DOCSLIB.ORG

Variability in Dentofacial Phenotypes in Four Families with WNT10A Mutations

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Variability in Dentofacial Phenotypes in Four Families with WNT10A Mutations European Journal of Human Genetics (2014) 22, 1063–1070 & 2014 Macmillan Publishers Limited All rights reserved 1018-4813/14 www.nature.com/ejhg ARTICLE Variability in dentofacial phenotypes in four families with WNT10A mutations Christian P Vink1, Charlotte W Ockeloen2,3, Sietske ten Kate2, David A Koolen2, Johannes Kristian Ploos van Amstel4, Anne-Marie Kuijpers-Jagtman1,3, Celeste C van Heumen3,5, Tjitske Kleefstra2,3 and Carine EL Carels*,1,3,6,7 This article describes the inter- and intra-familial phenotypic variability in four families with WNT10A mutations. Clinical characteristics of the patients range from mild to severe isolated tooth agenesis, over mild symptoms of ectodermal dysplasia, to more severe syndromic forms like odonto-onycho-dermal dysplasia (OODD) and Scho¨pf–Schulz–Passarge syndrome (SSPS). Recurrent WNT10A mutations were identified in all affected family members and the associated symptoms are presented with emphasis on the dentofacial phenotypes obtained with inter alia three-dimensional facial stereophotogrammetry. A comprehensive overview of the literature regarding WNT10A mutations, associated conditions and developmental defects is presented. We conclude that OODD and SSPS should be considered as variable expressions of the same WNT10A genotype. In all affected individuals, a dished-in facial appearance was observed which might be helpful in the clinical setting as a clue to the underlying genetic etiology. European Journal of Human Genetics (2014) 22, 1063–1070; doi:10.1038/ejhg.2013.300; published online 8 January 2014 Keywords: ectodermal dysplasia; odonto-onycho-dermal dysplasia; Scho¨pf–Schulz–Passarge syndrome; tooth agenesis; WNT10A INTRODUCTION including homozygous, compound heterozygous and heterozygous Tooth agenesis (TA) is the most common, often heritable, develop- mutations. mental anomaly of the human dentition. Depending on the tooth It has been shown that specific facial features can differ significantly type and number of teeth involved, the prevalence of TA ranges from between patients with and without isolated TA.12 Therefore, in 10 to 30% for TA of third molars to 0.2% for severe TA of six teeth or addition to the description of the dental and general syndromic ED more (excluding the third molars).1 An overall incidence of TA of features, the aim in this study was to document the facial phenotypic permanent teeth excluding third molars of 2.6–11.3% was reported, variations in four families with WNT10A mutations and to give a depending on demographic and geographic profiles.1 comprehensive overview of the literature regarding WNT10A As tooth formation shares mechanisms with the development of mutations, associated conditions and developmental defects. other ectodermal appendages, TA often occurs as part of a variety of ectodermal dysplasia (ED) syndromes including Witkop syndrome, PATIENTS AND METHODS hypohydrotic ectodermal dysplasia, odonto-onycho-dermal dysplasia In four families at least one member, referred to as proband or index patient, (OODD), Scho¨pf–Schulz–Passarge syndrome (SSPS) and others. For was referred for diagnosis or treatment to the Department of Orthodontics and these human TA syndromes, mutations have been identified, respec- Craniofacial Biology, the Radboud Center for Cleft Palate and Craniofacial tively, in MSX1,2 EDA, EDAR,3–5 EDARADD,6 and WNT10A.7,8 Anomalies and/or the Center for Special Dental Care or the Department of WNT10A mutations were identified in a family of which four Human Genetics, Radboud University Medical Center (RUMC). Informed members were affected with isolated TA or microdontia,9 whereas consent for publication of data and photographs was obtained from all more recently in a larger cohort of 34 patients with isolated TA, 56% patients and their enrolled relatives. appeared to have WNT10A mutations.10 Patients referred for orthodontic treatment received full diagnostic records, including digital or plaster dental casts, a lateral headfilm and orthopantomo- Besides pathogenic mutations within the coding regions of the gram (OPT) (In order to allow an exact quantitative phenotype profiling, the WNT10A gene in 62% of the tested patients, a significant association term TA with addition of