A single mutation in the prM protein of Zika virus contributes to fetal microcephaly

Science. 2017 Nov 17;358(6365):933-936. doi: 10.1126/science.aam7120. Epub 2017 Sep 28.


Zika virus (ZIKV) has evolved into a global health threat because of its unexpected causal link to microcephaly. Phylogenetic analysis reveals that contemporary epidemic strains have accumulated multiple substitutions from their Asian ancestor. Here we show that a single serine-to-asparagine substitution [Ser139→Asn139 (S139N)] in the viral polyprotein substantially increased ZIKV infectivity in both human and mouse neural progenitor cells (NPCs) and led to more severe microcephaly in the mouse fetus, as well as higher mortality rates in neonatal mice. Evolutionary analysis indicates that the S139N substitution arose before the 2013 outbreak in French Polynesia and has been stably maintained during subsequent spread to the Americas. This functional adaption makes ZIKV more virulent to human NPCs, thus contributing to the increased incidence of microcephaly in recent ZIKV epidemics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Americas / epidemiology
  • Amino Acid Substitution
  • Animals
  • Asparagine / genetics
  • Cell Line, Tumor
  • Cricetinae
  • Disease Outbreaks
  • Humans
  • Incidence
  • Mice
  • Microcephaly / epidemiology
  • Microcephaly / virology*
  • Mutation
  • Neural Stem Cells / virology
  • Polynesia / epidemiology
  • Serine / genetics
  • Viral Envelope Proteins / genetics*
  • Zika Virus / genetics*
  • Zika Virus / pathogenicity*
  • Zika Virus Infection / complications
  • Zika Virus Infection / epidemiology
  • Zika Virus Infection / virology*


  • Viral Envelope Proteins
  • prM protein, Flavivirus
  • Serine
  • Asparagine