{"id":999,"date":"2025-11-20T00:00:00","date_gmt":"2025-11-20T00:00:00","guid":{"rendered":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2025.1690468"},"modified":"2025-11-20T00:00:00","modified_gmt":"2025-11-20T00:00:00","slug":"why-all-mody-variants-in-transcription-factor-genes-are-dominantly-inherited","status":"publish","type":"post","link":"https:\/\/sebigec.es\/blog\/index.php\/2025\/11\/20\/why-all-mody-variants-in-transcription-factor-genes-are-dominantly-inherited\/","title":{"rendered":"Why all MODY variants in transcription factor genes are dominantly inherited"},"content":{"rendered":"Maturity-onset diabetes of the young (MODY) is an autosomal dominant form of monogenic diabetes, frequently caused by heterozygous loss-of-function variants in transcription factor (TF) genes. Why are MODY variants in TF genes dominantly inherited? Here I present a systems biology-based explanation. The fact that MODY-associated TFs are master regulators of pancreatic \u03b2 cell fate suggests that pathogenic variants cause defects in cell fate determination. From a systems biology perspective, cell fate defects are based on disrupted bistability, a crucial feature of dynamical systems to make binary choices. Bistability requires both positive feedback and ultrasensitivity, the latter often in the form of cooperativity. MODY-associated TFs exhibit both features, which not only allows for bistability, but also makes these TFs extremely dosage sensitive, which explains why heterozygous loss of function is sufficient to cause a disease phenotype. A review of the literature strongly supports this hypothesis. Moreover, the hypothesis also helps to explain why incomplete penetrance is such a pervasive feature of MODY-associated variants in TF genes.","protected":false},"excerpt":{"rendered":"<p>Maturity-onset diabetes of the young (MODY) is an autosomal dominant form of monogenic diabetes, frequently caused by heterozygous loss-of-function variants in transcription factor (TF) genes. Why are MODY variants in TF genes dominantly inherited? Her&#8230;<\/p>\n","protected":false},"author":201,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[6,12,13,81],"tags":[71],"class_list":["post-999","post","type-post","status-publish","format-standard","hentry","category-articulos","category-enfermedades-raras","category-frontiers-in-genetics","category-opinion","tag-frontgenet"],"_links":{"self":[{"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/posts\/999","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\/201"}],"replies":[{"embeddable":true,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/comments?post=999"}],"version-history":[{"count":1,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/posts\/999\/revisions"}],"predecessor-version":[{"id":1000,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/posts\/999\/revisions\/1000"}],"wp:attachment":[{"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/media?parent=999"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/categories?post=999"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/tags?post=999"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}