the exact number of teeth which failed to develop 11 between SNPs in the WNT10A gene and the risk for TA was found. (excluding the third molars) is used as the terms hypodontia and oligodontia These recent studies indicate that changes in WNT10A are highly can be misleading.13 To identify the present/absent teeth, the Fe´de´ration frequent in terms of the risk or the presence of isolated or syndromic Dentaire Internationale tooth numbering system is used.). Both intra- and hypodontia, presenting with variable phenotypes and genotypes, extra-oral two-dimensional (2D) photographs as well as facial 3D 1Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, Nijmegen, The Netherlands; 2Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; 3Radboud Center for Cleft Palate and Craniofacial Anomalies, Radboud University Medical Center, Nijmegen, The Netherlands; 4Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands; 5Center for Special Dental Care, Radboud University Medical Center, Nijmegen, The Netherlands and 6Department of Oral Health Sciences, KU Leuven, Leuven, Belgium *Correspondence: Profesor CEL Carels, Department of Orthodontics & Craniofacial Biology, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. Tel: þ 31 24 361 4005; Fax: þ 31 24 354 0631; E-mail: [email protected] 7Shipping address: Philips van Leijdenlaan 25, 6525 EX Nijmegen, The Netherlands. Received 7 June 2013; revised 16 October 2013; accepted 20 November 2013; published online 8 January 2014 Dentofacial phenotypes with WNT10A mutations CP Vink et al 1064 stereophotogrammetry images were made. The 3D surface images were taken relative to the maxillary dental arch (Class II/1 relation). The 3D facial with a 3dMDface system (3dMD, Atlanta, GA, USA). All data were separately image demonstrates an underlying hypodivergent skeletal pattern, evaluated by two staff orthodontists of the Department of Orthodontics and with a retrusive mandible and a deepened plica mentalis. Craniofacial Biology of the RUMC. Additional ED features are present, comprising nail dystrophy and A medical and dental history was taken, including the family history; a full keratodermata at his feet. Temporary alopecia of the skull hair had physical examination was also performed by a clinical geneticist. The patients’ occurred at the age of 7. He was clinically diagnosed with OODD. DNA was isolated from leukocytes from their peripheral blood samples according to a standard protocol. Sequence analysis of WNT10A (RefSeq: Clinical examination of the first degree relatives. Both the proband’s NM_025216.2) was performed at the DNA diagnostics laboratory of the University Medical Center Utrecht, The Netherlands, using the standard Sanger father and his brother show no clinical symptoms of ED and all teeth sequencing technique. After identifying the mutations in the probands their are present. His mother however misses one tooth (35), and shows first degree relatives were contacted and were asked to participate in the study. generalized small-sized teeth with various diastemas in both jaws. Like The clinical examination and blood samples of the enrolled family members her youngest son, she showed some retroclination of her maxillary were taken in the same way as in the index patient while the oral and facial front teeth, prior to her orthodontic treatment. documentation in the family members was limited to a clinical examination and 2D facial photographs. Genetic diagnosis. A compound heterozygous mutation was identi- Complete documentation was obtained with regard to all index patients fied in WNT10A:c.321C4A;682T4A, p.(Cys107*);(Phe228Ile). In except one (patient D II-1). At the time of inclusion this patient was already either parent the presence of a heterozygous change in WNT10A was treated prosthodontically and no adequate documentation could be retrieved confirmed, the asymptomatic father harbored the c.321C4A, from the period before treatment. Also for some of the first degree relatives p.(Cys107*) mutation and the c.682T4A, p.(Phe228Ile) mutation included in this study, only limited data were available. was identified in the mother who was missing one tooth. The mutation analysis in the proband’s brother revealed he is a hetero- RESULTS zygous carrier of the c.321C4A, p.