title: Functional characterization of a novel loss-of-function mutation of PRPS1 related to early-onset progressive nonsyndromic hearing loss in Koreans (DFNX1): Potential implications on future therapeutic intervention.
abstract: BACKGROUND
  The symptoms of phosphoribosyl pyrophosphate synthetase 1 (PRPS1) deficiency diseases have been reported to be alleviated by medication. In the present study, we report biochemical data that favor PRPS1 deficiency-related hearing loss as a potential target for pharmaceutical treatment.
  
  
  METHODS
  We recruited 42 probands from subjects aged less than 15 years with a moderate degree of nonsyndromic autosomal-recessive or sporadic sensorineural hearing loss (SNHL) in at least one side. Molecular genetic testing, including targeted exome sequencing (TES) of 129 genes for deafness, and in silico prediction were performed.
  
  
  RESULTS
  A strong candidate variant (p.A82P) of PRPS1 is co-segregated with SNHL in X-linked recessive inheritance from one Korean multiplex SNHL family. Subsequent measurement of in vitro enzymatic activities of PRPS1 from erythrocytes of affected and unaffected family members, as well as unrelated normal controls, confirmed a pathogenic role of this variant. In detail, compared to normal hearing controls (0.23-0.26 nmol/ml/h), the proband, the affected sibling and their normal hearing mother demonstrated a significantly decreased PRPS1 enzymatic activity (0.07, 0.03 and 0.11 nmol/ml/h, respectively). This novel loss-of-function mutation of PRPS1 (p.A82P) is the ninth and sixth most reported mutation in the world and in Asia, respectively.
  
  
  CONCLUSIONS
  DFNX1 was found to account for approximately 2.4% (1/42) of moderate SNHL in a Korean pediatric population. Confirmation of PRPS1 activity deficiency and an audiologic phenotype that initially begins in a milder form of SNHL, as in our family, should indicate the need for rigorous genetic screening as early as possible.
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, CHA Bundang Medical Center, CHA University, Seongnam, South Korea.
authors.forename: So Young
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Ah Reum
authors.initials: AR
authors.lastname: Kim
authors.affiliation: Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea.
authors.forename: Nayoung K D
authors.initials: NK
authors.lastname: Kim
authors.affiliation: Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea.|Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Suwon, South Korea.
authors.forename: Chung
authors.initials: C
authors.lastname: Lee
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea.
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Han
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea.
authors.forename: Min Young
authors.initials: MY
authors.lastname: Kim
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea.
authors.forename: Eun-Hee
authors.initials: EH
authors.lastname: Jeon
authors.affiliation: Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea.|Department of Molecular Cell Biology, School of Medicine, Sungkyunkwan University, Seoul, South Korea.
authors.forename: Woong-Yang
authors.initials: WY
authors.lastname: Park
authors.affiliation: Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Mittal
authors.affiliation: Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors.forename: Denise
authors.initials: D
authors.lastname: Yan
authors.affiliation: Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors.forename: Xue Zhong
authors.initials: XZ
authors.lastname: Liu
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea.|Wide River Institute of Immunology, Seoul National University College of Medicine, Hongcheon, South Korea.
authors.forename: Byung Yoon
authors.initials: BY
authors.lastname: Choi
mesh_terms: D001483:Base Sequence; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D003638:Deafness / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D056910:Republic of Korea; D012268:Ribose-Phosphate Pyrophosphokinase / Q000235:genetics*; D000073359:Exome Sequencing
chemical_list: C510474:PRPS1 protein, human; D012268:Ribose-Phosphate Pyrophosphokinase
keywords: DFNX1 (X-linked nonsyndromic sensorineural deafness type 1); Korean; PRPS1; S-adenosylmethionine (SAM); p.A82P