Mutation of a serine near the catalytic site of the choline acetyltransferase a gene almost completely abolishes motility of the zebrafish embryo

PLoS One. 2018 Nov 20;13(11):e0207747. doi: 10.1371/journal.pone.0207747. eCollection 2018.

Abstract

In zebrafish, the gene choline acetyltransferase a (chata) encodes one of the two ChAT orthologs responsible for the synthesis of acetylcholine. Acetylcholine (ACh) is essential for neuromuscular transmission and its impaired synthesis by ChAT can lead to neuromuscular junction disorders such as congenital myasthenic syndromes in humans. We have identified a novel mutation in the chata gene of zebrafish, chatatk64, in a collection of uncharacterised ENU-induced mutants. This mutant carries a missense mutation in the codon of a highly conserved serine changing it to an arginine (S102R). This serine is conserved among ChATs from zebrafish, rat, mice and chicken to humans. It resides within the catalytic domain and in the vicinity of the active site of the enzyme. However, it has not been reported so far to be required for enzymatic activity. Modelling of the S102R variant change in the ChAT protein crystal structure suggests that the change affects protein structure and has a direct impact on the catalytic domain of the protein which abolishes embryo motility almost completely.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Amino Acid Sequence
  • Amino Acid Substitution
  • Animals
  • Catalytic Domain*
  • Choline O-Acetyltransferase / chemistry*
  • Choline O-Acetyltransferase / genetics*
  • Choline O-Acetyltransferase / metabolism
  • Embryo, Nonmammalian / physiology*
  • Enzyme Stability
  • Humans
  • Movement*
  • Mutation, Missense
  • Protein Structure, Secondary
  • Serine*
  • Zebrafish / embryology*
  • Zebrafish / genetics

Substances

  • Serine
  • Choline O-Acetyltransferase

Grants and funding

This project has received funding from the European Union’s Horizon 3952020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No. 643062 (ZENCODE-ITN) <https://zencode-itn.eu>. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.