(Cys107*) mutation, which was Overview literature regarding WNT10A mutations inherited from the father (see Table 2). On the 13th of March 2013, a literature search was performed, screening the NCBI database for WNT10A mutations. Filters only Family B allowing articles in English, German or Dutch, yielded 90 articles. This Dutch family was referred to the Department of Orthodontics When adding Tooth Agenesis AND Ectodermal Dysplasia, and Craniofacial Biology because of TA in their three children. In all Odonto-Onycho-Dermal Dysplasia, Scho¨pf–Schulz–Passarge Syndrome family members, the deciduous dentition was either not affected or AND/OR derivates to WNT10A mutations, 14 articles7–11,14–22 met could not be verified. the inclusion criteria and suggested a causative relationship of WNT10A mutations with isolated TA or/and ED phenotypes. Clinical examination proband. The proband was 19 years old at the Adaimy et
Load more

Recommended publications
  • A High-Fat/High-Sucrose Diet Induces WNT4 Expression in Mouse Pancreatic Β-Cells
    This is “Advance Publication Article” Kurume Medical Journal, 65, 00-00, 2018 Original Article A High-Fat/High-Sucrose Diet Induces WNT4 Expression in Mouse Pancreatic β-cells YAYOI KURITA, TSUYOSHI OHKI, ERI SOEJIMA, XIAOHONG YUAN, SATOMI KAKINO, NOBUHIKO WADA, TOSHIHIKO HASHINAGA, HITOMI NAKAYAMA, JUNICHI TANI, YUJI TAJIRI, YUJI HIROMATSU, KENTARO YAMADA* AND MASATOSHI NOMURA Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan, *Diabetes Center of Asakura Medical Association Hospital, Asakura 838-0069, Japan Received 12 February 2018, accepted 1 May 2018 J-STAGE advance publication 11 March 2019 Edited by MAKOTO TAKANO Summary: Aims/Introduction: Several lines of evidence suggest that dysregulation of the WNT signaling pathway is involved in the pathogenesis of type 2 diabetes. This study was performed to elucidate the effects of a high-fat/high-sucrose (HF/HS) diet on pancreatic islet functions in relation to modulation of WNT ligand expression in β-cells. Materials and Methods: Mice were fed either standard mouse chow or a HF/HS diet from 8 weeks of age. At 20 weeks of age, intraperitoneal glucose tolerance tests were performed in both groups of mice, followed by euthanasia and isolation of pancreatic islets. WNT-related gene expression in islets and MIN6 cells was measured by quantitative real-time RT-PCR. To explore the direct effects of WNT signals on pancreatic β-cells, MIN6 cells were exposed to recombinant mouse WNT4 protein (rmWNT4) for 48 h, and glucose-induced insulin secre- tion was measured. Furthermore, Wnt4 siRNAs were transfected into MIN6 cells, and cell viability and insulin secretion were measured in control and Wnt4 siRNA-transfected MIN6 cells.
    [Show full text]
  • WNT10A Gene Wnt Family Member 10A
    WNT10A gene Wnt family member 10A Normal Function The WNT10A gene is part of a large family of WNT genes, which play critical roles in development starting before birth. These genes provide instructions for making proteins that participate in chemical signaling pathways in the body. Wnt signaling controls the activity of certain genes and regulates the interactions between cells during embryonic development. The protein produced from the WNT10A gene plays a role in the development of many parts of the body. It appears to be essential for the formation of tissues that arise from an embryonic cell layer called the ectoderm. These tissues include the skin, hair, nails, teeth, and sweat glands. Researchers believe that the WNT10A protein is particularly important for the formation and shaping of both baby (primary) teeth and adult ( permanent) teeth. Health Conditions Related to Genetic Changes Hypohidrotic ectodermal dysplasia Several mutations in the WNT10A gene have been found to cause hypohidrotic ectodermal dysplasia, the most common form of ectodermal dysplasia. Starting before birth, ectodermal dysplasias result in the abnormal development of the skin, hair, nails, teeth, and sweat glands. Hypohidrotic ectodermal dysplasia is characterized by a reduced ability to sweat (hypohidrosis), sparse scalp and body hair (hypotrichosis), and several missing teeth (hypodontia) or teeth that are malformed. WNT10A gene mutations account for about 5 percent of all cases of hypohidrotic ectodermal dysplasia. Most of the WNT10A gene mutations associated with hypohidrotic ectodermal dysplasia change single protein building blocks (amino acids) in the WNT10A protein, which impairs its function. The resulting shortage of functional WNT10A protein disrupts Wnt signaling during the development of ectodermal tissues, particularly the teeth.
