title: Additive reductions in zebrafish PRPS1 activity result in a spectrum of deficiencies modeling several human PRPS1-associated diseases.
abstract: Phosphoribosyl pyrophosphate synthetase-1 (PRPS1) is a key enzyme in nucleotide biosynthesis, and mutations in PRPS1 are found in several human diseases including nonsyndromic sensorineural deafness, Charcot-Marie-Tooth disease-5, and Arts Syndrome. We utilized zebrafish as a model to confirm that mutations in PRPS1 result in phenotypic deficiencies in zebrafish similar to those in the associated human diseases. We found two paralogs in zebrafish, prps1a and prps1b and characterized each paralogous mutant individually as well as the double mutant fish. Zebrafish prps1a mutants and prps1a;prps1b double mutants showed similar morphological phenotypes with increasingly severe phenotypes as the number of mutant alleles increased. Phenotypes included smaller eyes and reduced hair cell numbers, consistent with the optic atrophy and hearing impairment observed in human patients. The double mutant also showed abnormal development of primary motor neurons, hair cell innervation, and reduced leukocytes, consistent with the neuropathy and recurrent infection of the human patients possessing the most severe reductions of PRPS1 activity. Further analyses indicated the phenotypes were associated with a prolonged cell cycle likely resulting from reduced nucleotide synthesis and energy production in the mutant embryos. We further demonstrated the phenotypes were caused by delays in the tissues most highly expressing the prps1 genes.
authors.affiliation: Translational and Functional Genomics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA.
authors.forename: Wuhong
authors.initials: W
authors.lastname: Pei
authors.affiliation: Translational and Functional Genomics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA.
authors.forename: Lisha
authors.initials: L
authors.lastname: Xu
authors.affiliation: Translational and Functional Genomics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA.
authors.forename: Gaurav K
authors.initials: GK
authors.lastname: Varshney
authors.affiliation: Translational and Functional Genomics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA.
authors.forename: Blake
authors.initials: B
authors.lastname: Carrington
authors.affiliation: Translational and Functional Genomics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Bishop
authors.affiliation: Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA.
authors.forename: MaryPat
authors.initials: M
authors.lastname: Jones
authors.affiliation: Translational and Functional Genomics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA.
authors.forename: Sunny C
authors.initials: SC
authors.lastname: Huang
authors.affiliation: Translational and Functional Genomics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Idol
authors.affiliation: Department of Biology, Hanover College, Hanover, IN, 47243, USA.
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Pretorius
authors.affiliation: Section on Sensory Cell Development and Function, National Institute on Deafness and Other Communication Disorders, Bethesda, MD 20892, USA.
authors.forename: Alisha
authors.initials: A
authors.lastname: Beirl
authors.affiliation: Departments of Otorhinolaryngology and Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Schimmenti
authors.affiliation: Section on Sensory Cell Development and Function, National Institute on Deafness and Other Communication Disorders, Bethesda, MD 20892, USA.
authors.forename: Katie S
authors.initials: KS
authors.lastname: Kindt
authors.affiliation: Translational and Functional Genomics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA.
authors.forename: Raman
authors.initials: R
authors.lastname: Sood
authors.affiliation: Translational and Functional Genomics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Burgess
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D001921:Brain / Q000196:embryology / Q000378:metabolism; D007758:Ear, Inner / Q000196:embryology / Q000294:innervation / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000378:metabolism; D005123:Eye / Q000378:metabolism / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D006410:Hematopoiesis; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D008954:Models, Biological; D009046:Motor Neurons / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D010858:Pigmentation / Q000235:genetics; D012268:Ribose-Phosphate Pyrophosphokinase / Q000235:genetics / Q000378:metabolism*; D012436:S-Adenosylmethionine / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D029961:Zebrafish Proteins; D012436:S-Adenosylmethionine; D000255:Adenosine Triphosphate; C510474:PRPS1 protein, human; D012268:Ribose-Phosphate Pyrophosphokinase; C000627588:prps1a protein, zebrafish