Zebrafish slc30a10 deficiency revealed a novel compensatory mechanism of Atp2c1 in maintaining manganese homeostasis

PLoS Genet. 2017 Jul 10;13(7):e1006892. doi: 10.1371/journal.pgen.1006892. eCollection 2017 Jul.

Abstract

Recent studies found that mutations in the human SLC30A10 gene, which encodes a manganese (Mn) efflux transporter, are associated with hypermanganesemia with dystonia, polycythemia, and cirrhosis (HMDPC). However, the relationship between Mn metabolism and HMDPC is poorly understood, and no specific treatments are available for this disorder. Here, we generated two zebrafish slc30a10 mutant lines using the CRISPR/Cas9 system. Compared to wild-type animals, mutant adult animals developed significantly higher systemic Mn levels, and Mn accumulated in the brain and liver of mutant embryos in response to exogenous Mn. Interestingly, slc30a10 mutants developed neurological deficits in adulthood, as well as environmental Mn-induced manganism in the embryonic stage; moreover, mutant animals had impaired dopaminergic and GABAergic signaling. Finally, mutant animals developed steatosis, liver fibrosis, and polycythemia accompanied by increased epo expression. This phenotype was rescued partially by EDTA- CaNa2 chelation therapy and iron supplementation. Interestingly, prior to the onset of slc30a10 expression, expressing ATP2C1 (ATPase secretory pathway Ca2+ transporting 1) protected mutant embryos from Mn exposure, suggesting a compensatory role for Atp2c1 in the absence of Slc30a10. Notably, expressing either wild-type or mutant forms of SLC30A10 was sufficient to inhibit the effect of ATP2C1 in response to Mn challenge in both zebrafish embryos and HeLa cells. These findings suggest that either activating ATP2C1 or restoring the Mn-induced trafficking of ATP2C1 can reduce Mn accumulation, providing a possible target for treating HMDPC.

MeSH terms

  • Animals
  • Brain / metabolism
  • Brain / pathology
  • CRISPR-Cas Systems
  • Calcium-Transporting ATPases / genetics*
  • Cation Transport Proteins / deficiency
  • Cation Transport Proteins / genetics*
  • Genotype
  • HeLa Cells
  • Homeostasis / genetics*
  • Humans
  • Manganese / metabolism*
  • Metabolic Diseases / genetics*
  • Metabolic Diseases / metabolism
  • Metabolic Diseases / pathology
  • Mutation
  • Zebrafish / genetics
  • Zinc Transporter 8

Substances

  • Cation Transport Proteins
  • SLC30A8 protein, human
  • Zinc Transporter 8
  • Manganese
  • ATP2C1 protein, human
  • Calcium-Transporting ATPases

Supplementary concepts

  • Hypermanganesemia with Dystonia Polycythemia and Cirrhosis

Grants and funding

This work was supported by research grants from the National Natural Science Foundation of China (http://www.nsfc.gov.cn/) (31501181 to ZX; 31330036, 31225013 and 31530034 to FW; 31570791 and 91542205 to JM and 31401016 to LZ), the Natural Science Foundation of Zhejiang Province (http://www.zjnsf.gov.cn/)(LQ15C110001 to ZX). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.