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XB-ART-55907
Front Physiol January 1, 2019; 10 388.

A YWHAZ Variant Associated With Cardiofaciocutaneous Syndrome Activates the RAF-ERK Pathway.

Popov IK , Hiatt SM , Whalen S , Keren B , Ruivenkamp C , van Haeringen A , Chen MJ , Cooper GM , Korf BR , Chang C .


Abstract
Cardiofaciocutaneous (CFC) syndrome is a genetic disorder characterized by distinctive facial features, congenital heart defects, and skin abnormalities. Several germline gain-of-function mutations in the RAS/RAF/MEK/ERK pathway are associated with the disease, including KRAS, BRAF, MEK1, and MEK2. CFC syndrome thus belongs to a group of disorders known as RASopathies, which are all caused by pathogenic mutations in various genes encoding components of the RAS pathway. We recently identified novel variants in YWHAZ, a 14-3-3 family member, in individuals with a phenotype consistent with CFC that may potentially be deleterious and disease-causing. In the current study, we take advantage of the vertebrate model Xenopus laevis to analyze the functional consequence of a particular YWHAZ variant, S230W, and investigate the molecular mechanisms underlying its activity. We show that compared with wild type YWHAZ, the S230W variant induces severe embryonic defects when ectopically expressed in early Xenopus embryos. The S230W variant also rescues the defects induced by a dominant negative FGF receptor more efficiently and enhances Raf-stimulated Erk phosphorylation to a higher level than wild type YWHAZ. Although neither YWHAZ nor the variant promotes membrane recruitment of Raf proteins, the variant binds to more Raf and escapes phosphorylation by casein kinase 1a. Our data provide strong support to the hypothesis that the S230W variant of YWHAZ is a gain-of-function mutation in the RAS-ERK pathway and may underlie a CFC phenotype.

PubMed ID: 31024343
PMC ID: PMC6465419
Article link: Front Physiol
Grant support: [+]

Species referenced: Xenopus
Genes referenced: braf csnk1a1 fgfr1 kras map2k1 map2k4 mapk1 ptpn11 raf1 sos1 tbxt ywhaz
GO keywords: gastrulation

Disease Ontology terms: Costello syndrome [+]
Phenotypes: Xla + Hsa.YWHAZ (Fig 2C middle panel) [+]

Article Images: [+] show captions
References [+] :
Aitken, 14-3-3 proteins: a historic overview. 2006, Pubmed