    [Show full text]
  • Theranostics WNT6 Is a Novel Oncogenic Prognostic Biomarker In
    Theranostics 2018, Vol. 8, Issue 17 4805 Ivyspring International Publisher Theranostics 2018; 8(17): 4805-4823. doi: 10.7150/thno.25025 Research Paper WNT6 is a novel oncogenic prognostic biomarker in human glioblastoma Céline S. Gonçalves1,2, Joana Vieira de Castro1,2, Marta Pojo1,2, Eduarda P. Martins1,2, Sandro Queirós1,2, Emmanuel Chautard3,4, Ricardo Taipa5, Manuel Melo Pires5, Afonso A. Pinto6, Fernando Pardal7, Carlos Custódia8, Cláudia C. Faria8,9, Carlos Clara10, Rui M. Reis1,2,10, Nuno Sousa1,2, Bruno M. Costa1,2 1. Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal 2. ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal 3. Université Clermont Auvergne, INSERM, U1240 IMoST, 63000 Clermont Ferrand, France 4. Pathology Department, Université Clermont Auvergne, Centre Jean Perrin, 63011 Clermont-Ferrand, France 5. Neuropathology Unit, Department of Neurosciences, Centro Hospitalar do Porto, Porto, Portugal 6. Department of Neurosurgery, Hospital Escala Braga, Sete Fontes - São Victor 4710-243 Braga, Portugal 7. Department of Pathology, Hospital Escala Braga, Sete Fontes - São Victor 4710-243 Braga, Portugal 8. Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal 9. Neurosurgery Department, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte (CHLN), Lisbon, Portugal 10. Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos - S. Paulo, Brazil. Corresponding author: Bruno M. Costa, Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal. Email: [email protected]; Phone: (+351)253604837; Fax: (+351)253604831 © Ivyspring International Publisher.
    [Show full text]
  • Wnt-Independent and Wnt-Dependent Effects of APC Loss on the Chemotherapeutic Response
    International Journal of Molecular Sciences Review Wnt-Independent and Wnt-Dependent Effects of APC Loss on the Chemotherapeutic Response Casey D. Stefanski 1,2 and Jenifer R. Prosperi 1,2,3,* 1 Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46617, USA; [email protected] 2 Mike and Josie Harper Cancer Research Institute, South Bend, IN 46617, USA 3 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine-South Bend, South Bend, IN 46617, USA * Correspondence: [email protected]; Tel.: +1-574-631-4002 Received: 30 September 2020; Accepted: 20 October 2020; Published: 22 October 2020 Abstract: Resistance to chemotherapy occurs through mechanisms within the epithelial tumor cells or through interactions with components of the tumor microenvironment (TME). Chemoresistance and the development of recurrent tumors are two of the leading factors of cancer-related deaths. The Adenomatous Polyposis Coli (APC) tumor suppressor is lost in many different cancers, including colorectal, breast, and prostate cancer, and its loss correlates with a decreased overall survival in cancer patients. While APC is commonly known for its role as a negative regulator of the WNT pathway, APC has numerous binding partners and functional roles. Through APC’s interactions with DNA repair proteins, DNA replication proteins, tubulin, and other components, recent evidence has shown that APC regulates the chemotherapy response in cancer cells. In this review article, we provide an overview of some of the cellular processes in which APC participates and how they impact chemoresistance through both epithelial- and TME-derived mechanisms. Keywords: adenomatous polyposis coli; chemoresistance; WNT signaling 1.
