title: GREMLIN 2 Mutations and Dental Anomalies.
abstract: Isolated or nonsyndromic tooth agenesis or hypodontia is the most common human malformation. It has been associated with mutations in MSX1, PAX9, EDA, AXIN2, EDAR, EDARADD, and WNT10A. GREMLIN 2 (GREM2) is a strong bone morphogenetic protein (BMP) antagonist that is known to regulate BMPs in embryogenesis and tissue development. Bmp4 has been shown to have a role in tooth development. Grem2(-/-) mice have small, malformed maxillary and mandibular incisors, indicating that Grem2 has important roles in normal tooth development. Here, we demonstrate for the first time that GREM2 mutations are associated with human malformations, which include isolated tooth agenesis, microdontia, short tooth roots, taurodontism, sparse and slow-growing hair, and dry and itchy skin. We sequenced WNT10A, WNT10B, MSX1, EDA, EDAR, EDARADD, AXIN2, and PAX9 in all 7 patients to rule out the effects of other ectodermal dysplasias and other tooth-related genes and did not find mutations in any of them. GREM2 mutations exhibit variable expressivity even within the same families. The inheritance is autosomal dominant with incomplete penetrance. The expression of Grem2 during the early development of mouse teeth and hair follicles and the evaluation of the likely effects of the mutations on the protein structure substantiate these new findings.
authors.affiliation: Center of Excellence in Medical Genetics Research, Chiang Mai University, Chiang Mai, Thailand Division of Pediatric Dentistry, Department of Orthodontics and Pediatric Dentistry, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand Dentaland Clinic, Chiang Mai, Thailand dentaland17@gmail.com.
authors.forename: P N
authors.initials: PN
authors.lastname: Kantaputra
authors.affiliation: Center of Excellence in Medical Genetics Research, Chiang Mai University, Chiang Mai, Thailand Division of Pediatric Dentistry, Department of Orthodontics and Pediatric Dentistry, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: M
authors.initials: M
authors.lastname: Kaewgahya
authors.affiliation: Dental Home Clinic, Khon Kaen, Thailand.
authors.forename: A
authors.initials: A
authors.lastname: Hatsadaloi
authors.affiliation: Department of Veterinary Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: P
authors.initials: P
authors.lastname: Vogel
authors.affiliation: Division of Oral Anatomy, Department of Oral Biological Science, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kawasaki
authors.affiliation: Division of Oral Anatomy, Department of Oral Biological Science, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Ohazama
authors.affiliation: School of Biochemistry, Institute of Science, and Center for Biomolecular Structure, Function and Application, Suranaree University of Technology, Nakhon Ratchasima, Thailand Laboratory of Biochemistry, Chulabhorn Research Institute, Bangkok, Thailand.
authors.forename: J R
authors.initials: JR
authors.lastname: Ketudat Cairns
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000848:Anodontia / Q000235:genetics; D016207:Cytokines; D006801:Humans; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics*; D014070:Tooth / Q000254:growth & development; D014071:Tooth Abnormalities / Q000235:genetics*
chemical_list: D016207:Cytokines; C495107:GREM2 protein, human; D036341:Intercellular Signaling Peptides and Proteins
keywords: hypodontia; microdontia; missing teeth; short tooth roots; taurodontism; tooth agenesis