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Sci Rep. 2016 Jul 18;6:29946. doi: 10.1038/srep29946.

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

Author information

1
Translational and Functional Genomics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA.
2
Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA.
3
Department of Biology, Hanover College, Hanover, IN, 47243, USA.
4
Section on Sensory Cell Development and Function, National Institute on Deafness and Other Communication Disorders, Bethesda, MD 20892, USA.
5
Departments of Otorhinolaryngology and Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA.

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.

PMID:
27425195
PMCID:
PMC4947902
DOI:
10.1038/srep29946
[Indexed for MEDLINE]
Free PMC Article

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