{"id":424,"date":"2024-01-31T16:56:35","date_gmt":"2024-01-31T16:56:35","guid":{"rendered":"http:\/\/sebgc.es\/blog\/?guid=26165631460adb187f52d83e8b5ac842"},"modified":"2024-02-07T23:32:17","modified_gmt":"2024-02-07T23:32:17","slug":"znf142-mutation-causes-sex-dependent-neurologic-disorder","status":"publish","type":"post","link":"https:\/\/sebigec.es\/blog\/index.php\/2024\/01\/31\/znf142-mutation-causes-sex-dependent-neurologic-disorder\/","title":{"rendered":"ZNF142 mutation causes sex-dependent neurologic disorder"},"content":{"rendered":"<sec><st>Background<\/st><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.<\/p><\/sec><sec><st>Methods<\/st><p>Linkage analysis, whole exome sequencing, generation of CRISPR\/cas9 knock-in mice, mouse behaviour and molecular studies<\/p><\/sec><sec><st>Results<\/st><p>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<sup>R1508*<\/sup><\/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<sup>R1508*<\/sup><\/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<sup>R1508*<\/sup><\/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<sup>R1508*<\/sup><\/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.<\/p><\/sec><sec><st>Conclusion<\/st><p><I>ZNF142<\/I> mutation downregulates <I>Mllt6<\/I> and <I>Taok1,<\/I> causing a neurodevelopmental phenotype in humans and mice with female preponderance.<\/p><\/sec>","protected":false},"excerpt":{"rendered":"<p>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 developme&#8230;<\/p>\n","protected":false},"author":1,"featured_media":461,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[6,8],"tags":[],"class_list":["post-424","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-articulos","category-jmg-first"],"_links":{"self":[{"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/posts\/424","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/comments?post=424"}],"version-history":[{"count":1,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/posts\/424\/revisions"}],"predecessor-version":[{"id":425,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/posts\/424\/revisions\/425"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/media\/461"}],"wp:attachment":[{"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/media?parent=424"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/categories?post=424"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/tags?post=424"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}