title: Mutations in PRPS1 causing syndromic or nonsyndromic hearing impairment: intrafamilial phenotypic variation complicates genetic counseling.
abstract: BACKGROUND
  PRPS1 encodes isoform I of phosphoribosylpyrophosphate synthetase (PRS-I), a key enzyme in nucleotide biosynthesis. Different missense mutations in PRPS1 cause a variety of disorders that include PRS-I superactivity, nonsyndromic sensorineural hearing impairment, Charcot-Marie-Tooth disease, and Arts syndrome. It has been proposed that each mutation would result in a specific phenotype, depending on its effects on the structure and function of the enzyme.
  
  
  METHODS
  Thirteen Spanish unrelated families segregating X-linked hearing impairment were screened for PRPS1 mutations by Sanger sequencing. In two positive pedigrees, segregation of mutations was studied, and clinical data from affected subjects were compared.
  
  
  RESULTS
  We report two novel missense mutations in PRPS1, p.Ile275Thr and p.Gly306Glu, which were found in the propositi of two unrelated Spanish families, both subjects presenting with nonsyndromic hearing impairment. Further investigation revealed syndromic features in other hemizygous carriers from one of the pedigrees. Sequencing of genes that are functionally related to PRPS1 did not reveal any candidate variant that might act as a phenotype modifier.
  
  
  CONCLUSIONS
  This case of intrafamilial phenotypic variation associated with a single PRPS1 mutation complicates the genotype-phenotype correlations, which makes genetic counseling of mutation carriers difficult because of the wide spectrum of severity of the associated disorders.
authors.affiliation: 1] Servicio de Genética, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain [2] Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Gandía
authors.affiliation: Unidad de Genética, Departamento de Pediatría, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Fernández-Toral
authors.affiliation: Servicio de Otorrinolaringología, Hospital Universitario de Valme, Sevilla, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Solanellas
authors.affiliation: 1] Servicio de Genética, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain [2] Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Domínguez-Ruiz
authors.affiliation: 1] Servicio de Genética, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain [2] Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Gómez-Rosas
authors.affiliation: 1] Servicio de Genética, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain [2] Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Del Castillo
authors.affiliation: 1] Servicio de Genética, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain [2] Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
authors.forename: Manuela
authors.initials: M
authors.lastname: Villamar
authors.affiliation: 1] Servicio de Genética, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain [2] Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Moreno-Pelayo
authors.affiliation: 1] Servicio de Genética, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain [2] Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Del Castillo
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D041321:Chromosomes, Human, X; D003638:Deafness / Q000235:genetics; D005192:Family Health; D005260:Female; D056726:Genetic Association Studies; D005817:Genetic Counseling; D005820:Genetic Testing; D034381:Hearing Loss / Q000235:genetics*; D057898:Hemizygote; D006579:Heterozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D012268:Ribose-Phosphate Pyrophosphokinase / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D013030:Spain
chemical_list: C510474:PRPS1 protein, human; D012268:Ribose-Phosphate Pyrophosphokinase