    [Show full text]
  • Deregulated Wnt/Β-Catenin Program in High-Risk Neuroblastomas Without
    Oncogene (2008) 27, 1478–1488 & 2008 Nature Publishing Group All rights reserved 0950-9232/08 $30.00 www.nature.com/onc ONCOGENOMICS Deregulated Wnt/b-catenin program in high-risk neuroblastomas without MYCN amplification X Liu1, P Mazanek1, V Dam1, Q Wang1, H Zhao2, R Guo2, J Jagannathan1, A Cnaan2, JM Maris1,3 and MD Hogarty1,3 1Division of Oncology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA; 2Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA and 3Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA Neuroblastoma (NB) is a frequently lethal tumor of Introduction childhood. MYCN amplification accounts for the aggres- sive phenotype in a subset while the majority have no Neuroblastoma (NB) is a childhood embryonal malig- consistently identified molecular aberration but frequently nancy arising in the peripheral sympathetic nervous express MYC at high levels. We hypothesized that acti- system. Half of all children with NB present with features vated Wnt/b-catenin (CTNNB1) signaling might account that define their tumorsashigh riskwith poor overall for this as MYC is a b-catenin transcriptional target and survival despite intensive therapy (Matthay et al., 1999). multiple embryonal and neural crest malignancies have A subset of these tumors are characterized by high-level oncogenic alterations in this pathway. NB cell lines without genomic amplification of the MYCN proto-oncogene MYCN amplification express higher levels of MYC and (Matthay et al., 1999) but the remainder have no b-catenin (with aberrant nuclear localization) than MYCN- consistently identified aberration to account for their amplified cell lines.
    [Show full text]
  • Towards an Integrated View of Wnt Signaling in Development Renée Van Amerongen and Roel Nusse*
    HYPOTHESIS 3205 Development 136, 3205-3214 (2009) doi:10.1242/dev.033910 Towards an integrated view of Wnt signaling in development Renée van Amerongen and Roel Nusse* Wnt signaling is crucial for embryonic development in all animal Notably, components at virtually every level of the Wnt signal species studied to date. The interaction between Wnt proteins transduction cascade have been shown to affect both β-catenin- and cell surface receptors can result in a variety of intracellular dependent and -independent responses, depending on the cellular responses. A key remaining question is how these specific context. As we discuss below, this holds true for the Wnt proteins responses take shape in the context of a complex, multicellular themselves, as well as for their receptors and some intracellular organism. Recent studies suggest that we have to revise some of messengers. Rather than concluding that these proteins are shared our most basic ideas about Wnt signal transduction. Rather than between pathways, we instead propose that it is the total net thinking about Wnt signaling in terms of distinct, linear, cellular balance of signals that ultimately determines the response of the signaling pathways, we propose a novel view that considers the receiving cell. In the context of an intact and developing integration of multiple, often simultaneous, inputs at the level organism, cells receive multiple, dynamic, often simultaneous and of both Wnt-receptor binding and the downstream, sometimes even conflicting inputs, all of which are integrated to intracellular response. elicit the appropriate cell behavior in response. As such, the different signaling pathways might thus be more intimately Introduction intertwined than previously envisioned.
