Shalash, AS;
Rösler, TW;
Müller, SH;
Salama, M;
Deuschl, G;
Müller, U;
Opladen, T;
... Höglinger, GU; + view all
(2017)
c.207C>G mutation in sepiapterin reductase causes autosomal dominant dopa-responsive dystonia.
Neurology Genetics
, 3
(6)
, Article e197. 10.1212/NXG.0000000000000197.
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Abstract
Objective: To elucidate the genetic cause of an Egyptian family with dopa-responsive dystonia (DRD), a childhood-onset dystonia, responding therapeutically to levodopa, which is caused by mutations in various genes. Methods: Rare variants in all coding exons of GCH1 were excluded by Sanger sequencing. Exome sequencing was applied for 1 unaffected and 2 affected family members. To investigate the functional consequences of detected genetic variants, urinary sepiapterin concentrations were determined by high-performance liquid chromatography. Results: A heterozygous rare nonsynonymous variant in exon 1 of sepiapterin reductase (SPR, c.207C>G, p.Asp69Glu) was found in all affected family members. Urinary concentrations of sepiapterin were above the standard of normal controls in most SPR mutation carriers, suggesting functional biochemical consequences of the mutation. Variant filtering of all genes involved in the tetrahydrobiopterin pathway, required for levodopa synthesis, revealed an additional common variant in dihydrofolate reductase (DHFR, rs70991108). The presence of both variants was significantly stronger associated with the biochemical abnormality and the clinical disease state as opposed to 1 variant only. Conclusions: The rare SPR mutation can cause autosomal dominant DRD with incomplete penetrance. The common DHFR variant might have synergistic effects on production of tetrahydrobiopterin and levodopa, thereby increasing penetrance.
| Type: | Article |
|---|---|
| Title: | c.207C>G mutation in sepiapterin reductase causes autosomal dominant dopa-responsive dystonia |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1212/NXG.0000000000000197 |
| Publisher version: | https://doi.org/10.1212/NXG.0000000000000197 |
| Language: | English |
| Additional information: | This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Health Informatics UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Health Informatics > Clinical Epidemiology |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10064126 |
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