RAP1-mediated MEK/ERK pathway defects in Kabuki syndrome

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dc.contributor.authorBoegershausen, Nina
dc.contributor.authorTsai, I.-Chun
dc.contributor.authorPohl, Esther
dc.contributor.authorKiper, Pelin Ozlem Simsek
dc.contributor.authorBeleggia, Filippo
dc.contributor.authorPercin, E. Ferda
dc.contributor.authorKeupp, Katharina
dc.contributor.authorMatchan, Angela
dc.contributor.authorMilz, Esther
dc.contributor.authorAlanay, Yasemin
dc.contributor.authorKayserili, Hulya
dc.contributor.authorLiu, Yicheng
dc.contributor.authorBanka, Siddharth
dc.contributor.authorKranz, Andrea
dc.contributor.authorZenker, Martin
dc.contributor.authorWieczorek, Dagmar
dc.contributor.authorElcioglu, Nursel
dc.contributor.authorProntera, Paolo
dc.contributor.authorLyonnet, Stanislas
dc.contributor.authorMeitinger, Thomas
dc.contributor.authorStewart, A. Francis
dc.contributor.authorDonnai, Dian
dc.contributor.authorStrom, Tim M.
dc.contributor.authorBoduroglu, Koray
dc.contributor.authorYigit, Goekhan
dc.contributor.authorLi, Yun
dc.contributor.authorKatsanis, Nicholas
dc.contributor.authorWollnik, Bernd
dc.date.accessioned2023-02-21T12:42:10Z
dc.date.available2023-02-21T12:42:10Z
dc.date.issued2015-01-01
dc.description.abstractThe genetic disorder Kabuki syndrome (KS) is characterized by developmental delay and congenital anomalies. Dominant mutations in the chromatin regulators lysine (K)-specific methyltransferase 2D (KMT2D) (also known as MLL2) and lysine (K)-specific demethylase 6A (KDM6A) underlie the majority of cases. Although the functions of these chromatin-modifying proteins have been studied extensively, the physiological systems regulated by them are largely unknown. Using whole-exome sequencing, we identified a mutation in RAP1A that was converted to homozygosity as the result of uniparental isodisomy (UPD) in a patient with KS and a de novo, dominant mutation in RAP1B in a second individual with a KS-like phenotype. We elucidated a genetic and functional interaction between the respective KS-associated genes and their products in zebrafish models and patient cell lines. Specifically, we determined that dysfunction of known KS genes and the genes identified in this study results in aberrant MEK/ERK signaling as well as disruption of F-actin polymerization and cell intercalation. Moreover, these phenotypes could be rescued in zebrafish models by rebalancing MEK/ERK signaling via administration of small molecule inhibitors of MEK. Taken together, our studies suggest that the KS pathophysiology overlaps with the RASopathies and provide a potential direction for treatment design.
dc.description.issue9
dc.description.issueSEP
dc.description.pages3585-3599
dc.description.volume125
dc.identifier.doi10.1172/JCI80102
dc.identifier.urihttps://hdl.handle.net/11443/2791
dc.identifier.urihttp://dx.doi.org/10.1172/JCI80102
dc.identifier.wosWOS:000362303600032
dc.publisherAMER SOC CLINICAL INVESTIGATION INC
dc.relation.ispartofJOURNAL OF CLINICAL INVESTIGATION
dc.titleRAP1-mediated MEK/ERK pathway defects in Kabuki syndrome
dc.typeArticle
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