    [Show full text]
  • Role of DNA Methylation in Adipogenesis
    Georgia State University ScholarWorks @ Georgia State University Biology Theses Department of Biology Summer 8-12-2014 Role of DNA Methylation in Adipogenesis Yii-Shyuan Chen Follow this and additional works at: https://scholarworks.gsu.edu/biology_theses Recommended Citation Chen, Yii-Shyuan, "Role of DNA Methylation in Adipogenesis." Thesis, Georgia State University, 2014. https://scholarworks.gsu.edu/biology_theses/57 This Thesis is brought to you for free and open access by the Department of Biology at ScholarWorks @ Georgia State University. It has been accepted for inclusion in Biology Theses by an authorized administrator of ScholarWorks @ Georgia State University. For more information, please contact [email protected]. ROLE OF DNA METHYLATION IN ADIPOGENESIS by YII-SHYUAN CHEN Under the Direction of Bingzhong Xue ABSTRACT The increase in the prevalence of obesity and obesity-related diseases has caused greater attention to be placed on the molecular mechanisms controlling adipogenesis. In this study, we studied the role of 5-aza-2'-deoxycytidine (5-Aza-dC), an inhibitor of DNA methylation, on adipocyte differentiation. We found that inhibiting DNA methylation by 5-Aza-dC significantly inhibited adipocyte differentiation whereas promoting osteoblastogenesis. Wnt10a was up- regulated by 5-Aza-dC treatment and it was suggested that Wnt10a might play a vital role in suppressing adipogenesis and promoting osteoblastogenesis by inhibiting DNA methylation. In 3T3-L1 cells, Wnt signaling inhibitor IWP-2 was found to reverse the inhibitory effect of 5-Aza- dC on Adipocyte differentiation, whereas in mesenchymal stem cell line, ST2 cells, IWP-2 treatment reversed the effect of 5-Aza-dC on promoting osteoblastogenesis.
    [Show full text]
  • Wnt4/B2catenin Signaling in Medullary Kidney Myofibroblasts
    BASIC RESEARCH www.jasn.org Wnt4/b2Catenin Signaling in Medullary Kidney Myofibroblasts † †‡ | Derek P. DiRocco,* Akio Kobayashi,* Makoto M. Taketo,§ Andrew P. McMahon, and †‡ Benjamin D. Humphreys* *Renal Division, Brigham and Women’s Hospital, Boston, Massachusetts; †Harvard Medical School, Boston, Massachusetts; ‡Harvard Stem Cell Institute, Cambridge, Massachusetts; §Department of Pharmacology, Graduate School of Medicine, Kyoto University, Yoshida-Konoé-cho, Sakyo, Kyoto, Japan; and |Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad-CIRM Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine of the University of Southern California, Los Angeles, California ABSTRACT Injury to the adult kidney induces a number of developmental genes thought to regulate repair, including Wnt4. During kidney development, early nephron precursors and medullary stroma both express Wnt4, where it regulates epithelialization and controls smooth muscle fate, respectively. Expression patterns and roles for Wnt4 in the adult kidney, however, remain unclear. In this study, we used reporters, lineage analysis, and conditional knockout or activation of the Wnt/b-catenin pathway to investigate Wnt4 in the adult kidney. Proliferating, medullary, interstitial myofibroblasts strongly expressed Wnt4 during renal fibrosis, whereas tubule epithelia, except for the collecting duct, did not. Exogenous Wnt4 drove myofi- broblast differentiation of a pericyte-like cell line, suggesting that Wnt4 might regulate pericyte-to-myo- fibroblast transition through autocrine signaling. However, conditional deletion of Wnt4 in interstitial cells did not reduce myofibroblast proliferation, cell number, or myofibroblast gene expression during fibrosis. Because the injured kidney expresses multiple Wnt ligands that might compensate for the absence of Wnt4, we generated a mouse model with constitutive activation of canonical Wnt/b-catenin signaling in interstitial pericytes and fibroblasts.
