pro23Leu mutacije nosili su i još jednu mutaciju u GCH1 genu. Učestalost ove mutacije u kontrolnoj populaciji bila je 0/200 hromozoma (Zirn et al, 2008b) 1/210 hromozoma (Jarman et al, 1997 ), odnosno 1/174 hromozoma .…”

Section: Promene U Kodirajućim Regionimunclassified

Study of the genetic basis of dystonia in Serbian population

Dobričić¹

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ZAHVALNICAOva doktorska disertacija urađena je u Laboratoriji za molekularnu i genetičku dijagnostiku neuroloških oboljenja Klinike za neurologiju, KCS. Zahvaljujem se svim kolegama sa Klinike, a posebno osnivaču laboratorije prof. dr Vladimiru Kostiću i koleginicama prof. dr Ivani Novaković, Mileni Janković, Vesni Ralić i Mileni Žarković, na nesebičnoj pomoći i podršci. Najveće hvala mojoj strpljivoj porodici.STUDIJA GENETSKE OSNOVE PRIMARNIH DISTONIJA U POPULACIJI SRBIJE REZIME Uvod: Distonije pripadaju grupi poremećaja pokreta i karakterišu se nevoljnim uvrtanjem, repetitivnim pokretima ili zauzimanjem abnormalnog položaja delova tela, uključujući i trup. Procenjeno je da je prevalencija distonija barem 10 na 100 000 osoba.Postoji više klasifikacija distonija. Etiološka klasifikacija podrazumeva postojanje primarnih (idiopatskih) distonija gde je distonija jedini simptom bolesti i sekundarnih (simptomatskih) distonije gde je distonija samo jedan od simptoma bolesti i izazvane su različitim poznatim uzrocima (npr. trauma, lekovi/toksini, moždani udar). U grupu primarnih distonija svrstavaju se i distonija-plus sindromi za koje je karakteristično da se pored distonije, koja je glavni simptom, javlja i još neki simptom iz grupe poremećaja pokreta. Najnovija klasifikacija distonija je molekularna klasifikacija. Ona je izvršena prema genskim lokusima vezanim za određene tipove distonija. Do sada je okarakterisano najmanje dvadeset monogenskih distonija (lokusi DYT1-DYT21; pri čemu je DYT14=DYT5a i DYT9=DYT18), od kojih je za jedanaest identifikovan i gen koji je odgovoran za pojavu bolesti. Od ovih jedanaest monogenskih distonija, osam se nasleđujeautozomno recesivno (TH/DYT5b i PRKRA/DYT16) i jedna X-vezano recesivno (TAF1/DYT3). Na osnovu podataka iz literature, dosadašnje kličke prakse i epidemioloških podataka pokazalo se da se kod pacijenata obolelih od primarne distonije najčešće radi o DYT1, DYT5a, DYT6, DYT8, DYT11 ili DYT18. Cilj:Ovo istraživanje je imalo za cilj utvrđivanje učestalosti i spektra mutacija u genima DYT1, DYT5a, DYT6, DYT8, DYT11 i DYT18 kod bolesnika sa primarnom distonijom u populaciji Srbije. Zatim, ispitivanje potencijalnih korelacija između genotipa i fenotipa kod pacijenata kod kojih su detektovane mutacije i utvrđivanje da li je na osnovu dobijenih rezultata moguće formirati šemu za genetsko testiranje distonija u našoj populaciji.

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