The Molecular Basis of Hereditary Enamel Defects in Humans

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JDRXXX10.1177/0022034514556708Journal of Dental ResearchMolecular Basis of Hereditary Enamel Defects research-article5567082014

Research Reports: Clinical

Journal of Dental Research 2015, Vol. 94(1) 52–61 The Molecular Basis of Hereditary Enamel © International & American Associations for Dental Research 2014 Reprints and permissions: Defects in Humans sagepub.com/journalsPermissions.nav DOI: 10.1177/0022034514556708 jdr.sagepub.com

J.T. Wright1, I.A. Carrion2, and C. Morris3

Abstract The formation of human enamel is highly regulated at the molecular level and involves thousands of genes. Requisites for development of this highly mineralized tissue include cell differentiation; production of a unique extracellular matrix; processing of the extracellular matrix; altering of cell function during different stages of enamel formation; cell movement and attachment; regulation of ion and protein movement; and regulation of hydration, pH, and other conditions of the microenvironment, to name just a few. Not surprising, there is a plethora of hereditary conditions with an enamel phenotype. The objective of this review was to identify the hereditary conditions listed on Online Mendelian Inheritance in Man (OMIM) that have an associated enamel phenotype and whether a causative gene has been identified. The OMIM database was searched with the terms amelogenesis, enamel, dental, and tooth, and all results were screened by 2 individuals to determine if an enamel phenotype was identified. Gene and gene product function was reviewed on OMIM and from publications identified in PubMed. The search strategy revealed 91 conditions listed in OMIM as having an enamel phenotype, and of those, 71 have a known molecular etiology or linked genetic loci. The purported protein function of those conditions with a known genetic basis included enzymes, regulatory proteins, extracellular matrix proteins, transcription factors, and transmembrane proteins. The most common enamel phenotype was a deficient amount of enamel, or enamel hypoplasia, with hypomineralization defects being reported less frequently. Knowing these molecular defects allows an initial cataloging of molecular pathways that lead to hereditary enamel defects in humans. This knowledge provides insight into the diverse molecular pathways involved in enamel formation and can be useful when searching for the genetic etiology of hereditary conditions that involve enamel.

