{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T21:15:41Z","timestamp":1769721341176,"version":"3.49.0"},"reference-count":39,"publisher":"BMJ","issue":"6","funder":[{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["2034\/18 and 2463\/23"],"award-info":[{"award-number":["2034\/18 and 2463\/23"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Knowledge Center for Rare\/Orphan Diseases of the Israel Ministry of Science"},{"name":"Morris Kahn family Foundation"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2024,1,16]]},"published-print":{"date-parts":[[2024,6]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Linkage analysis, whole exome sequencing, generation of CRISPR\/cas9 knock-in mice, mouse behaviour and molecular studies<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Linkage analysis and whole exome sequencing studies of the affected kindred delineated a ~5\u2009Mbp disease-associated chromosome 2q35 locus, containing a novel homozygous frameshift truncating mutation in <jats:italic>ZNF142<\/jats:italic>, in line with recent studies depicting similar <jats:italic>ZNF142<\/jats:italic> 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 <jats:italic>Zfp142<jats:sup>R1508*<\/jats:sup>\n                     <\/jats:italic> 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 <jats:italic>Zfp142<jats:sup>R1508*<\/jats:sup>\n                     <\/jats:italic> mice showed depletion of lymphoid and haematopoietic cells, mostly in females. RT-PCR showed lower expression of <jats:italic>Zpf142<\/jats:italic> 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 <jats:italic>Zfp142<jats:sup>R1508*<\/jats:sup>\n                     <\/jats:italic> mice demonstrated differentially expressed genes. Notably, expression of <jats:italic>Taok1<\/jats:italic> in the cortex and of <jats:italic>Mllt6<\/jats:italic> in the hippocampus was downregulated in homozygous <jats:italic>Zfp142<jats:sup>R1508*<\/jats:sup>\n                     <\/jats:italic> mice. <jats:italic>Taok1<\/jats:italic> mutations have been associated with aberrant neurodevelopment and behaviour. <jats:italic>Mllt6<\/jats:italic> expression is regulated by sex hormones and <jats:italic>Mllt6<\/jats:italic> null-mutant mice present with haematopoietic, immune system and female-specific behaviour phenotypes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>\n                     <jats:italic>ZNF142<\/jats:italic> mutation downregulates <jats:italic>Mllt6<\/jats:italic> and <jats:italic>Taok1,<\/jats:italic> causing a neurodevelopmental phenotype in humans and mice with female preponderance.<\/jats:p>\n               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