PUBLICATION

Additive reductions in zebrafish PRPS1 activity result in a spectrum of deficiencies modeling several human PRPS1-associated diseases

Authors
Pei, W., Xu, L., Varshney, G.K., Carrington, B., Bishop, K., Jones, M., Huang, S.C., Idol, J., Pretorius, P.R., Beirl, A., Schimmenti, L.A., Kindt, K.S., Sood, R., Burgess, S.M.
ID
ZDB-PUB-160720-9
Date
2016
Source
Scientific Reports   6: 29946 (Journal)
Registered Authors
Beirl, Alisha, Burgess, Shawn, Kindt, Katie, Pei, Wuhong, Pretorius, Pamela, Schimmenti, Lisa A., Sood, Raman, Varshney, Gaurav, Xu, Lisha
Keywords
Disease model, Neurodevelopmental disorders
MeSH Terms
  • Adenosine Triphosphate/biosynthesis
  • Animals
  • Brain/embryology
  • Brain/metabolism
  • Ear, Inner/embryology
  • Ear, Inner/innervation
  • Ear, Inner/metabolism
  • Embryo, Nonmammalian/metabolism
  • Eye/metabolism
  • Eye/pathology
  • Gene Expression Regulation, Developmental
  • Hematopoiesis
  • Humans
  • Leukocytes/metabolism
  • Models, Biological
  • Motor Neurons/metabolism
  • Mutation/genetics
  • Phenotype
  • Pigmentation/genetics
  • Ribose-Phosphate Pyrophosphokinase/metabolism*
  • S-Adenosylmethionine/metabolism
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish/metabolism*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed
27425195 Full text @ Sci. Rep.
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.
Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes