Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Ror-family receptor tyrosine kinases (RTKs) play crucial roles in the development of various organs and tissues. In mammals, Ror2, a member of the Ror-family RTKs, has been shown to act as a receptor or coreceptor for Wnt5a to mediate noncanonical Wnt signaling. Ror2- and Wnt5a-deficient mice exhibit similar abnormalities during developmental morphogenesis, reflecting their defects in convergent extension movements and planar cell polarity, characteristic features mediated by noncanonical Wnt signaling. Furthermore, mutations within the human Ror2 gene are responsible for the genetic skeletal disorders dominant brachydactyly type B and recessive Robinow syndrome. Accumulating evidence demonstrate that Ror2 mediates noncanonical Wnt5a signaling by inhibiting the beta-catenin-TCF pathway and activating the Wnt/JNK pathway that results in polarized cell migration. In this article, we review recent progress in understanding the roles of noncanonical Wnt5a/Ror2 signaling in developmental morphogenesis and in human diseases, including heritable skeletal disorders and tumor invasion.
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PMID:Ror-family receptor tyrosine kinases in noncanonical Wnt signaling: their implications in developmental morphogenesis and human diseases. 1953 Jan 73

Aarskog-Scott syndrome (ASS) is a rare X-linked recessive genetic disorder caused by FGD1 mutations. FGD1 regulates the actin cytoskeleton and regulates cell growth and differentiation by activating the c-Jun N-terminal kinase signaling cascade. ASS is characterized by craniofacial dysmorphism, short stature, interdigital webbing and shawl scrotum. However, there is a wide phenotypic heterogeneity because of the additional clinical features. ASS and some syndromes including the autosomal dominant inherited form of Robinow syndrome, Noonan syndrome, pseudohypoparathyroidism, Silver-Russel and SHORT syndrome have some overlapping phenotypic features. Herein, we report a patient with ASS and a large anterior fontanel who was initially diagnosed as Robinow syndrome. He was found to have a novel c.1340+2 T>A splice site mutation on the FGD1 gene.
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PMID:A novel splice site mutation of FGD1 gene in an Aarskog-Scott syndrome patient with a large anterior fontanel. 2754 18

The study of rare genetic diseases provides valuable insights into human gene function. Here, we investigate dominant Robinow syndrome (RS), which affects the WNT5A signaling pathway. Autosomal dominant RS is caused by missense mutations in WNT5A or nonsense mutations in the adaptor protein DVL1 or DVL3. The recessive form of the disease is caused by loss-of-function mutations in the receptor ROR2. RS is characterized by hypertelorism, midface, and mandibular hypoplasia. Here, we focus on the missense mutations in WNT5A, since the impact on function is difficult to predict from in silico analysis. We used chicken embryo to express wild-type or 2 mutant versions of human WNT5A in the mandible and then examined the morphologic, cellular, and molecular effects. The 3 experimental viruses-wt WNT5A, WNT5AC83S, or WNT5AC182R-all caused shortening of the mandible on the injected side as compared with GFP controls. Although the phenotypes initially appeared similar, we uncovered specific disruption of chondrocyte polarity and shape, inhibition of cell migration, differences in target gene expression, and absence of JNK signaling only in the presence of mutant viruses. In addition, the missense mutations do not appear to block receptor binding, since in paracrine experiments, the mutant protein inhibits cell migration. In this study, we ruled out a straightforward gain or loss of function caused by the WNT5A missense mutations. Instead, the mutations are likely redirecting WNT signaling away from JNK-PCP toward other noncanonical pathways. We conclude that in RS, WNT5A missense mutations have dominant neomorphic effects that interfere with the function of the wild-type protein.
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PMID:Abnormal WNT5A Signaling Causes Mandibular Hypoplasia in Robinow Syndrome. 2866 48