    [Show full text]
  • Induction of Apoptosis Increases Expression of Non-Canonical WNT Genes in Myeloid Leukemia Cell Lines
    1563-1569 7/11/07 19:04 Page 1563 ONCOLOGY REPORTS 18: 1563-1569, 2007 Induction of apoptosis increases expression of non-canonical WNT genes in myeloid leukemia cell lines HAKKI OGUN SERCAN1, MELEK PEHLIVAN1, OZLENEN SIMSEK1, HALIL ATES2 and ZEYNEP SERCAN1 Depatments of 1Medical Biology and Genetics, 2Hematology/Oncology, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey Received May 3, 2007; Accepted July 20, 2007 Abstract. With the aim of determining the differential and cyclin D. The presence or exclusion of co-receptors (low expression of WNT and FZD genes, before and after density lipoprotein receptor-related protein 5 and 6-LRP5/6) induction of apoptosis in BCR-ABL positive cells, we treated or secreted Wnt antagonists (soluble frizzled related proteins the myeloid cell line K562 and control cell line HL60 with - sFRPs- and Dickkopf proteins) increases the complexity of imatinib mesylate and etoposide, and analyzed relative the molecular mechanisms underlying cellular outcomes. mRNA expression levels of WNT, FZD and sFRP genes Non-canonical pathway activation is independent of ß- under normal and apoptotic conditions by real-time RT-PCR. catenin. Two non-canonical pathways have also been defined: We observed marked increase in mRNA levels of FZD4, the planar cell polarity (PCP) and the Wnt/Ca2+ pathways (3-6). FZD5, FZD7 and WNT5b, correlating with apoptotic activity There is an overlap of proposed Wnt and Fzd proteins and and independent of the agent or cell line used. Our results secondary messengers participating in these non-canonical suggest the involvement of non-canonical Wnt signaling in pathways, complicating further the interpretation of experi- executing programmed cell death in myeloid cell lines.
    [Show full text]
  • Novel Missense Mutations in the AXIN2 Gene Associated with Non
    a r c h i v e s o f o r a l b i o l o g y 5 9 ( 2 0 1 4 ) 3 4 9 – 3 5 3 Available online at www.sciencedirect.com ScienceDirect journal homepage: http://www.elsevier.com/locate/aob Novel missense mutations in the AXIN2 gene associated with non-syndromic oligodontia a,1 a,1 b a Singwai Wong , Haochen Liu , Baojing Bai , Huaiguang Chang , c,d e a, a, Hongshan Zhao , Yixiang Wang , Dong Han **, Hailan Feng * a Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing, China b Department of Prosthodontics, Beijing Stomatology Hospital, Beijing, China c Department of Medical Genetics, Peking University Health Science Center, Beijing, China d Peking University Center for Human Disease Genomics, Peking University Health Science Center, Beijing, China e Central Laboratory, Peking University School and Hospital of Stomatology, Beijing, China a r t i c l e i n f o a b s t r a c t Article history: Objective: Oligodontia, which is the congenital absence of six or more permanent teeth Accepted 23 December 2013 excluding third molars, may contribute to masticatory dysfunction, speech alteration, aesthetic problems and malocclusion. To date, mutations in EDA, AXIN2, MSX1, PAX9, Keywords: WNT10A, EDAR, EDARADD, NEMO and KRT 17 are known to associate with non-syndromic oligodontia. The aim of the study was to search for AXIN2 mutations in 96 patients with non- Non-syndromic oligodontia syndromic oligodontia. Mutation screening AXIN2 Design: We performed mutation analysis of 10 exons of the AXIN2 gene in 96 patients with isolated non-syndromic oligodontia.
    [Show full text]
  • The WNT10A Gene in Ectodermal Dysplasias and Selective Tooth Agenesis Gabriele Mues,1* John Bonds,1 Lilin Xiang,1 Alexandre R
    RESEARCH ARTICLE The WNT10A Gene in Ectodermal Dysplasias and Selective Tooth Agenesis Gabriele Mues,1* John Bonds,1 Lilin Xiang,1 Alexandre R. Vieira,2 Figen Seymen,3 Ophir Klein,4,5,6 and Rena N. D’Souza1 1Department of Biomedical Sciences, Texas A&M University-HSC Baylor College of Dentistry, Dallas, Texas 2Department of Oral Biology, University of Pittsburgh School of Dental Medicine, Pittsburgh, Pennsylvania 3University of Istanbul Faculty of Dentistry, Istanbul, Turkey 4Department of Orofacial Sciences, University of California San Francisco, San Francisco, California 5Department of Pediatrics, University of California San Francisco, San Francisco, California 6Institute for Human Genetics and Regeneration Medicine, University of California San Francisco, San Francisco, California Manuscript Received: 8 October 2013; Manuscript Accepted: 30 January 2014 Mutations in the WNT10A gene were first detected in the rare syndrome odonto-onycho-dermal dysplasia (OODD, How to Cite this Article: OMIM257980) but have now also been found to cause about Mues G, Bonds J, Xiang L, Vieira AR, 35–50% of selective tooth agenesis (STHAG4, OMIM150400), a Seymen F, Klein O, D’Souza RN. 2014. common disorder that mostly affects the permanent dentition. The WNT10A gene in ectodermal In our random sample of tooth agenesis patients, 40% had at least dysplasias and selective tooth agenesis. one mutation in the WNT10A gene. The WNT10A Phe228Ile variant alone reached an allele frequency of 0.21 in the tooth Am J Med Genet Part A 164A:2455–2460. agenesis cohort, about 10 times higher than the allele frequency reported in large SNP databases for Caucasian populations. Patients with bi-allelic WNT10A mutations have severe tooth syndrome (OMIM 224750) which additionally features eyelid cysts agenesis while heterozygous individuals are either unaffected or and predisposition to adnexal skin tumors.
