Universität zu Köln

Boegershausen, Nina, Tsai, I-Chun, Pohl, Esther, Kiper, Pelin Ozlem Simsek, Beleggia, Filippo ORCID: 0000-0003-0234-7094, Percin, E. Ferda, Keupp, Katharina, Matchan, Angela, Milz, Esther, Alanay, Yasemin ORCID: 0000-0003-0683-9731, Kayserili, Hulya ORCID: 0000-0003-0376-499X, Liu, Yicheng, Banka, Siddharth ORCID: 0000-0002-8527-2210, Kranz, Andrea, Zenker, Martin, Wieczorek, Dagmar ORCID: 0000-0003-2812-6492, Elcioglu, Nursel, Prontera, Paolo ORCID: 0000-0003-4960-9223, Lyonnet, Stanislas ORCID: 0000-0001-5426-9417, Meitinger, Thomas ORCID: 0000-0002-8838-8403, Stewart, A. Francis, Donnai, Dian, Strom, Tim M., Boduroglu, Koray ORCID: 0000-0001-6260-1942, Yigit, Goekhan, Li, Yun, Katsanis, Nicholas and Wollnik, Bernd (2015). RAP1-mediated MEK/ERK pathway defects in Kabuki syndrome. J. Clin. Invest., 125 (9). S. 3585 - 3600. ANN ARBOR: AMER SOC CLINICAL INVESTIGATION INC. ISSN 1558-8238

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Abstract

The 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Boegershausen, Nina UNSPECIFIED UNSPECIFIED UNSPECIFIED Tsai, I-Chun UNSPECIFIED UNSPECIFIED UNSPECIFIED Pohl, Esther UNSPECIFIED UNSPECIFIED UNSPECIFIED Kiper, Pelin Ozlem Simsek UNSPECIFIED UNSPECIFIED UNSPECIFIED Beleggia, Filippo UNSPECIFIED orcid.org/0000-0003-0234-7094 UNSPECIFIED Percin, E. Ferda UNSPECIFIED UNSPECIFIED UNSPECIFIED Keupp, Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Matchan, Angela UNSPECIFIED UNSPECIFIED UNSPECIFIED Milz, Esther UNSPECIFIED UNSPECIFIED UNSPECIFIED Alanay, Yasemin UNSPECIFIED orcid.org/0000-0003-0683-9731 UNSPECIFIED Kayserili, Hulya UNSPECIFIED orcid.org/0000-0003-0376-499X UNSPECIFIED Liu, Yicheng UNSPECIFIED UNSPECIFIED UNSPECIFIED Banka, Siddharth UNSPECIFIED orcid.org/0000-0002-8527-2210 UNSPECIFIED Kranz, Andrea UNSPECIFIED UNSPECIFIED UNSPECIFIED Zenker, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Wieczorek, Dagmar UNSPECIFIED orcid.org/0000-0003-2812-6492 UNSPECIFIED Elcioglu, Nursel UNSPECIFIED UNSPECIFIED UNSPECIFIED Prontera, Paolo UNSPECIFIED orcid.org/0000-0003-4960-9223 UNSPECIFIED Lyonnet, Stanislas UNSPECIFIED orcid.org/0000-0001-5426-9417 UNSPECIFIED Meitinger, Thomas UNSPECIFIED orcid.org/0000-0002-8838-8403 UNSPECIFIED Stewart, A. Francis UNSPECIFIED UNSPECIFIED UNSPECIFIED Donnai, Dian UNSPECIFIED UNSPECIFIED UNSPECIFIED Strom, Tim M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Boduroglu, Koray UNSPECIFIED orcid.org/0000-0001-6260-1942 UNSPECIFIED Yigit, Goekhan UNSPECIFIED UNSPECIFIED UNSPECIFIED Li, Yun UNSPECIFIED UNSPECIFIED UNSPECIFIED Katsanis, Nicholas UNSPECIFIED UNSPECIFIED UNSPECIFIED Wollnik, Bernd UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-395601
DOI:	10.1172/JCI80102
Journal or Publication Title:	J. Clin. Invest.
Volume:	125
Number:	9
Page Range:	S. 3585 - 3600
Date:	2015
Publisher:	AMER SOC CLINICAL INVESTIGATION INC
Place of Publication:	ANN ARBOR
ISSN:	1558-8238
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MAKE-UP-SYNDROME; CONVERGENT EXTENSION; MAP KINASE; HISTONE H3; METHYLTRANSFERASE COMPLEX; CELL-MIGRATION; RAP1; MUTATIONS; GENES; ACTIVATION Multiple languages Medicine, Research & Experimental Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/39560