<i>ZNF142</i> mutation causes sex-dependent neurologic disorder.

Abstract

Sex-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. Linkage analysis, whole exome sequencing, generation of CRISPR/cas9 knock-in mice, mouse behaviour and molecular studies RESULTS: Linkage 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 in <i>ZNF142</i>, in line with recent studies depicting similar <i>ZNF142</i> putative 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 homozygous <i>Zfp142^R1508*</i> 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 homozygous <i>Zfp142^R1508*</i> mice showed depletion of lymphoid and haematopoietic cells, mostly in females. RT-PCR showed lower expression of <i>Zpf142</i> in brain compartments of female versus male wild-type mice. RNA-seq studies of hippocampus, hypothalamus, cortex and cerebellum of female wild-type versus homozygous <i>Zfp142^R1508*</i> mice demonstrated differentially expressed genes. Notably, expression of <i>Taok1</i> in the cortex and of <i>Mllt6</i> in the hippocampus was downregulated in homozygous <i>Zfp142^R1508*</i> mice. <i>Taok1</i> mutations have been associated with aberrant neurodevelopment and behaviour. <i>Mllt6</i> expression is regulated by sex hormones and <i>Mllt6</i> null-mutant mice present with haematopoietic, immune system and female-specific behaviour phenotypes. <i>ZNF142</i> mutation downregulates <i>Mllt6</i> and <i>Taok1,</i> causing a neurodevelopmental phenotype in humans and mice with female preponderance.