Keywords: genes, amelogenesis, mutations, protein, matrix, development

Introduction Some of the processes requisite for enamel formation are likely sensitive to perturbations leading to abnormal amelo- Enamel is the hardest mammalian tissue and is derived from blast functions. For example, abnormal secretion and pro- the ectodermally derived oral epithelium (Simmer and cessing of the enamel extracellular matrix result from Fincham 1995). The oral epithelium interacts with the ecto- different allelic and nonallelic mutations (Lagerstrom- mesenchyme through a series of signaling events that result Fermer et al. 1995; Hu and Yamakoshi 2003; Hart et al. in the epithelial cells differentiating to ameloblasts. 2004; Gasse et al. 2013). Phenotypes resulting from the Ameloblasts generate the enamel tissue that covers the altered gene expression and gene products are varied and human dental crown and are responsible for establishing the can affect the amount, structure, and/or composition of enamel’s unique composition and structure that account for enamel (Wright 2006). One would predict that the enamel its remarkable wear, fracture resistance, and insulating phenotypes will be determined by the specific genetic muta- properties. This process of amelogenesis is accomplished tion, the nature of the mutation and changes in the derived through a temporally restricted and highly regulated series protein, the function of the protein, and the temporal and of events that include development of a specific extracellular matrix, matrix processing, and controlling the microenvironment of the developing enamel tissue (Smith 1998; He 1Department of Pediatric Dentistry, School of Dentistry, The University et al. 2010; Lacruz et al. 2012). These processes are highly of North Carolina, Chapel Hill, NC, USA 2Meharry School of Dentistry, Nashville, TN, USA regulated at the molecular level, with amelogenesis ulti- 3Bon Secours Pediatric Dental Associates, Richmond, VA, USA mately involving thousands of genes and their products (Sehic et al. 2010; Lacruz et al. 2011). Not unexpectedly, Corresponding Author: J.T. Wright, Department of Pediatric Dentistry, School of Dentistry these processes involve numerous developmental and regu- Brauer Hall #7450, The University of North Carolina, Chapel Hill, NC latory pathways that could lead to abnormal enamel devel- 27599, USA. opment and pathology. Email: [email protected] Molecular Basis of Hereditary Enamel Defects 53 spatial expression of the protein (Wright et al. 2003). provide a framework for grouping or classifying these con- Molecular defects can alter enamel development by directly ditions based on the molecular defect and the resulting affecting gene expression of the enamel forming cells (e.g., functional change. ameloblasts secrete an abnormal matrix) or secondarily or indirectly where the gene may not be expressed by amelo- Methods blasts but the resulting changes influence enamel formation (e.g., systemic changes in pH regulation). Genetic mutations The OMIM database (http://www.ncbi.nlm.nih.gov/omim/) can directly affect the oral epithelium, thereby altering the was interrogated for genes or known hereditary conditions differentiation or function of the ameloblasts or adjacent listing any phenotype with an enamel component. The data- supporting cells (e.g., stratum intermedium). For example, base was searched with the terms amelogenesis, enamel, junctional epidermolysis bullosa (Online Mendelian dental, and tooth. All results were screened by 2 individuals Inheritance of Man [OMIM] 226700, 226650) is associated to determine if an enamel phenotype was identified. Positive with enamel hypoplasia secondary to abnormal laminin 5 hits were interrogated regarding the nature and phenotype formation that is critical for cell attachment (Wright et al. of the enamel defect by review of articles cited in OMIM. 1993; Aberdam et al. 1994). There are many syndromes The primary outcome measured was enamel phenotype. caused by genes that are expressed by the oral epithelium Genes associated with enamel formation but not associated and ameloblasts and that have an associated enamel pheno- with an enamel phenotype were not included. The purported type. Transient expression of a gene and its altered protein function of each gene and its protein were searched in (e.g., dentin sialophosphoprotein expression by preamelo- OMIM. Additional articles from PubMed were pulled to blasts) can be associated with abnormal enamel formation help ascertain the function of the different genes and their (Wang et al. 2011). Genes coding for proteins important for products associated with known enamel malformations. enamel formation have diverse functions. Mutations in these The search was completed August 30, 2014. genes produce changes affecting molecular pathways, resulting in a variety of enamel phenotypes, such as a deficiency Results in amount (hypoplasia), a change in composition (e.g., hypomineralization), or a change in structure. Interrogation of the OMIM database revealed responses when Genetic alterations also can affect enamel formation it was searched via tooth (n = 958), dental (n = 677), enamel through secondary actions or distresses that do not involve (n = 162), and amelogenesis (n = 47). Further interrogation of ameloblast dysfunction caused by gene expression of the these citations revealed 91 conditions listed in OMIM that had ameloblast. Through a variety of diverse processes, genes an enamel phenotype. The most common enamel phenotype that are transiently or not expressed by ameloblasts can was a deficient amount of enamel or enamel hypoplasia with result in altered enamel development. Genes expressed by hypomineralization defects being less commonly reported. the ectomesenchyme or its derived odontoblast cells appear Dysplastic enamel was described for many cases, but it was to be critical for signaling the ameloblasts, and abnormali- not defined regarding the exact nature of the defect. The data ties in this process could result in aberrant ameloblast func- presented in the tables represent the enamel phenotype tion. This may well occur in certain cases of dentinogenesis descriptions provided in OMIM. While the different designa- imperfecta type II (OMIM 125490) caused by DSPP mutations of enamel defects can be confusing (e.g., dysplastic, tions that display enamel defects in addition to the more hypomineralized, hypocalcified, hypomaturation), we did not typical dentin defects. Interrogation of databases of human attempt to presume that we could cluster these disparate phe- mutations can provide insights into the molecular etiologies notypes even when we referred to the original publications to associated with developmental defects of human teeth. The help clarify the phenotype. Of the 91 conditions with a database OMIM provides a valuable resource of regularly described enamel phenotype, 71 had a known molecular etiol- updated genetic and phenotype information on hereditary ogy or linked genetic loci listed in the OMIM database (Table human conditions. The OMIM database is updated regu- 1). The molecular basis of 23% of the hereditary enamel larly and is organized to help delineate the mode of inheri- defects was unknown or not listed on OMIM. The purported tance and to facilitate practitioners searching for current protein function of those conditions with a known genetic information on hereditary conditions. The database includes basis included enzymes, regulatory proteins, extracellular hereditary conditions with known phenotypes and includes matrix proteins, transcription factors, transmembrane pro- information related to genes that are not currently associ- teins, and a variety of other proteins with diverse functions ated with a phenotype (e.g., tuftelin, ameloblastin). The (Fig.). Functionality of the protein products of genes associ- purpose of this investigation was to explore our current ated with each hereditary enamel defect identified on OMIM understanding of the molecular mechanisms and the devel- was further interrogated (OMIM, PubMed search) regarding opmental pathways involved in the formation of enamel its putative role in enamel formation (Table 2). Despite exten- defects in humans. This knowledge will not only help sive research, the role of these diverse gene products in enamel explain how certain enamel phenotypes develop but also formation remain, for the most part, poorly understood. 54 Journal of Dental Research 94(1)

