The Molecular Basis of Hereditary Enamel Defects in Humans

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.

Introduction

Enamel is the hardest mammalian tissue and is derived from the ectodermally derived oral epithelium (Simmer and Fincham 1995). The oral epithelium interacts with the ectomesenchyme through a series of signaling events that result in the epithelial cells differentiating to ameloblasts. Ameloblasts generate the enamel tissue that covers the human dental crown and are responsible for establishing the enamel’s unique composition and structure that account for its remarkable wear, fracture resistance, and insulating properties. This process of amelogenesis is accomplished through a temporally restricted and highly regulated series of events that include development of a specific extracellular matrix, matrix processing, and controlling the microenvironment of the developing enamel tissue (Smith 1998; He et al. 2010; Lacruz et al. 2012). These processes are highly regulated at the molecular level, with amelogenesis ultimately involving thousands of genes and their products (Sehic et al. 2010; Lacruz et al. 2011). Not unexpectedly, these processes involve numerous developmental and regulatory pathways that could lead to abnormal enamel development and pathology.

Some of the processes requisite for enamel formation are likely sensitive to perturbations leading to abnormal ameloblast functions. For example, abnormal secretion and processing of the enamel extracellular matrix result from different allelic and nonallelic mutations (Lagerstrom-Fermer et al. 1995; Hu and Yamakoshi 2003; Hart et al. 2004; Gasse et al. 2013). Phenotypes resulting from the altered gene expression and gene products are varied and can affect the amount, structure, and/or composition of enamel (Wright 2006). One would predict that the enamel phenotypes will be determined by the specific genetic mutation, the nature of the mutation and changes in the derived protein, the function of the protein, and the temporal and spatial expression of the protein (Wright et al. 2003). Molecular defects can alter enamel development by directly affecting gene expression of the enamel forming cells (e.g., ameloblasts secrete an abnormal matrix) or secondarily or indirectly where the gene may not be expressed by ameloblasts but the resulting changes influence enamel formation (e.g., systemic changes in pH regulation). Genetic mutations can directly affect the oral epithelium, thereby altering the differentiation or function of the ameloblasts or adjacent supporting cells (e.g., stratum intermedium). For example, junctional epidermolysis bullosa (Online Mendelian Inheritance of Man [OMIM] 226700, 226650) is associated with enamel hypoplasia secondary to abnormal laminin 5 formation that is critical for cell attachment (Wright et al. 1993; Aberdam et al. 1994). There are many syndromes caused by genes that are expressed by the oral epithelium and ameloblasts and that have an associated enamel phenotype. Transient expression of a gene and its altered protein (e.g., dentin sialophosphoprotein expression by preameloblasts) can be associated with abnormal enamel formation (Wang et al. 2011). Genes coding for proteins important for enamel formation have diverse functions. Mutations in these genes produce changes affecting molecular pathways, resulting in a variety of enamel phenotypes, such as a deficiency in amount (hypoplasia), a change in composition (e.g., hypomineralization), or a change in structure.

Genetic alterations also can affect enamel formation through secondary actions or distresses that do not involve ameloblast dysfunction caused by gene expression of the ameloblast. Through a variety of diverse processes, genes that are transiently or not expressed by ameloblasts can result in altered enamel development. Genes expressed by the ectomesenchyme or its derived odontoblast cells appear to be critical for signaling the ameloblasts, and abnormalities in this process could result in aberrant ameloblast function. This may well occur in certain cases of dentinogenesis imperfecta type II (OMIM 125490) caused by DSPP mutations that display enamel defects in addition to the more typical dentin defects. Interrogation of databases of human mutations can provide insights into the molecular etiologies associated with developmental defects of human teeth. The database OMIM provides a valuable resource of regularly updated genetic and phenotype information on hereditary human conditions. The OMIM database is updated regularly and is organized to help delineate the mode of inheritance and to facilitate practitioners searching for current information on hereditary conditions. The database includes hereditary conditions with known phenotypes and includes information related to genes that are not currently associated with a phenotype (e.g., tuftelin, ameloblastin). The purpose of this investigation was to explore our current understanding of the molecular mechanisms and the developmental pathways involved in the formation of enamel defects in humans. This knowledge will not only help explain how certain enamel phenotypes develop but also provide a framework for grouping or classifying these conditions based on the molecular defect and the resulting functional change.

