neurogenetics

, Volume 12, Issue 3, pp 183–191 | Cite as

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
ORIGINAL ARTICLE

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.

Keywords

Dopa-responsive dystonia Sepiapterin reductase Neurotransmitter deficiency Splicing mutation Genotype–phenotype 

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Luisa Arrabal
    • 1
  • Libertad Teresa
    • 2
    • 3
  • Rocío Sánchez-Alcudia
    • 2
    • 3
  • Margarita Castro
    • 2
    • 3
  • Celia Medrano
    • 2
    • 3
  • Luis Gutiérrez-Solana
    • 4
  • Susana Roldán
    • 1
  • Aida Ormazábal
    • 3
    • 5
  • Celia Pérez-Cerdá
    • 2
    • 3
  • Begoña Merinero
    • 2
    • 3
  • Belén Pérez
    • 2
    • 3
  • Rafael Artuch
    • 3
    • 5
  • Magdalena Ugarte
    • 2
    • 3
  • Lourdes R. Desviat
    • 2
    • 3
  1. 1.Servicio de NeuropediatríaHospital Virgen de las NievesGranadaSpain
  2. 2.Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular Severo Ochoa, UAM-CSICUniversidad Autónoma de MadridMadridSpain
  3. 3.Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER)
  4. 4.Sección de Neurología PediátricaHospital Niño JesúsMadridSpain
  5. 5.Clinical Biochemistry DepartmentHospital Sant Joan de DéuBarcelonaSpain

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