variety of nomenclatures and terminologies are being used (Witkop 1989; Aldred et al. 2003). It is primarily in the past decade that a useful understanding of the molecular mechanisms leading to hereditary enamel defects has emerged with many of the genes responsible for enamel defects now identified. This knowledge provides the foundation for under- stating the molecular controls and pathways leading to hereditary developmental defects of enamel. As we show, the number of syndromes having associated enamel defects is extensive. Some classifications list hereditary enamel defects as syndromic and nonsyndromic forms of amelogenesis imperfecta to help delineate these 2 groups. Our search identified 10 genes listed in OMIM as being associated with conditions involving primarily the enamel (traditional non- Figure. The putative protein function of gene products syndromic amelogenesis imperfecta). These 10 genes allow affecting enamel indicated that extracellular matrix proteins and molecular diagnosis of the majority of amelogenesis imper- enzymes accounted for about 30% of conditions, about 20% fecta cases; however, there remain individuals with enamel were regulatory proteins or transcription factors, and about defects that have as yet to be identified genetic mutations 14% were transmembrane or other proteins. that cause the amelogenesis imperfecta phenotype (Wright et al. 2011). One of the genes listed on OMIM as an amelo- There were multiple conditions with the term amelogen- genesis imperfecta with gingival fibromatosis (OMIM esis imperfecta identified in the search. The conditions 614253), FAM20A, is now known to be causative of enamel- including the term amelogenesis involved nonsyndromic renal syndrome (OMIM 204690; Wang et al. 2014). These 2 enamel conditions, traditionally referred to as amelogenesis conditions are listed separately on OMIM but appear to be imperfectas, and syndromic conditions affecting tissues or the same entity. In some conditions, such as Kolschutters- organs in addition to the enamel phenotype (Table 1). Tonz syndrome (OMIM 226750, gene ROGDI), the enamel Syndromes with an associated enamel phenotype had a phenotype appears quite similar to the hypomineralized variety of other manifestations involving the brain, eyes, forms of amelogenesis imperfecta (Schossig et al. 2012). kidney, skin, and other tissues and organs depending on the The pathologic mechanism of this neurologic condition and condition. Delineation of hereditary enamel defects as non- function of the ROGDI gene product remain unknown, but syndromic and syndromic conditions can be problematic one could speculate that the causative gene is expressed by due to overlapping phenotypes and multiple listings for dis- ameloblasts and that its protein plays a critical role in enamel orders caused by allelic mutations (e.g., DLX3 mutations). biomineralization. While the genes are known for many Here we present these conditions separately in the tables, as hereditary enamel defects, the protein function and specific this classification approach is still recognized by most clini- mechanisms involved with these conditions remain poorly cians and this is how the conditions are presented in OMIM. understood. Future classification of hereditary enamel defects should include organization around the phenotype, mode of inheritance, molecular defect, and protein function Discussion and its role in enamel formation or pathologic mechanism. The number and functional diversity of genes associated Such a classification system would provide a robust organi- with hereditary enamel defects and the molecular pathways zational approach that would offer a logical and informative involved is not surprising given the complexity of enamel clustering of the diverse hereditary enamel conditions. development. Despite the diversity of molecular defects, the Many genetic alterations affect development of epithe- most common phenotype described in our OMIM query was lial derivatives and can have associated alterations in dental enamel hypoplasia. The specific enamel phenotype is often formation, as the oral epithelium is critical to tooth bud ini- not described in any detail in OMIM or in the manuscripts tiation. A classic example is the ectodermal dysplasias that reviewed from PubMed. It is not surprising that alterations are frequently associated with hypodontia and, in some in a variety of pathways can lead to a phenotype of enamel cases, enamel defects (e.g., ectrodactyly, ectodermal dys- hypoplasia given the sensitivity and exquisite regulation of plasia, and cleft lip/palate; OMIM 604292). Genes that are the amelogenesis processes. Future studies directed at critical for early tooth formation events, such as invagina- detailed phenotype characterization of hereditary enamel tion and proliferation of the oral epithelium, can result in defects will provide clues regarding the role of genes, pro- hypodontia or missing teeth. Such is indeed the case with teins, and pathways involved in enamel formation. x-linked hypohidrotic ectodermal dysplasias (OMIM The classification of developmental enamel defects has 305100). Mutations affecting genes involving the WNT been reviewed and modified for more than 70 years. A pathway can be associated with both hypodontia and enamel Molecular Basis of Hereditary Enamel Defects 55

Table 1. Hereditary Conditions with Enamel Defects: OMIM Designations and Genes.

OMIM Category of Condition and Inheritance Gene/Locus Enamel Phenotype Protein Function Nonsyndromic enamel conditions Autosomal dominant 104500 Amelogenesis imperfecta, type IB; AI1B ENAM Localized hypoplastic, generalized ECM secreted by hypoplastic ameloblasts 104510 Amelogenesis imperfecta, type IV; AI4 DLX3 TDO Transcription factor 104530 Amelogenesis imperfecta, hypoplastic nk Hypoplastic—failure to erupt and nk type calcification of pulp 130900 Amelogenesis imperfecta, type III; AI3 FAM83H Localized or generalized nk hypomineralized enamel Autosomal recessive 204650 Amelogenesis imperfecta, type IC; AI1C ENAM Generalized hypoplastic ECM secreted by ameloblasts 204700 Amelogenesis imperfecta, KLK4 Normal enamel thickness— Maturation stage enamel hypomaturation type, IIA1; AI2A1 hypomineralized orange brown proteinase color 612529 Amelogenesis imperfecta, MMP20 Normal enamel thickness— Secretory stage enamel hypomaturation type, IIA2; AI2A2 hypomineralized orange brown proteinase color 613211 Amelogenesis imperfecta, WDR72 Hypomaturation creamier, nk hypomaturation type, IIA3; AI2A3 opaque enamel upon eruption. discoloration and loss of tissue posteruption 614253 Amelogenesis imperfecta and gingival FAM20A Generalized hypoplastic and failure nk fibromatosis syndrome of tooth eruption, gingival hypertrophy 614832 Amelogenesis imperfecta, C4ORF26 Hypomaturation AI May encode an hypomaturation type, IIA4; AI2A4 extracellular matrix acidic phosphoprotein 615887 Amelogenesis imperfecta SLC24A4 Hypomaturation AI Na/K exchanger hypomaturation type 1A5 X-linked 301200 Amelogenesis imperfecta, type IE; AI1E AMELX Hypoplasia, hypomaturation ECM secreted by depending on mutation and protein ameloblasts effect 301201 Amelogenesis imperfecta, hypoplastic/ Xq22-q28 Enamel hypoplasia and nk hypomaturation, x-linked 2 hypomaturation Syndrome-associated enamel defects Autosomal dominant 103580 Pseudohypoparathyroidism, type IA; GNAS Enamel hypoplasia Transcription factor PHP1A 104570 Ameloonychohypohidrotic syndrome nk Enamel hypoplasia, hypomineralization nk 119600 Cleidocranial dysplasia RUNX2 Enamel hypoplasia, failure of Nuclear protein exfoliation of the primary dentition transcription factors 125500 Dentinogenesis imperfecta, shields DSPP Enamel hypoplasia, aplasia and pitting Two proteins associated type III with biomineralization of teeth 129540 Ectodermal dysplasia syndrome with nk Thin dental enamel nk distinctive facial appearance and preaxial polydactyly of feet 133705 External auditory canal, bilateral atresia nk Dysplastic enamel nk of, with congenital vertical talus 146300 Hypophosphatasia, adult ALPL Enamel hypoplasia Membrane bound glycosylated enzyme 149730 Lacrimoauriculodentodigital syndrome FGFR2; FGFR3, Enamel dysplasia, peg shaped lateral Polypeptide growth FGFR10 incisors factors involved in mitogenesis, angiogenesis, and wound healing 151050 Lenz-majewski hyperostotic dwarfism PTDSS1 Enamel dysplasia nk 162200 Neurofibromatosis, type I; NF1 NF1 Enamel hypoplasia Cytoplasmic protein, negative regulator 164200 Oculodentodigital dysplasia GJA1, connexin-43 Enamel hypoplasia Component of gap gene junctions (continued) 56 Journal of Dental Research 94(1)