Methods

The OMIM database (http://www.ncbi.nlm.nih.gov/omim/) was interrogated for genes or known hereditary conditions listing any phenotype with an enamel component. The database was searched with the terms amelogenesis, enamel, dental, and tooth. All results were screened by 2 individuals to determine if an enamel phenotype was identified. Positive hits were interrogated regarding the nature and phenotype of the enamel defect by review of articles cited in OMIM. The primary outcome measured was enamel phenotype. Genes associated with enamel formation but not associated with an enamel phenotype were not included. The purported function of each gene and its protein were searched in OMIM. Additional articles from PubMed were pulled to help ascertain the function of the different genes and their products associated with known enamel malformations. The search was completed August 30, 2014.

Results

Interrogation of the OMIM database revealed responses when it was searched via tooth (n = 958), dental (n = 677), enamel (n = 162), and amelogenesis (n = 47). Further interrogation of these citations revealed 91 conditions listed in OMIM that had an enamel phenotype. The most common enamel phenotype was a deficient amount of enamel or enamel hypoplasia with hypomineralization defects being less commonly reported. Dysplastic enamel was described for many cases, but it was not defined regarding the exact nature of the defect. The data presented in the tables represent the enamel phenotype descriptions provided in OMIM. While the different designations of enamel defects can be confusing (e.g., dysplastic, hypomineralized, hypocalcified, hypomaturation), we did not attempt to presume that we could cluster these disparate phenotypes even when we referred to the original publications to help clarify the phenotype. Of the 91 conditions with a described enamel phenotype, 71 had a known molecular etiology or linked genetic loci listed in the OMIM database (Table 1). The molecular basis of 23% of the hereditary enamel defects was unknown or not listed on OMIM. The purported protein function of those conditions with a known genetic basis included enzymes, regulatory proteins, extracellular matrix proteins, transcription factors, transmembrane proteins, and a variety of other proteins with diverse functions (Fig.). Functionality of the protein products of genes associated with each hereditary enamel defect identified on OMIM was further interrogated (OMIM, PubMed search) regarding its putative role in enamel formation (Table 2). Despite extensive research, the role of these diverse gene products in enamel formation remain, for the most part, poorly understood.

