{"id":13025,"date":"2026-03-19T16:00:20","date_gmt":"2026-03-19T16:00:20","guid":{"rendered":"http:\/\/sebigec.es\/blog\/?guid=ccfc7964209935f9d19d8abac5c9ae44"},"modified":"2026-03-19T16:00:20","modified_gmt":"2026-03-19T16:00:20","slug":"cdk4-and-cdk6-variants-in-patients-with-primary-microcephaly-lead-to-cell-cycle-defects-and-mitochondria-induced-apoptosis","status":"publish","type":"post","link":"https:\/\/sebigec.es\/blog\/index.php\/2026\/03\/19\/cdk4-and-cdk6-variants-in-patients-with-primary-microcephaly-lead-to-cell-cycle-defects-and-mitochondria-induced-apoptosis\/","title":{"rendered":"CDK4 and CDK6 variants in patients with primary microcephaly lead to cell cycle defects and mitochondria-induced apoptosis"},"content":{"rendered":"<sec><st>Background<\/st><p>The disruption of neural progenitor proliferation is a key mechanism underlying primary microcephaly, yet how cell cycle arrest leads to progenitor loss remains only partially understood. Cyclin-dependent kinases, <I>CDK4<\/I> and <I>CDK6,<\/I> are central regulators of the G&#x2081;\/S transition, but their role in cellular stress responses during neurodevelopment remains unclear.<\/p><\/sec><sec><st>Methods<\/st><p>We studied fibroblasts from affected individuals in two families: siblings homozygous for a <I>CDK4<\/I> frameshift (p.Glu94Argfs*65) presenting with microcephaly and pontine hypoplasia<\/p><p>and a child homozygous for a <I>CDK6<\/I> missense variant (p.Thr154Ile) with microcephaly, brain atrophy, neutropenia and ovarian failure.<\/p><\/sec><sec><st>Results<\/st><p>Loss-of-function variants in <I>CDK4<\/I> and <I>CDK6<\/I>, core G&#x2081;\/S regulators, impaired proliferation and induced mitochondrial stress responses and apoptosis. Mutant fibroblasts exhibited significantly reduced DNA synthesis and cell cycle progression, along with increased mitochondrial activity, elevated reactive oxygen species and increased apoptosis. Mitochondrial responses differed by gene: <I>CDK4<\/I> deficiency caused mitochondrial hyperpolarisation, while <I>CDK6<\/I> deficiency resulted in depolarisation, suggesting differences in mitochondrial apoptotic dynamics. Both variants affected mTOR pathway signalling, linking cell cycle kinase loss to disrupted metabolic regulation.<\/p><\/sec><sec><st>Conclusion<\/st><p>These findings uncover a previously unrecognised mitochondrial stress response accompanying proliferative failure, offering mechanistic insight into how cell cycle arrest could lead to neural progenitor depletion and brain growth disorders. More broadly, our results connect cyclin-dependent kinase dysfunction with mitochondrial homeostasis in neurodevelopment, highlighting shared pathways with neurodegeneration and cancer.<\/p><\/sec>","protected":false},"excerpt":{"rendered":"<p>BackgroundThe disruption of neural progenitor proliferation is a key mechanism underlying primary microcephaly, yet how cell cycle arrest leads to progenitor loss remains only partially understood. Cyclin-dependent kinases, CDK4 and CDK6, are central r&#8230;<\/p>\n","protected":false},"author":0,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[6,8],"tags":[],"class_list":["post-13025","post","type-post","status-publish","format-standard","hentry","category-articulos","category-jmg-first"],"_links":{"self":[{"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/posts\/13025","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"}],"replies":[{"embeddable":true,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/comments?post=13025"}],"version-history":[{"count":1,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/posts\/13025\/revisions"}],"predecessor-version":[{"id":13026,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/posts\/13025\/revisions\/13026"}],"wp:attachment":[{"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/media?parent=13025"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/categories?post=13025"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/tags?post=13025"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}