Table 1. (continued)

OMIM Category of Condition and Inheritance Gene/Locus Enamel Phenotype Protein Function 166750 Otodental dysplasia FGF3 Enamel defects, enlarged canines and Growth factor associated molars with mitogenic and cell survival activities 173650 Kindler syndrome KIND1 Enamel hypoplasia, dental caries Structural protein 180500 Axenfeld-rieger syndrome, type 1; PITX2; FOXC1 Enamel hypoplasia, conical and Bicoid class of RIEG1 misshapen teeth, hypodontia, and homeodomain impactions transcription factors 180849 Rubinstein-taybi syndrome CREBBP; EP300 Enamel hypoplasia, discoloration and Transcriptional wear coactivation of many different transcription factors 180849 Rubinstein-taybi syndrome 1 CREBBP Enamel hypoplasia, discoloration, Transcriptional hypodontia, talon cusps, coactivator CREB- screwdriver permanent incisors, binding protein enamel wear 182290 Smith-magenis syndrome 3.7-Mb deletion Enamel hypoplasia, hypomineralized Regulatory proteins 17p11.2; RAI1 enamel (enhancer) 190320 Trichodentoosseous syndrome DLX3 Enamel hypoplasia, taurodontism Transcription factor 191100 Tuberous sclerosis 1 TSC1 Pitted hypoplastic enamel Forms a protein complex that inhibits signal transduction 604292 Ectrodactyly, ectodermal dysplasia, and TP63 Enamel hypoplasia and hypodontia Transcription factors cleft lip/palate syndrome 3 612463 Pseudopseudo-hypoparathyroidism GNAS Enamel hypoplasia Regulatory proteins 612843 Keratosis follicularis spinulosa decalvans nk Enamel hypoplasia nk 614564 Cutaneous telangiectasia and cancer ATR Thin discolored enamel and dental Regulator of genomic syndrome, familial caries integrity; kinase enzyme Autosomal recessive 202900 Alaninuria with microcephaly, dwarfism, nk Enamel hypoplasia nk enamel hypoplasia, and diabetes mellitus 203550 Alopecia-contractures-dwarfism mental nk Enamel dysplasia and caries nk retardation syndrome 204690 Enamel-renal syndrome FAM20A Enamel hypoplasia, anodontia of nk permanent teeth 207780 Aredyld nk nk 210600 Seckel syndrome 1 ATR Enamel hypoplasia Kinase enzyme 211900 Tumoral calcinosis, hyperphosphatemic, GALNT3; Hypoplastic teeth with fully Catalytic enzyme; familial FGF23; KL developed enamel Growth factor; type-I membrane protein 212750 Celiac disease CELIAC1 Enamel hypoplasia Extracellular proteins 216400 Cockayne syndrome, type A; CSA ERCC8 Enamel hypoplasia, dental caries Regulatory proteins 217080 Jalili syndrome CNNM4 Cone-rod dystrophy and Role in metal ion amelogenesis imperfecta transport 224300 Dysosteosclerosis nk Hypomineralized enamel (chalky), nk delayed eruption of primary teeth 225410 Ehlers-danlos syndrome, type VII, ADAMTS2 Excises the N-propeptide of type Enzyme that excises the autosomal recessive I and type II procollagens. NPI N-propeptide of type enzyme is a metalloproteinase I, type II and type V procollagens 225500 Ellis-van creveld syndrome EVC1; EVC2 Enamel hypoplasia, conical shaped nk teeth, premature eruption of primary teeth 226440 Epidermolysis bullosa, late-onset nk Enamel hypoplasia nk localized junctional, with mental retardation 226600 Epidermolysis bullosa dystrophica, COL7A1 Generalized enamel hypoplasia Collagen beneath autosomal recessive stratified squamous epithelia 226650 Epidermolysis bullosa, junctional, non- COL17A1; Enamel hypoplasia Components of herlitz type LAMA3; hemidesmosomes LAMB3; important for cell LAMC2; ITGB4 attachment

(continued) Molecular Basis of Hereditary Enamel Defects 57

Table 1. (continued)

