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Mulibrey Nanism
Published in Dongyou Liu, 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).
Individual conditions grouped according to the international nosology and classification of genetic skeletal disorders*
Published in Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow, Fetal and Perinatal Skeletal Dysplasias, 2012
Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow
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.
Primordial germ cells: Origin, migration and testicular development
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
PGC migration is a very complex process with a myriad of cellular and biological processes taking place simultaneously with proliferation, survival and epigenetic reprogramming (35). Various proteins and transcription factors have been investigated for the maintenance of PGC migration and development. Knockdown of the Sox17, a SRY (sex-determining region Y)-box 17 transcription factor caused failure in PGCs’ migration to the genital ridge and instead resulted in their scattering in the extra-embryonic endoderm. The removal of Sox17 also caused improper development of hindgut endoderm in mice (36). Previous research has also suggested the need for Sdf-1 and its receptor CXCR4 as important factors for mouse PGC survival and proliferation. The expression of SDF-1 at the genital ridges in the surrounding mesenchyme and CXCR4 expression within the PGCs provide chemotactic and survival signals to the PGCs. This signaling pathway seems to be specific for the later stages for PGC migration only. The absence of either SDF-1 or CXCR4 leads to a diminished number of PGCs, while insufficient expression of SDF-1 causes inefficient PGCs colonization within the gonads (37,38). The c-Kit and its ligand Steel were well known for their roles in PGC proliferation, migration and survival. Recently, very specific roles of these two factors have been identified during the migration stage. Steel and c-Kit were seen to be responsible for the regulation of general PGC motility, as knockout of Steel leads to a very slow-paced migration of PGCs without any impairment to their direction of migration (39). Consistent with their roles in PGC motility throughout all stages of migration, c-Kit protein and Steel show expression in the PGCs and surrounding somatic cells, respectively (39). The noncanonical form of Wnt signaling also plays a crucial role in PGC migration, as Wnt5a receptor Ror2 was observed to be responsible for the control of motility in migrating PGCs (30). Complete functional loss and/or cKO mutant of the receptor resulted in an accumulation of a large number of germ cells outside the gonadal ridge at the end of the migration phase (30,40). Another autonomous function for Ror2 is in the regulation of PGC proliferation, as aberrantly high rates of cycling PGCs were found in the hindgut of both ubiquitous and PGC-specific mutants (40). Apart from signaling pathways, cell adhesion molecules also have a role in mammalian PGC migration. E-cad expression is observed in PGCs, disruption of which causes problems with PGC-PGC adhesion, resulting in impaired colonization inside the gonads (41,42). Integrin β1 is also required for proper PGC migration as it is responsible for the exit from the hindgut into the genital ridges (43).
A Review of Primary Thyroid Lymphoma: Molecular Factors, Diagnosis and Management
Published in Journal of Investigative Surgery, 2019
Efstathios T. Pavlidis, Theodoros E. Pavlidis
However, the association between PTL and Wnt5a/Ror2 is questionable because it is mainly based on the abovementioned single investigation. Furthermore, in this study, Wnt5a expression was associated with regional invasion, whereas Ror2 was only associated with stage IIE disease. Neither Wnt5a expression nor Ror2 were associated with survival, and the correlation of the expression of these two markers was not estimated. It appears that Ror2 is not expressed in other hematological malignancies.25 Increased Ror2 expression is present in normal thyroid tissue, and it is frequently downregulated in papillary thyroid cancer. Considering both the tumor-promoting and tumor-suppressing role of the Wnt signaling pathway, more solid data are needed to confirm the association between Wnt5a/Ror2 and thyroid lymphoma.
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).