PMC:4570552 / 21880-23609
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/4570552","sourcedb":"PMC","sourceid":"4570552","source_url":"https://www.ncbi.nlm.nih.gov/pmc/4570552","text":"Transcription factors operate in developmental processes to mediate inductive events and cell competence, and perturbation of their function or regulation can dramatically affect morphogenesis, organogenesis, and growth.37 Here we establish that missense mutations impairing GSK3-mediated MAF phosphorylation severely perturb multiple developmental processes. Inactivating missense mutations affecting the MAF DNA binding domain had been reported to cause congenital cataracts, microcornea and iris coloboma.13,30–33 Contrasting those mutations, we describe a class of missense changes not impairing DNA binding, but instead precluding post-translational modifications required for proteasomal degradation, resulting in mutants being more stable than wild-type MAF. In addition to defective degradation, this MAF mutation class showed perturbed in vitro transactivation activity, and endogenous expression in primary fibroblasts was associated with both up- and downregulation of genes identified as positively controlled MAF targets. These findings support the idea that, besides promoting degradation, GSK3-mediated MAF phosphorylation impacts protein activity through other mechanisms, as previously demonstrated for MAFA,24 and suggest a complex pathogenetic mechanism involving protein stability and functional dysregulation. Of note, dominant missense mutations affecting residues in the same regulatory motif of MAFB and NRL, including those homologous to Ser54, Pro59, Thr62, and Pro69, have been reported to cause multicentric carpotarsal osteolysis (MCTO [MIM 166300]) and autosomal dominant retinitis pigmentosa (RP27 [MIM 613750]) (Figure S2), respectively,38,39 further highlighting the critical role of this domain.","tracks":[{"project":"2_test","denotations":[{"id":"25865493-11772997-2044028","span":{"begin":514,"end":516},"obj":"11772997"},{"id":"25865493-16470690-2044028","span":{"begin":514,"end":516},"obj":"16470690"},{"id":"25865493-17982426-2044028","span":{"begin":514,"end":516},"obj":"17982426"},{"id":"25865493-19182255-2044028","span":{"begin":514,"end":516},"obj":"19182255"},{"id":"25865493-24664492-2044028","span":{"begin":514,"end":516},"obj":"24664492"},{"id":"25865493-18042454-2044029","span":{"begin":1225,"end":1227},"obj":"18042454"},{"id":"25865493-22387013-2044030","span":{"begin":1672,"end":1674},"obj":"22387013"},{"id":"25865493-10192380-2044030","span":{"begin":1672,"end":1674},"obj":"10192380"}],"attributes":[{"subj":"25865493-11772997-2044028","pred":"source","obj":"2_test"},{"subj":"25865493-16470690-2044028","pred":"source","obj":"2_test"},{"subj":"25865493-17982426-2044028","pred":"source","obj":"2_test"},{"subj":"25865493-19182255-2044028","pred":"source","obj":"2_test"},{"subj":"25865493-24664492-2044028","pred":"source","obj":"2_test"},{"subj":"25865493-18042454-2044029","pred":"source","obj":"2_test"},{"subj":"25865493-22387013-2044030","pred":"source","obj":"2_test"},{"subj":"25865493-10192380-2044030","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2_test","color":"#cdec93","default":true}]}]}}