RAP1-mediated MEK/ERK pathway defects in Kabuki syndrome.
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.
Nina
N
Bögershausen
I-Chun
IC
Tsai
Esther
E
Pohl
Pelin Özlem Simsek
PÖ
Kiper
Filippo
F
Beleggia
E Ferda
EF
Percin
Katharina
K
Keupp
Angela
A
Matchan
Esther
E
Milz
Yasemin
Y
Alanay
Hülya
H
Kayserili
Yicheng
Y
Liu
Siddharth
S
Banka
Andrea
A
Kranz
Martin
M
Zenker
Dagmar
D
Wieczorek
Nursel
N
Elcioglu
Paolo
P
Prontera
Stanislas
S
Lyonnet
Thomas
T
Meitinger
A Francis
AF
Stewart
Dian
D
Donnai
Tim M
TM
Strom
Koray
K
Boduroglu
Gökhan
G
Yigit
Yun
Y
Li
Nicholas
N
Katsanis
Bernd
B
Wollnik
D000015:Abnormalities, Multiple / Q000235:genetics* / Q000378:metabolism; D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002417:Cattle; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D059472:Exome; D005145:Face / Q000002:abnormalities*; D006402:Hematologic Diseases / Q000235:genetics* / Q000378:metabolism; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics*; D008297:Male; D051379:Mice; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015837:Vestibular Diseases / Q000235:genetics* / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
D000199:Actins; D004268:DNA-Binding Proteins; C120898:KMT2D protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000089804:Shelterin Complex; C440809:TERF2IP protein, human; D034501:Telomere-Binding Proteins; D029961:Zebrafish Proteins; D056466:Histone Demethylases; C523998:KDM6A protein, human; D020559:Monomeric GTP-Binding Proteins; C581234:terf2ip protein, zebrafish