Abstract
Sepiapterin reductase (SR) catalyzes the final step in the de novo synthesis of tetrahydrobiopterin, essential cofactor for phenylalanine, tyrosine, and tryptophan hydroxylases. SR deficiency is a very rare disease resulting in monoamine neurotransmitter depletion. Most patients present with clinical symptoms before the first year of age corresponding to a dopa-responsive dystonia phenotype with diurnal fluctuations, although some patients exhibit more complex motor and neurological phenotypes. Herein, we describe four new cases from Spain, their clinical phenotype and the biochemical and genetic analyses. Two mutations in the SPR gene were functionally expressed to provide a basis to establish genotype–phenotype correlations. Mutation c.751A>T is functionally null, correlating with the severe phenotype observed. The novel mutation c.304G>T was identified in three siblings with a strikingly mild phenotype without cognitive delay and close to asymptomatic in the eldest sister. Minigene analysis demonstrated that this mutation located in the last nucleotide of exon 1 affects splicing although some normal transcripts can be produced, resulting in the missense mutant p.G102C that retains partial activity. These results may account for the mild phenotype and the variable clinical presentations observed, which could depend on interindividual differences in relative abundance of correctly spliced and aberrant transcripts.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Thony B, Auerbach G, Blau N (2000) Tetrahydrobiopterin biosynthesis, regeneration and functions. Biochem J 347(Pt 1):1–16
Blau N, Thony B, Cotton GH, Hyland K (2001) Disorders of tetrahydrobioterin and related biogenic amines. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Vogelstein B (eds) The metabolic and molecular basis of inherited disease, 8th edn. McGraw-Hill, New York, pp 1725–1776
Bonafe L, Thony B, Penzien JM, Czarnecki B, Blau N (2001) Mutations in the sepiapterin reductase gene cause a novel tetrahydrobiopterin-dependent monoamine-neurotransmitter deficiency without hyperphenylalaninemia. Am J Hum Genet 69:269–277
Bonafe L, Thony B, Leimbacher W, Kierat L, Blau N (2001) Diagnosis of dopa-responsive dystonia and other tetrahydrobiopterin disorders by the study of biopterin metabolism in fibroblasts. Clin Chem 47:477–485
Thony B, Blau N (2006) Mutations in the BH4-metabolizing genes GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase, sepiapterin reductase, carbinolamine-4a-dehydratase, and dihydropteridine reductase. Hum Mutat 27:870–878
Neville BG, Parascandalo R, Farrugia R, Felice A (2005) Sepiapterin reductase deficiency: a congenital dopa-responsive motor and cognitive disorder. Brain 128:2291–2296
Echenne B, Roubertie A, Assmann B, Lutz T, Penzien JM, Thony B et al (2006) Sepiapterin reductase deficiency: clinical presentation and evaluation of long-term therapy. Pediatr Neurol 35:308–313
Clot F, Grabli D, Cazeneuve C, Roze E, Castelnau P, Chabrol B et al (2009) Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with Dopa-responsive dystonia. Brain 132:1753–1763
Friedman J, Hyland K, Blau N, MacCollin M (2006) Dopa-responsive hypersomnia and mixed movement disorder due to sepiapterin reductase deficiency. Neurology 67:2032–2035
Steinberger D, Blau N, Goriuonov D, Bitsch J, Zuker M, Hummel S et al (2004) Heterozygous mutation in 5′-untranslated region of sepiapterin reductase gene (SPR) in a patient with dopa-responsive dystonia. Neurogenetics 5:187–190
Ormazabal A, Garcia-Cazorla A, Fernandez Y, Fernandez-Alvarez E, Campistol J, Artuch R (2005) HPLC with electrochemical and fluorescence detection procedures for the diagnosis of inborn errors of biogenic amines and pterins. J Neurosci Methods 142:153–158
Zorzi G, Redweik U, Trippe H, Penzien JM, Thony B, Blau N (2002) Detection of sepiapterin in CSF of patients with sepiapterin reductase deficiency. Mol Genet Metab 75:174–177
