Genes involved in amelogenesis imperfecta. Part II* Genes involucrados en la amelogénesis imperfecta. Parte II* Víctor Simancas-Escorcia1, Alfredo Natera2, María Gabriela Acosta de Camargo3 * See Part I in Revista Facultad de Odontología Universidad de Antioquia, 2018; 30(1): 105-120. DOI: http://dx.doi.org/10.17533/udea. REVIEW ARTICLE REVIEW rfo.v30n1a10 1 DDS. MSc in Cell Biology, Physiology and Pathology. PhD candidate in Physiology and Pathology, Université Paris-Diderot, France. Grupo Interdisciplinario de Investigaciones y Tratamientos Odontológicos Universidad de Cartagena, Colombia (GITOUC). 2 DDS. Professor in the Department of Operative Dentistry, Universidad Central de Venezuela. Head of Centro Venezolano de Investigación Clínica para el Tratamiento de la Fluorosis Dental y Defectos del Esmalte (CVIC FLUOROSIS). 3 DDS. Specialist in Pediatric Dentistry, Universidad Santa María. PhD in Dentistry, Universidad Central de Venezuela. Professor in the Department of Dentistry of the Child and Adolescent, Universidad de Carabobo. ABSTRACT Amelogenesis imperfecta (AI) is a condition of genetic origin that alters the structure of tooth enamel. AI may exist in isolation or associated with other systemic conditions as part of a syndromic AI. Our goal is to describe in detail the genes involved in syndromic AI, the proteins encoded by these genes, and their functions according to current scientific evidence. An electronic literature search was carried out from the Keywords: year 2000 to December 2017, pre-selecting 1,573 articles, 40 of which were analyzed and discussed. The amelogenesis results indicate that mutations in 12 genes are responsible for syndromic AI: DLX3, COL17A1, LAMA3, imperfecta, tooth LAMB3, FAM20A, TP63, CNNM4, ROGDI, LTBP3, FAM20C, CLDN16, CLDN19. These genes participate enamel, tooth in the coding of proteins involved in phosphorylation, ion exchange, and production and degradation enamel proteins, of the constituent elements of the mineral and organic phase of tooth enamel. The scientific evidence dental aesthetics, confirms that AI can be part of the syndrome and requires special attention from the medical-dental genes, syndrome community. RESUMEN La amelogénesis imperfecta (AI) es una condición de origen genético que altera la estructura del esmalte dental. La AI puede existir de manera aislada o asociada a otras afecciones sistémicas en el contexto de una AI sindrómica. El objetivo es describir de manera detallada los genes involucrados en las AI sindrómicas, las proteínas codificadas por estos genes y sus funciones de acuerdo a la evidencia científica actual. Se realizó una búsqueda electrónica de literatura desde el año 2000 hasta diciembre de 2017, después de lo cual se Palabras clave: preseleccionaron 1.573 artículos, de los cuales 40 fueron analizados y discutidos. Los resultados indican amelogénesis que mutaciones en 12 genes son responsables de una AI sindrómica: DLX3, COL17A1, LAMA3, LAMB3, imperfecta, esmalte FAM20A, TP63, CNNM4, ROGDI, LTBP3, FAM20C, CLDN16, CLDN19. Estos genes están implicados dental, proteínas en la codificación de proteínas que participan en la fosforilación, intercambio de iones, y producción y del esmalte dental, degradación de los elementos constituyentes de la fase mineral y orgánica del esmalte dental. La evidencia estética dental, científica confirma que la AI puede ser parte del síndrome y amerita una especial atención de la comunidad genes, síndrome médica-odontológica. Submitted: January 16/2018 - Accepted: August 28/2018 How to quote this article: Simancas-Escorcia V, Natera A, Acosta-de-Camargo MG. Genes involved in amelogenesis imperfecta. Part II. Rev Fac Odontol Univ Antioq. 2019; 30(2): 224-235. DOI: http:// dx.doi.org/1017533/udea.rfo.v30n2a9 224 Revista Facultad de Odontología Universidad de Antioquia - Vol. 30 N.o 2 - First semester, 2019 / ISSN 0121-246X / ISSNe 2145-7670 Genes involved in amelogenesis imperfecta. Part II INTRODUCTION taurodontism; also, teeth with AI are more likely to be affected by carious processes Dental enamel is an acellular, avascular, and as a result of biofilm retention.5,6 Given the non-inert structure consisting of a mineral importance of AI as an alteration of tooth phase and an organic form composed of enamel affecting patients of different age structure proteins, lipids, phospholipids, groups, our goal is to describe the genes enzymes, and water.1 During enamel and mutations involved in syndromic AI, the formation, there can be alterations of the proteins encoded by these genes, and their enamel structure responsible for aesthetic functions according to current scientific and functional problems. One of these evidence. alterations is amelogenesis imperfecta (AI), a condition of genetic origin that impacts