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J Inherit Metab Dis. 2018 Jan;41(1):117-127. doi: 10.1007/s10545-017-0071-1. Epub 2017 Sep 14.

Impaired fertility and motor function in a zebrafish model for classic galactosemia.

Author information

1
Department of Clinical Genetics, Maastricht University Medical Centre, Universiteitssingel 50, P.O. Box 616, box 16, 6200 MD, Maastricht, The Netherlands. j.vanoevelen@maastrichtuniversity.nl.
2
GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands. j.vanoevelen@maastrichtuniversity.nl.
3
Department of Clinical Genetics, Maastricht University Medical Centre, Universiteitssingel 50, P.O. Box 616, box 16, 6200 MD, Maastricht, The Netherlands.
4
GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
5
Department of Pediatrics, Maastricht University Medical Centre, Maastricht, The Netherlands.
6
The Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
7
Department of Methodology and Statistics, School for Public Health and Primary Care (CAPHRI), Maastricht University, Maastricht, The Netherlands.
8
Department of Clinical Genetics, Maastricht University Medical Centre, Universiteitssingel 50, P.O. Box 616, box 16, 6200 MD, Maastricht, The Netherlands. estela.rubio@mumc.nl.
9
GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands. estela.rubio@mumc.nl.
10
Department of Pediatrics, Maastricht University Medical Centre, Maastricht, The Netherlands. estela.rubio@mumc.nl.

Abstract

Classic galactosemia is a genetic disorder of galactose metabolism, caused by severe deficiency of galactose-1-phosphate uridylyltransferase (GALT) enzyme activity due to mutations of the GALT gene. Its pathogenesis is still not fully elucidated, and a therapy that prevents chronic impairments is lacking. In order to move research forward, there is a high need for a novel animal model, which allows organ studies throughout development and high-throughput screening of pharmacologic compounds. Here, we describe the generation of a galt knockout zebrafish model and present its phenotypical characterization. Using a TALEN approach, a galt knockout line was successfully created. Accordingly, biochemical assays confirm essentially undetectable galt enzyme activity in homozygotes. Analogous to humans, galt knockout fish accumulate galactose-1-phosphate upon exposure to exogenous galactose. Furthermore, without prior exposure to exogenous galactose, they exhibit reduced motor activity and impaired fertility (lower egg quantity per mating, higher number of unsuccessful crossings), resembling the human phenotype(s) of neurological sequelae and subfertility. In conclusion, our galt knockout zebrafish model for classic galactosemia mimics the human phenotype(s) at biochemical and clinical levels. Future studies in our model will contribute to improved understanding and management of this disorder.

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