Fukushima T, Nixon JC (1980) Analysis of reduced forms of biopterin in biological tissues and fluids. Anal Biochem 102:176–188
Lopez-Laso E, Ormazabal A, Camino R, Gascon FJ, Ochoa JJ, Mateos ME et al (2006) Oral phenylalanine loading test for the diagnosis of dominant guanosine triphosphate cyclohydrolase 1 deficiency. Clin Biochem 39:893–897
Madira WM, Xavier F, Stern J, Wilcox AH, Barron JL (1992) Determination and assessment of the stability of phenylalanine and tyrosine in blood spots by HPLC. Clin Chem 38:2162–2163
Bastien R, Lewis TB, Hawkes JE, Quackenbush JF, Robbins TC, Palazzo J et al (2008) High-throughput amplicon scanning of the TP53 gene in breast cancer using high-resolution fluorescent melting curve analyses and automatic mutation calling. Hum Mutat 29:757–764
Ramaekers VT, Blau N (2004) Cerebral folate deficiency. Dev Med Child Neurol 46:843–851
Verbeek MM, Willemsen MA, Wevers RA, Lagerwerf AJ, Abeling NG, Blau N et al (2008) Two greek siblings with sepiapterin reductase deficiency. Mol Genet Metab 94:403–409
Leu-Semenescu S, Arnulf I, Decaix C, Moussa F, Clot F, Boniol C et al (2010) Sleep and rhythm consequences of a genetically induced loss of serotonin. Sleep 33:307–14
Kusmierska K, Jansen EE, Jakobs C, Szymanska K, Malunowicz E, Meilei D, et al (2009) Sepiapterin reductase deficiency in a 2-year-old girl with incomplete response to treatment during short-term follow-up. J Inherit Metab Dis. Short report # 137 Online
Auerbach G, Herrmann A, Gutlich M, Fischer M, Jacob U, Bacher A et al (1997) The 1.25 a crystal structure of sepiapterin reductase reveals its binding mode to pterins and brain neurotransmitters. EMBO J 16:7219–7230
Fujimoto K, Ichinose H, Nagatsu T, Nonaka T, Mitsui Y, Katoh S (1999) Functionally important residues tyrosine-171 and serine-158 in sepiapterin reductase. Biochim Biophys Acta 1431:306–314
Svenson IK, Ashley-Koch AE, Gaskell PC, Riney TJ, Cumming WJ, Kingston HM et al (2001) Identification and expression analysis of spastin gene mutations in hereditary spastic paraplegia. Am J Hum Genet 68:1077–1085
Roca X, Olson AJ, Rao AR, Enerly E, Kristensen VN, Borresen-Dale AL et al (2008) Features of 5′-splice-site efficiency derived from disease-causing mutations and comparative genomics. Genome Res 18:77–87
Krawczak M, Thomas NS, Hundrieser B, Mort M, Wittig M, Hampe J et al (2007) Single base-pair substitutions in exon–intron junctions of human genes: nature, distribution, and consequences for mRNA splicing. Hum Mutat 28:150–158
von Brederlow B, Bolz H, Janecke A, La OCA, Rudolph G, Lorenz B et al (2002) Identification and in vitro expression of novel CDH23 mutations of patients with Usher syndrome type 1D. Hum Mutat 19:268–273
Yamada K, Fukao T, Zhang G, Sakurai S, Ruiter JP, Wanders RJ et al (2007) Single-base substitution at the last nucleotide of exon 6 (c.671G>A), resulting in the skipping of exon 6, and exons 6 and 7 in human succinyl-CoA:3-ketoacid CoA transferase (SCOT) gene. Mol Genet Metab 90:291–297
Houdayer C, Dehainault C, Mattler C, Michaux D, Caux-Moncoutier V, Pages-Berhouet S et al (2008) Evaluation of in silico splice tools for decision-making in molecular diagnosis. Hum Mutat 29:975–982
Acknowledgments
This work was supported by grant SAF2007-61350 from Comisión Interministerial de Ciencia y Tecnología. The authors also acknowledge the support received from Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) and the institutional grant from the Fundación Ramón Areces to the Centro de Biología Molecular Severo Ochoa.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Arrabal, L., Teresa, L., Sánchez-Alcudia, R. et al. Genotype–phenotype correlations in sepiapterin reductase deficiency. A splicing defect accounts for a new phenotypic variant. Neurogenetics 12, 183–191 (2011). https://doi.org/10.1007/s10048-011-0279-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10048-011-0279-4