    [Show full text]
  • Supplementary Figure 1. Expression of Wnt Genes in SC of Naïve
    A Days after CCI Days after CCI Naive Sham 1 3 5 10 Naive Sham 1 3 5 10 500bp 400bp Wnt1 Wnt2 250bp 250bp 400bp 400bp Wnt2b Wnt3 250bp 250bp 400bp 400bp Wnt3a Wnt4 250bp 250bp 300bp 400bp Wnt5a Wnt5b 200bp 250bp 400bp 400bp Wnt6 Wnt7a 250bp 250bp 400bp 400bp Wnt7b Wnt8a 250bp 250bp 400bp 350bp Wnt8b Wnt9a 250bp 200bp 400bp 400bp Wnt9b Wnt10a 250bp 250bp 400bp 400bp Wnt10b Wnt11 250bp 250bp 400bp 400bp Wnt16 GAPDH 250bp 250bp B 5 Wnt1 5 Wnt2 5 Wnt3a ** 4 4 4 * ** ** 3 3 * 3 * * 2 2 * 2 1 1 1 0 0 0 NaïveSham 1 3 5 10 Naïve Sham 1 3 5 10 Naïve Sham 1 3 5 10 Days after CCI Days after CCI Days after CCI 5 Wnt5b 5 Wnt8b 4 4 ** 3 ** 3 ** Relative mRNA Expression (fold of change) ** 2 * 2 1 1 0 0 NaïveSham 1 3 5 10 NaïveSham 1 3 5 10 Days after CCI Days after CCI Supplementary Figure 1 A B Negative Weak Moderate Strong Negative Weak Moderate Strong Large-sized cells 100% 100% 80% 80% 60% 60% 40% 20% 40% 0% 20% Sham CCI-1d CCI-14d Medium-sized cells Wnt3a immunoreactivity cells 0% 100% CGRP(+) IB4(+) 80% Small cells 60% 40% 20% 0% Sham CCI-1d CCI-14d Wnt3a immunoreactivity cells Small cells 100% 80% 60% 40% 20% 0% Sham CCI-1d CCI-14d Fig. S2 4 Fz1 4 Fz3 4 Fz4 4 Fz5 ** 3 3 ** 3 3 2 ** 2 2 ** 2 * 1 1 1 1 0 0 0 0 NaïveSham 1 5 10 NaïveSham 1 5 10 Naïve Sham 1 5 10 NaïveSham 1 5 10 Days after CCI Days after CCI Days after CCI Days after CCI 4 Fz6 4 Fz7 4 Fz8 4 Fz9 (Fold of Change) of (Fold 3 3 3 ** 3 Relative mRNA Expression Expression mRNA Relative ** 2 2 2 ** 2 * 1 1 1 1 0 0 0 0 NaïveSham 1 5 10 NaïveSham 1 5 10 Naïve Sham 1d 5d 10d NaïveSham 1
    [Show full text]