the structure of tooth enamel and can appear as METHODS a syndromic alteration or isolated. When the enamel alteration affects a group of teeth An electronic literature search was conducted from both dentitions and there are systemic in the Medline (PubMed), EBSCOhost and clinical manifestations, the etiological origin Scopus (Science Direct) databases using the is likely due to genetic alterations.2 following keywords: amelogenesis imperfecta, AI has an autosomal dominant, autosomal genes AND/OR amelogenesis imperfecta, and recessive, X- and Y-linked inheritance or syndrome AND/OR amelogenesis sporadic pattern. According to the scarce imperfecta. Full articles in English, accessible epidemiological studies available, the in PDF and produced from 2000 until prevalence of AI can vary from 1/700 to December 2017 were obtained as inclusion 1/14.000 in countries like Switzerland and criteria. No age or sex restrictions were used. the United States respectively.3 Alterations Dissertations, newspapers, conferences, in the dental structure are usually widespread news, commentaries, and editorials were and affect all or most teeth. There are three excluded. forms of AI: hypoplastic, hypocalcified, and The articles used in this literature review hypomaturation. Various AI classifications were collected and stored using the Zotero have been proposed, but the Witkop4 software, which also allowed to eliminate classification is still widely accepted as it duplicate bibliographic references. The includes aspects like phenotype, radiographic articles were independently evaluated by appearance, and mode of transmission. two reviewers according to the above The clinical manifestations of AI include loss of criteria. Finally, a screening was conducted enamel translucency, tooth hypersensitivity, applying the criteria to the articles found yellow, gray or brown pigmentation, and in the databases, and 1,573 articles were early attrition at the incisal level and at preselected; of these, 40 met the inclusion the cusps of molars. Dental eruption and criteria and were therefore analyzed and gingival alterations are common, as well as discussed (Table 1). Revista Facultad de Odontología Universidad de Antioquia - Vol. 30 N.o 2 - First semester, 2019 / ISSN 0121-246X / ISSNe 2145-7670 225 Genes involved in amelogenesis imperfecta. Part II Table 1. Summary of the approach used for the electronic literature search Keywords Medline (PubMed) EBSCOhost Science Direct (Elsevier) Amelogenesis imperfecta 262 400 219 Gene and/or Amelogenesis imperfecta 138 194 142 Syndrome and/or Amelogenesis imperfecta 53 92 73 Source: Simancas V, Natera A, Acosta MG RESULTS Mutations in the COL17A1, LAMA3, LAMB3 genes are responsible for junctional The results showed that mutations in 12 epidermolysis bullosa (JEB) and AI. JEB is a genes are responsible for syndromic AI. form of hereditary epidermolysis bullosa Below is a description of each gene. characterized by the formation of blistery lesions between dermis and epidermis, and Genes involved in syndromic by the healing of lesions with atrophy and/or amelogenesis imperfecta formation of granulation tissue.10-12 1. DLX3 2. COL17A1 The DLX3 gene (OMIM 600525, distal-less The COL17A1 gene (OMIM 113811, homeobox 3) has 3 exons and is located collagen, type XVII, alpha-1) is located in on chromosome 17, position 17q21.33. chromosome 10, position 10q24,3-q25.1. This gene encodes for a protein that is key It has 56 exons and encodes for type XVII in regulating the expression of osteocalcin collagen. Nakamura et al13 reported two during embryogenesis, along with Dlx3, patients with JEB and a dental phenotype Dlx5, Msx2 and Runx2. DLX3 has shown consistent with hypoplastic AI. The first to be an enhancer in the expression of patient had a deletion at position c.1.285 in amelogenin and enameline. DLX3 expresses exon 15 which resulted in the presence of in bones and dental tissues, particularly in a premature termination codon. This same odontoblasts and ameloblasts during the patient also had a transition of cytosine to 7 secretion stage. thymine at position c.4.264 in exon 53 that The DLX3 gene mutation produces a caused the conversion of codon CAG into a hypomaturation-hypoplastic AI with broad premature termination codon in amino acid pulp chambers and taurodontism. Indeed, 1.387. In the second patient, the COL17A1 this gene is reported to be the cause of gene mutation occurred at position c.4.335 the tricho-dento-osseous syndrome (TDO). in exon 53, a deletion that led to the presence TDO belongs to the ectodermal dysplasia of a premature termination codon. group, characterized by curly hair from In a report describing different forms of JEB in birth, enamel hypoplasia with discoloration the Netherlands caused by