ORIGINAL ARTICLE Genotype–phenotype correlations in sepiapterin reductase deficiency. A splicing defect accounts for a new phenotypic variant Luisa Arrabal & Libertad Teresa & Rocío Sánchez-Alcudia & Margarita Castro & Celia Medrano & Luis Gutiérrez-Solana & Susana Roldán & Aida Ormazábal & Celia Pérez-Cerdá & Begoña Merinero & Belén Pérez & Rafael Artuch & Magdalena Ugarte & Lourdes R. Desviat Received: 14 January 2011 /Accepted: 18 February 2011 /Published online: 24 March 2011 # Springer-Verlag 2011 Abstract Sepiapterin reductase (SR) catalyzes the final step in the de novo synthesis of tetrahydrobiopterin, essential cofactor for phenylalanine, tyrosine, and tryptophan hydrox- ylases. 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. Keywords Dopa-responsive dystonia . Sepiapterin reductase . Neurotransmitter deficiency . Splicing mutation . Genotype–phenotype Introduction Sepiapterin reductase (SR, EC 1.1.1.153) deficiency (MIM #612716) is a very rare autosomal recessive disorder of tetrahydrobiopterin (BH 4 ) metabolism. BH 4 is an essential cofactor required by phenylalanine (Phe), tryptophan, and tyrosine (Tyr) hydroxylases, as well as by nitric oxide L. Arrabal : S. Roldán Servicio de Neuropediatría, Hospital Virgen de las Nieves, Granada, Spain L. Teresa : R. Sánchez-Alcudia : M. Castro : C. Medrano : C. Pérez-Cerdá : B. Merinero : B. Pérez : M. Ugarte (*) : L. R. Desviat (*) Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular Severo Ochoa, UAM-CSIC, Universidad Autónoma de Madrid, 28049 Madrid, Spain e-mail: mugarte@cbm.uam.es e-mail: lruiz@cbm.uam.es L. Teresa : R. Sánchez-Alcudia : M. Castro : C. Medrano : A. Ormazábal : C. Pérez-Cerdá : B. Merinero : B. Pérez : R. Artuch : M. Ugarte : L. R. Desviat Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) URL: http://www.ciberer.es/ L. Gutiérrez-Solana Sección de Neurología Pediátrica, Hospital Niño Jesús, Madrid, Spain A. Ormazábal : R. Artuch Clinical Biochemistry Department, Hospital Sant Joan de Déu, Esplugues, Barcelona, Spain Neurogenetics (2011) 12:183–191 DOI 10.1007/s10048-011-0279-4