OMIM Category of Condition and Inheritance Gene/Locus Enamel Phenotype Protein Function 226670 Epidermolysis bullosa simplex with PLEC1 Enamel hypoplasia Intermediate filament- muscular dystrophy binding protein 226700 Epidermolysis bullosa, junctional, herlitz LAMA3; LAMB3; Enamel hypoplasia Cell adhesion, signal type LAMC3 transduction and differentiation of keratinocytes 226730 Epidermolysis bullosa junctionalis with ITGB4; ITGA6 Enamel hypoplasia Transmembrane pyloric atresia glycoprotein receptors 226750 Kohlschutter-tonz syndrome ROGDI Hypomineralized enamel Leucine-zipper protein 233400 Perrault syndrome HSD17B4 Enamel hypomineralization Multifunctional peroxisomal enzyme 234580 Hearing loss, sensorineural, with nk Hypomineralized enamel nk enamel hypoplasia and nail defects 240300 Autoimmune polyendocrine AIRE Enamel hypoplasia Autoimmune regulator syndrome, type I; APS1 gene and transcriptional activator 241510 Hypophosphatasia, childhood ALPL Enamel hypoplasia, Membrane bound odontohypophosphatasia glycosylated enzyme 244460 Kenny-caffey syndrome, type 1; KCS1 TBCE Enamel hypoplasia Hypocalcemia, seizures, protein folding cofactor 245660 Laryngoonychocutaneous syndrome LAMA3 Hypoplastic enamel, allelic to Cell adhesion ligand for herlitz EB integrins 251190 Microcephalic primordial dwarfism, nk Enamel hypoplasia nk toriello type 253000 Morquio syndrome a GALNS Enamel hypoplasia; pitted and Lysosomal enzyme reduced thickness involved in the catabolism of keratin and chondroitin sulfate 253010 Morquio syndrome b GLB1 Enamel hypoplasia Lysosomal enzyme 257850 Oculodentodigital dysplasia, autosomal GJA1 Enamel hypoplasia codes CONNEXIN 43 a recessive major protein of gap junctions 259775 Raine syndrome FAM20C Enamel dysplasia, small teeth nk 261560 Pfeiffer-palm-teller syndrome nk Enamel hypoplasia nk 261900 Pili torti, early-onset nk Enamel hypoplasia nk 264700 Vitamin d hydroxylation-deficient CYP27B1 Enamel discoloration permanent Catalytic enzyme rickets, type 1A teeth 601539 Peroxisome Biogenesis Disorder PEX1, PEX2, Enamel hypoplasia ATPase enzymes PEX26 270200 Sjogren-larsson syndrome ALDH3A2 Enamel hypoplasia Catalytic enzyme 275450 Trichoodontoonychial dysplasia nk Enamel hypoplasia, anodontia nk 277440 Vitamin d-dependent rickets, type 2A; VDR Dental anomalies Hormone receptor VDDR2A 601216 Platyspondyly with amelogenesis nk Enamel hypoplasia and hypodontia, nk imperfecta discolored enamel 601701 Arthrogryposis and ectodermal nk Enamel abnormalities nk dysplasia 604278 Renal tubular acidosis, proximal, with SLC4A4 Enamel hypoplasia Sodium bicarbonate ocular abnormalities and mental cotransporter, retardation regulator 605472 Usher syndrome, type IIC; USH2C GPR98, PDZD7 Enamel hypoplasia Transmembrane receptor 607626 Ichthyosis, leukocyte vacuoles, alopecia, CLDN1 Enamel dysplasia Claudin-1 is a tight- and sclerosing cholangitis junction protein 610319 Rhizomelic dysplasia, scoliosis, and nk Amelogenesis imperfecta mentioned, nk retinitis pigmentosa hypomaturation 611174 Hypertelorism, severe, with midface IRX5 Enamel hypoplasia Gene regulation; involved prominence, myopia, mental in several embryonic retardation, and bone fragility developmental processes 612783 Immune dysfunction with t-cell STIM1 Enamel defect Calcium sensor that inactivation due to calcium entry conveys the calcium defect 2 load of the endoplasmic reticulum

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Table 1. (continued)

