Mulibrey Nanism
Dongyou Liu in Handbook of Tumor Syndromes, 2020
Differential diagnoses for mulibrey nanism include Silver−Russell syndrome (growth failure/dwarfism and facial dysmorphism in the absence of cardiomyopathy, hepatomegaly, and ophthalmologic involvements, chromosomes 11p15 and 7 abnormalities), 3M-syndrome (short stature/dwarfism, triangle-shaped face with a broad, prominent forehead, pointed chin, hypoplastic midface, CUL7 and OBSL1 mutations), Robinow syndrome (mild to moderate short stature due to postnatal growth retardation, distinctive craniofacial abnormalities, additional skeletal malformations, and/or genital abnormalities, ROR2, FZD2, WNT5A, DVL1, and DVL3 mutations), and primary empty sella syndrome (an empty space filled with cerebrospinal fluid in the sella turcica area of the brain due to a defect in the sella diaphragm, unusual facial features, a high-arched palate, moderate short stature, increased bone density/osteosclerosis, and normal pituitary function).
Targeted Therapy for Cancer Stem Cells
Surinder K. Batra, Moorthy P. Ponnusamy in Gene Regulation and Therapeutics for Cancer, 2021
Wnt has become a substantial new target for drug development to treat cancer because of its signaling cascade that plays a central role in regulating significant functions of malignant epithelial cells. Wnt ligands and signals drive the Wnt signaling pathway through canonical (β-catenin dependent) or non-canonical (β-catenin independent) paths. The Wnt ligand binds to various transmembrane receptors, such as Frizzled (FZD), Receptor tyrosine kinases (RTKs) and Receptor tyrosine kinase-like orphan receptor (ROR) 1 or ROR2. The pathway is activated with the binding of Wnt ligand to its receptor, followed by the activation of β-catenin. In the absence of Wnt ligand, β-catenin undergoes phosphorylation by a destruction complex containing glycogen synthase kinase 3b (GSK3b), adenomatous polyposis coli (APC) and axin, followed by degradation of β-catenin.
Individual conditions grouped according to the international nosology and classification of genetic skeletal disorders*
Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow in Fetal and Perinatal Skeletal Dysplasias, 2012
Genetics: caused by heterozygous mutations in the gene ROR2; this encodes a receptorlike tyrosine kinase essential for normal chondrocyte growth and differentiation. ROR2 BDB-associated mutations typically cause truncation of either the N-terminal or C-terminal receptor of the intracellular tyrosine kinase domain. Homozygous mutations in the same gene cause the autosomal recessive form of Robinow syndrome.
Deficiency of the Wnt receptor Ryk causes multiple cardiac and outflow tract defects
Published in Growth Factors, 2018
Kumudhini Kugathasan, Michael M. Halford, Peter G. Farlie, Damien Bates, Darrin P. Smith, You Fang Zhang, James P. Roy, Maria L. Macheda, Dong Zhang, James L. Wilkinson, Margaret L. Kirby, Donald F. Newgreen, Steven A. Stacker
The heart and outflow tract phenotypes observed in Ryk−/− embryos have similarities to those seen in mice deficient for other Wnt-binding RTKs that also participate in PCP signalling such as Ror1, Ror2 and Ptk7 (Roy et al., 2018). Interestingly all of these receptors when disrupted in the mouse result in death either in the perinatal period or just after birth (Roy et al., 2018). Ror2 is expressed in the heart and branchial arches of mice with Ror2-deficient mice have ventricular septal defects (Nomi et al., 2001; Takeuchi et al., 2000). These are enhanced in the Ror1/Ror2 double mutant mice where septal defects and transposition of the great arteries are observed. Ror1-deficient mice have no detectable cardiac abnormalities (Nomi et al., 2001). A novel ENU-induced mouse mutant called chuzhoi which disrupts the expression of two PTK7 protein isoforms results in heart defects including DORV with a ventricular septal defect (VSD) or parallel arterial trunks (Paudyal et al., 2010); interestingly these defects were not reported in a Ptk7 gene trap allele (Lu et al., 2004). Our studies therefore confirm the importance of Ryk signalling for heart and outflow tract development and indicate the possible role of PCP signalling in this process.
The biochemistry, signalling and disease relevance of RYK and other WNT-binding receptor tyrosine kinases
Published in Growth Factors, 2018
James P. Roy, Michael M. Halford, Steven A. Stacker
The skeletal and craniofacial defects of the Ryk knockout mice indicate the potential for involvement of RYK dysfunction in human disorders of the skeletal system. Given the known genetic involvement of WNT5A in Robinow syndrome (Person et al., 2010; Roifman et al., 2015) and the phenotypic similarities of Wnt5A−/− and Ryk−/−; Vangl2−/− mice, it was suggested that RYK may play a role in this rare musculoskeletal syndrome (Andre et al., 2012; Andre & Yang, 2013; Mazzeu, 2013). Another pathology characterized by abnormalities of the phalanges, Brachydactyly Type B, is also caused by ROR2 mutations (Oldridge et al., 2000; Schwabe et al., 2000). A mutation in RYK, seemingly reducing the receptor’s activity, has been found in a patient with cleft lip and palate (Watanabe et al., 2006). Further strengthening the link between aberrant signalling by WNT-binding RTKs and skeletal system abnormalities, PTK7 has been implicated in scoliosis, a disorder resulting in abnormal curvature of the spine. Ptk7 mutant zebrafish display scoliosis (Grimes et al., 2016; Hayes et al., 2014) and a missense mutation in the sixth Ig-like domain of PTK7, resulting in a loss of WNT/PTK7 signalling, was discovered in a scoliosis patient (Hayes et al., 2014).
Structure, function and disease relevance of Wnt inhibitory factor 1, a secreted protein controlling the Wnt and hedgehog pathways
Published in Growth Factors, 2019
Krisztina Kerekes, László Bányai, Mária Trexler, László Patthy
The key importance of the canonical Wnt/β-catenin pathway in stem cell control may be illustrated by the fact that mutations that inactivate the tumor suppressors APC and axin or activate β-catenin, resulting in constitutive activation of the Wnt signaling pathway, are among the most frequent causes of carcinogenesis (Zhan, Rindtorff, and Boutros 2017). The genes for these proteins (APC, AXIN1 and CTNNB1) are included in the list of the 125 most important genes whose mutation drives carcinogenesis (Vogelstein et al. 2013). Additional genes of the Wnt pathways (e.g. BTRC, DKK3, DKK4, LEF1, PTK7, ROR1, ROR2, RYK, SFRP4 and WIF1) are included in the Cancer Gene Census (Sondka et al. 2018, https://cancer.sanger.ac.uk/census) and/or in the list of cancer genes (Candidate Cancer Gene Database, Abbott et al. 2015, http://ccgd-starrlab.oit.umn.edu/about.php) identified by forward genetic screens in mice (see Supplementary Table S1).
Related Knowledge Centers
- Bone
- Cartilage
- Chromosome 9
- Protein
- Receptor Tyrosine Kinase
- Brachydactyly
- Gene
- Robinow Syndrome
- Receptor Tyrosine Kinase-Like Orphan Receptor
- Single-Pass Membrane Protein