title: Expanding the phenotype of PRPS1 syndromes in females: neuropathy, hearing loss and retinopathy.
abstract: BACKGROUND
  Phosphoribosyl pyrophosphate synthetase (PRS) I deficiency is a rare medical condition caused by missense mutations in PRPS1 that lead to three different phenotypes: Arts Syndrome (MIM 301835), X-linked Charcot-Marie-Tooth (CMTX5, MIM 311070) or X-linked non-syndromic sensorineural deafness (DFN2, MIM 304500). All three are X-linked recessively inherited and males affected display variable degree of central and peripheral neuropathy. We applied whole exome sequencing to a three-generation family with optic atrophy followed by retinitis pigmentosa (RP) in all three cases, and ataxia, progressive peripheral neuropathy and hearing loss with variable presentation.
  
  
  METHODS
  Whole exome sequencing was performed in two affecteds and one unaffected member of the family. Sanger sequencing was used to validate and segregate the 12 candidate mutations in the family and to confirm the absence of the novel variant in PRPS1 in 191 controls. The pathogenic role of the novel mutation in PRPS1 was assessed in silico and confirmed by enzymatic determination of PRS activity, mRNA expression and sequencing, and X-chromosome inactivation.
  
  
  RESULTS
  A novel missense mutation was identified in PRPS1 in the affected females. Age of onset, presentation and severity of the phenotype are highly variable in the family: both the proband and her mother have neurological and ophthalmological symptoms, whereas the phenotype of the affected sister is milder and currently confined to the eye. Moreover, only the proband displayed a complete lack of expression of the wild type allele in leukocytes that seems to correlate with the degree of PRS deficiency and the severity of the phenotype. Interestingly, optic atrophy and RP are the only common manifestations to all three females and the only phenotype correlating with the degree of enzyme deficiency.
  
  
  CONCLUSIONS
  These results are in line with recent evidence of the existence of intermediate phenotypes in PRS-I deficiency syndromes and demonstrate that females can exhibit a disease phenotype as severe and complex as their male counterparts.
authors.affiliation: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. castillob@email.chop.edu.
authors.forename: Berta
authors.initials: B
authors.lastname: Almoguera
authors.affiliation: College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China. hesijie@genomics.cn.|BGI-Shenzhen, Shenzhen, 518083, China. hesijie@genomics.cn.
authors.forename: Sijie
authors.initials: S
authors.lastname: He
authors.affiliation: Department of Genetics and Genomics, IIS-Fundación Jiménez Díaz University Hospital (IISFJD, UAM), 28040, Madrid, Spain. mcorton@fjd.es.|Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain. mcorton@fjd.es.
authors.forename: Marta
authors.initials: M
authors.lastname: Corton
authors.affiliation: Department of Genetics and Genomics, IIS-Fundación Jiménez Díaz University Hospital (IISFJD, UAM), 28040, Madrid, Spain. patricia.fernandez@fjd.es.|Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain. patricia.fernandez@fjd.es.
authors.forename: Patricia
authors.initials: P
authors.lastname: Fernandez-San Jose
authors.affiliation: Department of Genetics and Genomics, IIS-Fundación Jiménez Díaz University Hospital (IISFJD, UAM), 28040, Madrid, Spain. fblancok@fjd.es.|Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain. fblancok@fjd.es.
authors.forename: Fiona
authors.initials: F
authors.lastname: Blanco-Kelly
authors.affiliation: Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain. milopez@fjd.es.|Department of Ophthalmology, Fundación Jiménez Díaz, 28040, Madrid, Spain. milopez@fjd.es.
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: López-Molina
authors.affiliation: Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain. bgarcia@fjd.es.|Department of Ophthalmology, Fundación Jiménez Díaz, 28040, Madrid, Spain. bgarcia@fjd.es.
authors.forename: Blanca
authors.initials: B
authors.lastname: García-Sandoval
authors.affiliation: Department of Neurology, Fundación Jiménez Díaz, 28040, Madrid, Spain. JdelVal@fjd.es.
authors.forename: Javier
authors.initials: J
authors.lastname: Del Val
authors.affiliation: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. guoy@email.chop.edu.
authors.forename: Yiran
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. tianl@email.chop.edu.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Tian
authors.affiliation: BGI-Shenzhen, Shenzhen, 518083, China. liuxuanzhu@genomics.cn.
authors.forename: Xuanzhu
authors.initials: X
authors.lastname: Liu
authors.affiliation: BGI-Shenzhen, Shenzhen, 518083, China. guanliping@genomics.cn.
authors.forename: Liping
authors.initials: L
authors.lastname: Guan
authors.affiliation: Department of Biochemistry, La Paz University Hospital IdiPaz, Madrid, 28046, Spain. rosa.torres@salud.madrid.org.
authors.forename: Rosa J
authors.initials: RJ
authors.lastname: Torres
authors.affiliation: Department of Internal Medicine, Metabolic-Vascular Unit, La Paz University Hospital IdiPaz, Madrid, 28046, Spain. juangarciapuig@gmail.com.
authors.forename: Juan G
authors.initials: JG
authors.lastname: Puig
authors.affiliation: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. hakonarson@email.chop.edu.
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.affiliation: BGI-Shenzhen, Shenzhen, 518083, China. xuxun@genomics.cn.|The Guangdong Enterprise Key Laboratory of Human Disease Genomics, Shenzhen, China. xuxun@genomics.cn.
authors.forename: Xun
authors.initials: X
authors.lastname: Xu
authors.affiliation: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. bkeating@mail.med.upenn.edu.
authors.forename: Brendan
authors.initials: B
authors.lastname: Keating
authors.affiliation: Department of Genetics and Genomics, IIS-Fundación Jiménez Díaz University Hospital (IISFJD, UAM), 28040, Madrid, Spain. cayuso@fjd.es.|Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain. cayuso@fjd.es.
authors.forename: Carmen
authors.initials: C
authors.lastname: Ayuso
mesh_terms: D000595:Amino Acid Sequence; D005260:Female; D034381:Hearing Loss / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D010523:Peripheral Nervous System Diseases / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D010641:Phenotype; D017433:Protein Structure, Secondary; D011686:Purine-Pyrimidine Metabolism, Inborn Errors / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D012174:Retinitis Pigmentosa / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D012268:Ribose-Phosphate Pyrophosphokinase / Q000172:deficiency* / Q000235:genetics; D013577:Syndrome
chemical_list: C510474:PRPS1 protein, human; D012268:Ribose-Phosphate Pyrophosphokinase