Female-specific synaptic dysfunction and cognitive impairment in a mouse model of PCDH19 disorder

Abstract

More is not always better Mutations in X-linked genes usually affect male individuals more than females, but the opposite characterizes the Protocadherin-19 gene ( PCDH19 ) on the X chromosome. Mutations in the PCDH19 cell-adhesion molecule cause cognitive impairment, affecting females more than males. Hoshina et al. studied mice with PCDH19 mutations, showing that a mismatch between PCDH19 and another cell-adhesion molecule causes trouble when mossy fibers of the brain are forming synapses (see the Perspective by Shohayeb and Cooper). In the heterozygous setting, mutant PCDG19 sequesters the partner cell-adhesion molecule into dysfunctional complexes. In the hemizygous setting, as in males, enough of that partner cell-adhesion molecule roams free to make functional interactions. Science , this issue p. eaaz3893 ; see also p. 235