ZNF142mutation causes sex-dependent neurologic disorder

Abstract

BackgroundSex-specific predilection in neurological diseases caused by mutations in autosomal genes is a phenomenon whose molecular basis is poorly understood. We studied females of consanguineous Bedouin kindred presenting with severe global developmental delay and epilepsy.MethodsLinkage analysis, whole exome sequencing, generation of CRISPR/cas9 knock-in mice, mouse behaviour and molecular studiesResultsLinkage analysis and whole exome sequencing studies of the affected kindred delineated a ~5 Mbp disease-associated chromosome 2q35 locus, containing a novel homozygous frameshift truncating mutation inZNF142, in line with recent studies depicting similarZNF142putative loss-of-function human phenotypes with female preponderance. We generated knock-in mice with a truncating mutation adjacent to the human mutation in the mouse ortholog. Behaviour studies of homozygousZfp142R1508*mice showed significant phenotype only in mutant females, with learning and memory deficits, hyperactivity and aberrant loss of fear of open spaces. Bone marrow and spleen of homozygousZfp142R1508*mice showed depletion of lymphoid and haematopoietic cells, mostly in females. RT-PCR showed lower expression ofZpf142in brain compartments of female versus male wild-type mice. RNA-seq studies of hippocampus, hypothalamus, cortex and cerebellum of female wild-type versus homozygousZfp142R1508*mice demonstrated differentially expressed genes. Notably, expression ofTaok1in the cortex and ofMllt6in the hippocampus was downregulated in homozygousZfp142R1508*mice.Taok1mutations have been associated with aberrant neurodevelopment and behaviour.Mllt6expression is regulated by sex hormones andMllt6null-mutant mice present with haematopoietic, immune system and female-specific behaviour phenotypes.ConclusionZNF142mutation downregulatesMllt6andTaok1,causing a neurodevelopmental phenotype in humans and mice with female preponderance.