Exon deletions in the
            <i>GCHI</i>
            gene in two of four Turkish families with dopa-responsive dystonia

Klein, Christine; Hedrich, Katja; Kabakci, Kemal; Mohrmann, K.; Wiegers, Karin; Landt, Olfert; Hagenah, Johann; Schwinger, E.; Pramstaller, Peter P.; Ozelius, L. J.; Gücüyener, Kıvılcım; Aysun, Sabiha; Demir, Eşref

doi:10.1212/01.wnl.0000035629.04791.3f

Cited by 32 publications

(30 citation statements)

References 11 publications

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“…In addition, most of the deletions of GCH1 identified in previous studies comprised the entire gene (Furukawa et al, 2000;Hagenah et al, 2005;Steinberger et al, 2007;Zirn et al, 2008) or were multi-exonic (Klein et al, 2002;Hagenah et al, 2005;Steinberger et al, 2007;Wu-Chou et al, 2010), but few were single-exon deletions [exon 1 (Klein et al, 2002); exon 2 (Liu et al, 2010)]. In our study, we found the third reported single-exon deletion of the GCH1 gene in patients with DRD.…”

Section: Discussionsupporting

confidence: 52%

“…The MLPA method of analysis was first applied to patients with DRD by Steinberger et al (2007); it is more convenient and faster than some traditional methods used for detection of heterozygous deletions such as Southern blotting (Furukawa et al, 2000;Klein et al, 2002) or duplex semi-quantitative PCR (Hagenah et al, 2005;Wider et al, 2008). Rather than amplifying the DNA directly using standard PCR, probes are hybridized across the sample DNA such that each probe in an MLPA probe mix generates a PCR product with a distinct length following amplification with a common set of primers.…”

Section: Discussionmentioning

confidence: 99%

“…To investigate whether exonic deletions in GCH1 (or other DRD-related genes) contribute to the genetic background of DRD, we performed multiple ligation-dependent probe amplification analyses (MLPA) to search for plausible deletions. MLPA can be used to determine the copy number of up to 50 DNA sequences in a single multiplex polymerase chain reaction (PCR)-based reaction, and it has been widely employed for the detection of exonic deletions including within DRD (Furukawa et al, 2000;Klein et al, 2002;Hagenah et al, 2005;Steinberger et al, 2007;Wider et al, 2008;Zirn et al, 2008;Wu-Chou et al, 2010). In this study, we conducted MLPA analyses on three DRD pathogenic genes in Han Chinese DRD pedigrees and subjects with sporadic DRD to determine whether heterozygous exonic deletions could be found in addition to point mutations.…”

Section: Introductionmentioning

confidence: 99%

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Han Chinese patients with dopa-responsive dystonia exhibit a low frequency of exonic deletion in the GCH1 gene

Cai

et al. 2015

Genet. Mol. Res.

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ABSTRACT. We identified three novel mutations of the GTP cyclohydrolase 1 (GCH1) gene in patients with familial dopa-responsive dystonia (DRD), but were unable to identify meaningful sporadic mutations in patients with no obvious family DRD background. To investigate whether GCH1 regional deletions account for the etiology of DRD, we screened for heterozygous exonic deletions in DRD families and in patients with sporadic DRD. Multiple ligation-dependent probe amplification analysis and quantitative real-time polymerase chain reaction amplification was performed in all members of our DRD cohort and in controls to detect exonic deletions in GCH1, tyrosine hydroxylase, and the epsilon-sarcoglycan-encoding (SGCE) genes. Using these techniques, we detected a GCH1 exon 1 heterozygous deletion in 1 of 10 patients with sporadic DRD. Therefore, we concluded that exonic deletion in the GCH1 gene only accounted for the etiology in a small percentage of patients with sporadic DRD in our Han Chinese cohort.

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Han Chinese patients with dopa-responsive dystonia exhibit a low frequency of exonic deletion in the GCH1 gene

Cai

et al. 2015

Genet. Mol. Res.

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“…7 Recently, families have been described with heterozygous exonic deletions in GCH1, which were not detected by conventional screening techniques. [8][9][10][11] In this study, we report more comprehensive clinical and genetic investigations of a multigenerational DRD family, in which a previous study had found linkage to a novel locus nominated DYT14 on chromosome 14q13, adjacent to the DYT5 locus. 12 Expanded data allowed us to exclude DYT14, and to identify a novel deletion in GCH1 as the disease-causing mutation in this family.…”