OMIM Category of Condition and Inheritance Gene/Locus Enamel Phenotype Protein Function X-linked nk 302350 Nance-horan syndrome NHS Enamel hypoplasia, supernumerary Vasopressin receptor teeth and screwdriver incisors 304800 Diabetes insipidus, nephrogenic, AVPR2 Hypomineralized enamel Endoplasmic reticulum x-linked transmembrane protein 305600 Focal dermal hypoplasia PORCN Enamel hypoplasia transmembrane endopeptidase 307800 Hypophosphatemic rickets, x-linked PHEX Enamel hypoplasia Protease functioning dominant in the signal protein activation 308205 Ichthyosis follicularis, atrichia, and MBTPS2 Enamel dysplasia Membrane-embedded photophobia syndrome zinc metalloprotease that activates signaling proteins 308205 Ifap syndrome with or without MBTPS2 Enamel dysplasia Phosphatase enzyme bresheck syndrome 309000 Lowe oculocerebrorenal syndrome OCRL1 Enamel hypoplasia nk 312830 Scarf syndrome nk Enamel hypocalicification, hypoplasia nk Inheritance not clearly defined and other 600907 Enamel hypoplasia, cataracts, and nk Enamel hypoplasia of the Tumor suppressor by aqueductal stenosis hypomaturation-hypocalcification activation of GPTases type 603641 Neuroendocrine carcinoma of salivary nk Enamel hypoplasia Contiguous gene deletion glands, sensorineural hearing loss, syndrome; regulatory and enamel hypoplasia protein (inhibitor) 613254 Tuberous sclerosis 2 TSC2 Enamel hypoplasia ECM secreted by ameloblasts 613675 Chromosome 17q11.2 deletion 17q11.2; NF1 Enamel hypoplasia Transcription factor syndrome, 1.4-MB nk indicates that the gene or chromosomal locus for this condition has not been identified and is not known. OMIM, Online Mendelian Inheritance of Man. hypoplasia characterized by thin or pitted enamel (e.g., laminin 5; Aberdam et al. 1994). Maintaining an intact sheath focal dermal hypoplasia; OMIM 305600; Wang et al. 2007). of ameloblasts is essential for controlling the microenviron- Because of these genes’ roles in epithelium development, ment critical for enamel biomineralization. The ameloblasts they are associated with many developmental perturbations control the enamel matrix microenvironment’s ion content, of ectodermally derived appendages. Table 1 lists those pH, and water content through the expression of numerous OMIM conditions and the known genes and their purported genes. Some of these genes are associated with enamel protein functions related to epithelial growth and develop- defects, such as the CFTR gene, which codes for the cystic ment (e.g., KIND1, PORCN, TP63). fibrosis conductance transmembrane regulator (Ferrazzano Numerous other critical developmental pathways affect et al. 2012). Mutations in CFTR cause cystic fibrosis (OMIM epithelium and are associated with enamel defects. For 219700), and although enamel defects are reported in about example, the WNT10A, TP63, PORCN, and DLX3 genes are half of affected individuals (Ferrazzano et al. 2012), an all associated with syndromes that have abnormal ectodermal enamel phenotype is not described in the OMIM database. appendage development and can have defective enamel for- Not only is this ion channel critical as a chloride ion channel, mation (Price et al. 1998; Adaimy et al. 2007; Wang et al. but it also plays a role in pH modulation (Arquitt et al. 2002). 2007; Koster 2010). Given that the genes and gene products Humans with SLC4A4 mutations (codes for electrogenic can be interactive (PORCN and WNT, TP63 and DLX3), it is sodium base transporter—an important pH regulator; OMIM not surprising that similar developmental defects and pheno- 3604278) have abnormal enamel development. Recent ani- types might occur. Mutations in the PORCN gene are associ- mal studies indicate that mutations in this gene are associated ated with the focal dermal hypoplasia syndrome (OMIM with proximal tubular acidosis resulting in a systemic acido- 305600). Focal dermal hypoplasia syndrome is known to sis that secondarily causes the defective enamel formation have a marked enamel hypoplasia phenotype, but the OMIM (Wen et al. 2014). This is another example of a genetic muta- description only notes hypoplastic teeth (Murakami et al. tion secondarily causing an enamel malformation (e.g., sys- 2011). Genetic mutations affecting epithelial integrity can temic acidosis). Nephrogenic diabetes insipidus (OMIM also be associated with developmental enamel defects (e.g., 304800; gene mutations in AVPR2) is associated with a Molecular Basis of Hereditary Enamel Defects 59

Table 2. Protein Function during Enamel Formation.

Protein/Category Function during Amelogenesis Phenotype Enzyme KLK4 Maturation stage enamel proteinase Normal enamel thickness— hypomineralized orange brown color MMP20 Secretory stage enamel proteinase Normal enamel thickness— hypomineralized orange brown color GALNT3; FGF23; KL Unknown Hypoplastic teeth with fully developed enamel ADAMTS2 Unknown Enamel attrition HSD17B4 Unknown Amelogenesis imperfecta GALNS Lysosomal enzyme involved in the catabolism of Enamel hypoplasia; pitted and reduced keratin and chondroitin sulfate thickness GLB1 Unknown Enamel hypoplasia CYP27B1 Catalytic enzyme forming biologically active Enamel discoloration permanent teeth vitamin D MBTPS2 Unknown Enamel dysplasia OCRL1 Unknown Enamel hypoplasia ALPL Hydrolyze monophosphate esters Enamel hypoplasia ATR Unknown Enamel hypoplasia PEX1, PEX2, PEX26 Unknown Enamel hypoplasia ALDH3A2 Unknown Enamel hypoplasia MBTPS2 Unknown Enamel dysplasia PTDSS1 Enzyme involved in phosphatidylserine production Extracellular protein LAMA3 Cell adhesion ligand for integrins Enamel hypoplasia GJA1, connexin-43 gene Component of gap junctions Enamel hypoplasia CELIAC1 Unknown Enamel hypoplasia LAMA3; LAMB3; LAMC3 Cell adhesion, signal transduction and Enamel hypoplasia differentiation of keratinocytes GJA1 Codes CONNEXIN 43 a major protein of gap Enamel hypoplasia junctions ENAM Important in crystallite growth Enamel hypoplasia AMELX Important in crystallite growth Enamel hypoplasia and hypomaturation C4ORF26 Support crystallite mineralization Enamel hypomineralization CNNM4 Transcellular Mg(2+) transport across epithelia Enamel hypoplasia and hypomineralization CLDN1 Claudin-1 is a tight-junction protein Enamel dysplasia DSPP Unknown Enamel hypoplasia Growth factor FGFR2; FGFR3, FGFR10 Polypeptide growth factors involved in a variety Enamel dysplasia, peg shaped lateral of activities, including mitogenesis, angiogenesis, incisors and wound healing FGF3 Growth factor associated with mitogenic and cell Enlarged canines and molars survival activities Regulatory protein GNAS Signaling related to parathyroid hormone activity Enamel hypoplasia ERCC8 Unknown Enamel hypoplasia, dental caries SLC4A4 Sodium bicarbonate cotransporter, regulator Enamel hypoplasia IRX5 Unknown Enamel hypoplasia CREBBP Transcriptional coactivator CREB-binding protein Enamel hypoplasia, hypodontia present during maturation stage 3.7-Mb deletion 17p11.2; RAI1 Unknown Enamel hypoplasia Unknown Enamel hypomineralization AIRE Unknown Enamel hypoplasia TSC2 Unknown Enamel hypoplasia

