Map3k20, also known as ZAK (Zeta-chain associated protein kinase), is a mitogen-activated protein kinase. It plays a crucial role in signal transduction pathways related to ribosome-associated stress responses. For instance, it functions as a sentinel for ribosome collisions, which can activate stress-activated protein kinase (SAPK) and GCN2-mediated stress response pathways [1]. It is also involved in the ribotoxic stress response (RSR), where it can phosphorylate proteins like NLRP1 in response to UVB and toxin-induced stress, leading to inflammasome-driven pyroptosis [2].

Biallelic pathogenic variants in Map3k20 are a rare cause of split-hand foot malformation (SHFM), hearing loss, and nail abnormalities or congenital myopathy [3]. Heterozygous de novo variants in a specific region of the gene are associated with diverse clinical features including craniosynostosis, limb anomalies, sensorineural hearing loss, and ectodermal dysplasia-like phenotypes [3]. In addition, a novel Map3k20 mutation has been found to cause centronuclear myopathy-6 with fiber-type disproportion in a Pakistani family [4]. Polymorphisms in Map3k20 are also significantly associated with reduced cryo-induced lipid peroxidation and DNA damage of frozen-thawed spermatozoa in boars, suggesting its potential role in sperm post-thaw semen quality [5].

In conclusion, Map3k20 is essential in ribosome-related stress response signaling. Genetic variants of Map3k20 are associated with various human disorders, including congenital myopathies, ectodermal dysplasia, and craniosynostosis, as well as potentially affecting sperm quality in boars. The study of Map3k20 through functional and genetic analysis helps to understand its role in normal biological processes and disease mechanisms.