mentioning

confidence: 91%

Study of a Swiss dopa-responsive dystonia family with a deletion in GCH1

Wider¹,

Melquist²,

Hauf³

et al. 2008

Neurology

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Objective-To repor the study of a multigenerational Swiss family with dopa-responsive dystonia (DRD).Methods-Clinical investigation was made of available family members, including historical and chart reviews. Subject examinations were video recorded. Genetic analysis included a genome-wide linkage study with microsatellite markers (STR), GTP cyclohydrolase I (GCH1) gene sequencing, and dosage analysis.Results-We evaluated 32 individuals, of whom 6 were clinically diagnosed with DRD, with childhood-onset progressive foot dystonia, later generalizing, followed by parkinsonism in the two older patients. The response to levodopa was very good. Two additional patients had late onset doparesponsive parkinsonism. Three other subjects had DRD symptoms on historical grounds. We found suggestive linkage to the previously reported DYT14 locus, which excluded GCH1. However, further study with more stringent criteria for disease status attribution showed linkage to a larger region, which included GCH1. No mutation was found in GCH1 by gene sequencing but dosage methods identified a novel heterozygous deletion of exons 3 to 6 of GCH1. The mutation was found in seven subjects. One of the patients with dystonia represented a phenocopy.Conclusions-This study rules out the previously reported DYT14 locus as a cause of disease, as a novel multiexonic deletion was identified in GCH1. This work highlights the necessity of an accurate clinical diagnosis in linkage studies as well as the need for appropriate allele frequencies, penetrance, and phenocopy estimates. Comprehensive sequencing and dosage analysis of known genes is recommended prior to genome-wide linkage analysis. Dopa-responsive dystonia (DRD) is a rare disorder characterized by childhood-onset fluctuating foot dystonia, which later generalizes and becomes associated with tremor and parkinsonism. 1-3 Response to small doses of levodopa is dramatic. In its classic form, also Although close to 100 mutations have been described in GCH1, 6 comprehensive screening fails to identify the responsible mutation in 40 to 50% of the families. 7 Recently, families have been described with heterozygous exonic deletions in GCH1, which were not detected by conventional screening techniques. 8-11In this study, we report more comprehensive clinical and genetic investigations of a multigenerational DRD family, in which a previous study had found linkage to a novel locus nominated DYT14 on chromosome 14q13, adjacent to the DYT5 locus. 12 Expanded data allowed us to exclude DYT14, and to identify a novel deletion in GCH1 as the disease-causing mutation in this family. METHODS Genealogy and clinical evaluationsInformation on the pedigree was collected by means of historical material, family records, and medical charts review, along with interviews with elderly family members.The project was approved by the local ethics committee. After signing an informed consent, subjects underwent a detailed videotaped neurologic evaluation. A clinical diagnosis of definite DRD was established in pa...

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“…p.K224R has been so far reported in three pedigrees associated with athetoid cerebral palsy (family Hu in Bandmann et al 1998), myoclonic dystonia (Leuzzi et al 2002) and adult-onset gait dystonia, rigidity and bradykinesia (Patient D97 in Garavaglia et al 2004). Since the first report (Furukawa et al 2000), few pedigrees harbouring gross deletion of the GCH1 gene have been reported (Klein et al 2002;Hagenah et al 2005;Ohta et al 2006;Clot et al 2009). Their phenotype overlaps with that of patients with less severe alterations.…”

Section: Discussionmentioning

confidence: 99%

Urinary Neopterin and Phenylalanine Loading Test as Tools for the Biochemical Diagnosis of Segawa Disease

et al. 2012

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Background. The diagnosis of autosomal dominant GTP-cyclohydrolase deficiency relies on the examination of the GCH1 gene and/or pterins and neurotransmitters in CSF. The aim of the study was to assess the diagnostic value, if any, of pterins in urine and blood phenylalanine (Phe) and tyrosine (Tyr) under oral Phe loading test.Methods. We report on two new pedigrees with four symptomatic and four asymptomatic carriers whose pattern of urinary pterins and blood Phe/Tyr ratio under oral Phe loading pointed to GTP-cyclohydrolase deficiency. The study was then extended to 3 further patients and 90 controls. The diagnostic specificity and sensitivity of these metabolic markers were analysed by backwards logistic analysis.Results. Two genetic alterations segregated alternatively in Family 1 (c.631-632 del AT and c.671A > G), while exon 1 deletion was transmitted along three generations in Family 2. Neopterin and biopterin concentrations in urine clustered differently in controls under and over the age of 15. Therefore patients and controls were sub grouped according to this age. Neopterin was significantly reduced in GCH1 mutated subjects younger than 15, and both neopterin and biopterin in those older than 15. Moreover, the Phe/Tyr ratios at the second and third hour were both significantly higher in patients than in controls. Backwards logistic regression demonstrated the high diagnostic sensitivity and specificity of combined values of neopterin concentration and Phe/Tyr ratio at the second hour.Conclusions. Pterins in urine and Phe loading test are non-invasive and reliable tools for the biochemical diagnosis of GTP-cyclohydrolase deficiency.

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Exon deletions in the GCHI gene in two of four Turkish families with dopa-responsive dystonia

Cited by 32 publications

References 11 publications

Han Chinese patients with dopa-responsive dystonia exhibit a low frequency of exonic deletion in the GCH1 gene

Han Chinese patients with dopa-responsive dystonia exhibit a low frequency of exonic deletion in the GCH1 gene

Study of a Swiss dopa-responsive dystonia family with a deletion in GCH1

Urinary Neopterin and Phenylalanine Loading Test as Tools for the Biochemical Diagnosis of Segawa Disease

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