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Table 2. (continued)

Protein/Category Function during Amelogenesis Phenotype NF1 Unknown Enamel hypoplasia TSC1 Unknown Enamel hypoplasia Structural protein KIND1 Unknown Enamel hypoplasia, dental caries PLEC1 Unknown Enamel hypoplasia Transcription factor RUNX2 Regulates expression of genes important to Enamel hypoplasia enamel formation PITX2; FOXC1 Bicoid class of homeodomain transcription factors Enamel hypoplasia, conical and misshapen teeth, hypodontia TP63 Regulates expression of genes important to Enamel hypoplasia and hypodontia enamel formation DLX3 Regulates expression of genes important to Enamel hypoplasia enamel formation Transmembrane protein COL7A1 May play role in ameloblast differentiation Enamel hypoplasia interactions COL17A1; LAMA3; LAMB3; LAMC2 Components of hemidesmosomes important for Enamel hypoplasia cell attachment ITGB4; ITGA6 Cell adhesion and migration Enamel hypoplasia VDR Role in regulating vitamin D endocrine system Enamel hypoplasia GPR98, PDZD7 Unknown Enamel hypoplasia STIM1 Calcium sensor that conveys the calcium load of Enamel hypoplasia the endoplasmic reticulum PORCN WNT signaling regulation Enamel hypoplasia PHEX Endopeptidase regulating phosphate Enamel hypoplasia AVPR2 Fluorosis secondary to excess water consumption Enamel hypomineralization Other proteins TBCE Unknown Enamel hypoplasia FAM20C Kinase that phosphorylates a secretory calcium- Enamel dysplasia binding phosphoprotein FAM20A Kinase that phosphorylates proteins important to Enamel hypoplasia amelogenesis WDR72 Maturation stage endocytotic trafficking Enamel hypomineralization PTDSS1 EVC1, EVC2 NHS ROGDI SLC24A4 Na+/K+/Ca2+ transporter Enamel hypomineralization

Unknown indicates that the gene and its protein have not been studied as related to potential function during amelogenesis. fluorotic enamel phenotype that occurs secondarily to the including eye, kidney, brain, and skin, to name just a few. inability of the renal collecting duct to respond to antidiuretic Identification of the genes associated with developmental hormone and the resulting polyuria and polydipsia (Klein defects of enamel has been extremely informative in help- 1975). ing advance our knowledge of the molecular control of The list of genes associated with enamel defects has enamel formation and how genes and gene products can grown tremendously over the past decade. The molecular have diverse functions in different tissues. Review of the pathways involved in the development of enamel defects OMIM database reveals that the phenotype characterization are diverse, and the functionality of the genes and gene of enamel defects is incomplete and future studies provid- products is heterogeneous. Syndrome-associated enamel ing more detailed phenotypic evaluation of enamel malfor- defects are caused by many genes that affect other tissues, mations are needed. Advancing our understanding of the Molecular Basis of Hereditary Enamel Defects 61 enamel phenotypes, protein function, and developmental Lacruz RS, Smith CE, Moffatt P, Chang EH, Bromage TG, Bringas pathways will assist in developing a logical and more useful P Jr, Nanci A, Baniwal SK, Zabner J, Welsh MJ, et al. 2012. classification system of hereditary enamel disorders. Requirements for ion and solute transport, and pH regulation during enamel maturation. J Cell Physiol. 227(4):1776–1785. Author Contributions Lagerstrom-Fermer M, Nilsson M, Bäckman B, Salido E, Shapiro L, Pettersson U, Landegren U. 1995. Amelogenin signal J.T. Wright, I.A. Carrion, contributed to conception, design, and peptide mutation: correlation between mutations in the ame- data analysis, drafted and critically revised the manuscript; C. logenin gene (AMGX) and manifestations of X-linked amelo- Morris, contributed to conception, design, and data analysis, genesis imperfecta. Genomics. 26(1):159–162. drafted the manuscript. All authors gave final approval and agree Murakami C, de Oliveira Lira Ortega A, Guimarães AS, to be accountable for all aspects of the work. Gonçalves-Bittar D, Bönecker M, Ciamponi AL. 2011. Focal dermal hypoplasia: a case report and literature review. Oral Acknowledgments Surg Oral Med Ooral Pathol. 112(2):e11–e18. The authors thank Cynthia Suggs for her support interrogating the Price JA, Bowden DW, Wright JT, Pettenati MJ, Hart TC. 1998. OMIM database. This study was supported by the National Identification of a mutation in DLX3 associated with tricho- Institute of Dental and Craniofacial Research (grant DE016079). dento-osseous (TDO) syndrome. Hum Mol Genet. 7(3):563–569. The authors declare no potential conflicts of interest with respect Schossig A, Wolf NI, Fischer C, Fischer M, Stocker G, Pabinger to the authorship and/or publication of this article. S, Dander A, Steiner B, Tönz O, Kotzot D, et al. 2012. Mutations in ROGDI cause Kohlschutter-Tonz syndrome. Am J Hum Genet. 90(4):701–707. References Sehic A, Risnes S, Khan QE, Khuu C, Osmundsen H. 2010. Gene Aberdam D, Aguzzi A, Baudoin C, Galliano MF, Ortonne JP, expression and dental enamel structure in developing mouse Meneguzzi G. 1994. Developmental expression of nicein incisor. Eur J Oral Sci. 118(2):118–130. adhesion protein (laminin-5) subunits suggests multiple mor- Simmer JP, Fincham AG. 1995. Molecular mechanisms of dental phogenic roles. Cell Adhes Communic. 2(2):115–129. enamel formation. Crit Rev Oral Biol Med. 6(2):84–108. Adaimy L, Chouery E, Megarbane H, Mroueh S, Delague V, Smith CE. 1998. Cellular and chemical events during enamel mat- Nicolas E, Belguith H, de Mazancourt P, Megarbane A. 2007. uration. Crit Rev Oral Biol Med. 9(2):128–161. Mutation in WNT10A is associated with an autosomal reces- Wang SK, Chan HC, Rajderkar S, Milkovich RN, Uston KA, Kim sive ectodermal dysplasia: the odonto-onycho-dermal dyspla- JW, Simmer JP, Hu JC. 2011. Enamel malformations associ- sia. Am J Human Genet. 81(4):821–828. ated with a defined dentin sialophosphoprotein mutation in Aldred MJ, Savarirayan R, Crawford PJ. 2003. Amelogenesis two families. Eur J Oral Sci. 119(Suppl 1):158–167. imperfecta: a classification and catalogue for the 21st century. Wang SK, Reid BM, Dugan SL, Roggenbuck JA, Read L, Aref P, Oral Dis. 9(1):19–23. Taheri AP, Yeganeh MZ, Simmer JP, Hu JC. 2014. FAM20A Arquitt CK, Boyd C, Wright JT. 2002. Cystic fibrosis transmem- mutations associated with enamel renal syndrome. J Dent brane regulator gene (CFTR) is associated with abnormal Res. 93(1):42–48. enamel formation. J Dent Res. 81(7):492–496. Wang X, Reid Sutton V, Omar Peraza-Llanes J, Yu Z, Rosetta Ferrazzano GF, Sangianantoni G, Cantile T, Amato I, Orlando S, R, Kou YC, Eble TN, Patel A, Thaller C, Fang P, et al. Ingenito A. 2012. Dental enamel defects in Italian children 2007. Mutations in X-linked PORCN, a putative regulator with cystic fibrosis: an observational study. Community Dent of Wnt signaling, cause focal dermal hypoplasia. Nat Genet. Health. 29(1):106–109. 39(7):836–838. Gasse B, Karayigit E, Mathieu E, Jung S, Garret A, Huckert M, Wen X, Kurtz I, Paine ML. 2014. Prevention of the disrupted Morkmued S, Schneider C, Vidal L, Hemmerlé J, et al. 2013. enamel phenotype in slc4a4-null mice using explant organ Homozygous and compound heterozygous MMP20 muta- culture maintained in a living host kidney capsule. PLoS One. tions in amelogenesis imperfecta. J Dent Res. 92(7):598–603. 9(5):e97318. Hart PS, Hart TC, Michalec MD, Ryu OH, Simmons D, Hong S, Witkop CJ Jr. 1989. Amelogenesis imperfecta, dentinogenesis Wright JT. 2004. Mutation in kallikrein 4 causes autosomal imperfecta and dentin dysplasia revisited, problems in clas- recessive hypomaturation amelogenesis imperfecta. J Med sification. J Oral Pathol. 17(9–10):547–553. Genet. 41(7):545–549. Wright JT. 2006. The molecular etiologies and associated phe- He P, Zhang Y, Kim SO, Radlanski RJ, Butcher K, Schneider notypes of amelogenesis imperfecta. Am J Med Genet A. RA, DenBesten PK. 2010. Ameloblast differentiation in the 140(23):2547–2555. human developing tooth: effects of extracellular matrices. Wright JT, Fine JD, Johnson LB. 1993. Developmental defects Matrix Biol. 29(5):411–419. of enamel in humans with hereditary epidermolysis bullosa. Hu JC, Yamakoshi Y. 2003. Enamelin and autosomal-dominant ame- Arch Oral Biol. 38(11):945–955. logenesis imperfecta. Crit Rev Oral Biol Med. 14(6):387–398. Wright JT, Hart PS, Aldred MJ, Seow K, Crawford PJ, Hong Klein H. 1975. Dental fluorosis associated with hereditary diabetes SP, Gibson CW, Hart TC. 2003. Relationship of phenotype insipidus. Oral Surg Oral Med Oral Pathol. 40(6):736–741. and genotype in X-linked amelogenesis imperfecta. Connect Koster MI. 2010. p63 in skin development and ectodermal dyspla- Tissue Res. 44(Suppl 1):72–78. sias. J Invest Dermatol. 130(10):2352–2358. Wright JT, Torain M, Long K, Seow K, Crawford P, Aldred MJ, Lacruz RS, Smith CE, Chen YB, Hubbard MJ, Hacia JG, Paine ML. Hart PS, Hart TC. 2011. Amelogenesis imperfecta: geno- 2011. Gene-expression analysis of early- and late-maturation- type-phenotype studies in 71 families. Cells Tissues Organs. stage rat enamel organ. Eur J Oral Sci. 119(Suppl 1):149–157. 194(2–4):279–283.