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 hypoplastic	ECM secreted by ameloblasts
104510	Amelogenesis imperfecta, type IV; AI4	DLX3	TDO	Transcription factor
104530	Amelogenesis imperfecta, hypoplastic type	nk	Hypoplastic—failure to erupt and calcification of pulp	nk
130900	Amelogenesis imperfecta, type III; AI3	FAM83H	Localized or generalized hypomineralized enamel	nk
Autosomal recessive
204650	Amelogenesis imperfecta, type IC; AI1C	ENAM	Generalized hypoplastic	ECM secreted by ameloblasts
204700	Amelogenesis imperfecta, hypomaturation type, IIA1; AI2A1	KLK4	Normal enamel thickness—hypomineralized orange brown color	Maturation stage enamel proteinase
612529	Amelogenesis imperfecta, hypomaturation type, IIA2; AI2A2	MMP20	Normal enamel thickness—hypomineralized orange brown color	Secretory stage enamel proteinase
613211	Amelogenesis imperfecta, hypomaturation type, IIA3; AI2A3	WDR72	Hypomaturation creamier, opaque enamel upon eruption. discoloration and loss of tissue posteruption	nk
614253	Amelogenesis imperfecta and gingival fibromatosis syndrome	FAM20A	Generalized hypoplastic and failure of tooth eruption, gingival hypertrophy	nk
614832	Amelogenesis imperfecta, hypomaturation type, IIA4; AI2A4	C4ORF26	Hypomaturation AI	May encode an extracellular matrix acidic phosphoprotein
615887	Amelogenesis imperfecta hypomaturation type 1A5	SLC24A4	Hypomaturation AI	Na/K exchanger
X-linked
301200	Amelogenesis imperfecta, type IE; AI1E	AMELX	Hypoplasia, hypomaturation depending on mutation and protein effect	ECM secreted by ameloblasts
301201	Amelogenesis imperfecta, hypoplastic/hypomaturation, x-linked 2	Xq22-q28	Enamel hypoplasia and hypomaturation	nk
Syndrome-associated enamel defects
Autosomal dominant
103580	Pseudohypoparathyroidism, type IA; PHP1A	GNAS	Enamel hypoplasia	Transcription factor
104570	Ameloonychohypohidrotic syndrome	nk	Enamel hypoplasia, hypomineralization	nk
119600	Cleidocranial dysplasia	RUNX2	Enamel hypoplasia, failure of exfoliation of the primary dentition	Nuclear protein transcription factors
125500	Dentinogenesis imperfecta, shields type III	DSPP	Enamel hypoplasia, aplasia and pitting	Two proteins associated with biomineralization of teeth
129540	Ectodermal dysplasia syndrome with distinctive facial appearance and preaxial polydactyly of feet	nk	Thin dental enamel	nk
133705	External auditory canal, bilateral atresia of, with congenital vertical talus	nk	Dysplastic enamel	nk
146300	Hypophosphatasia, adult	ALPL	Enamel hypoplasia	Membrane bound glycosylated enzyme
149730	Lacrimoauriculodentodigital syndrome	FGFR2; FGFR3, FGFR10	Enamel dysplasia, peg shaped lateral incisors	Polypeptide growth 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 gene	Enamel hypoplasia	Component of gap junctions
166750	Otodental dysplasia	FGF3	Enamel defects, enlarged canines and molars	Growth factor associated with mitogenic and cell survival activities
173650	Kindler syndrome	KIND1	Enamel hypoplasia, dental caries	Structural protein
180500	Axenfeld-rieger syndrome, type 1; RIEG1	PITX2; FOXC1	Enamel hypoplasia, conical and misshapen teeth, hypodontia, and impactions	Bicoid class of homeodomain transcription factors
180849	Rubinstein-taybi syndrome	CREBBP; EP300	Enamel hypoplasia, discoloration and wear	Transcriptional coactivation of many different transcription factors
180849	Rubinstein-taybi syndrome 1	CREBBP	Enamel hypoplasia, discoloration, hypodontia, talon cusps, screwdriver permanent incisors, enamel wear	Transcriptional coactivator CREB-binding protein
182290	Smith-magenis syndrome	3.7-Mb deletion 17p11.2; RAI1	Enamel hypoplasia, hypomineralized enamel	Regulatory proteins (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 cleft lip/palate syndrome 3	TP63	Enamel hypoplasia and hypodontia	Transcription factors
612463	Pseudopseudo-hypoparathyroidism	GNAS	Enamel hypoplasia	Regulatory proteins
612843	Keratosis follicularis spinulosa decalvans	nk	Enamel hypoplasia	nk
614564	Cutaneous telangiectasia and cancer syndrome, familial	ATR	Thin discolored enamel and dental caries	Regulator of genomic integrity; kinase enzyme
Autosomal recessive
202900	Alaninuria with microcephaly, dwarfism, enamel hypoplasia, and diabetes mellitus	nk	Enamel hypoplasia	nk
203550	Alopecia-contractures-dwarfism mental retardation syndrome	nk	Enamel dysplasia and caries	nk
204690	Enamel-renal syndrome	FAM20A	Enamel hypoplasia, anodontia of permanent teeth	nk
207780	Aredyld	nk		nk
210600	Seckel syndrome 1	ATR	Enamel hypoplasia	Kinase enzyme
211900	Tumoral calcinosis, hyperphosphatemic, familial	GALNT3;FGF23; KL	Hypoplastic teeth with fully developed enamel	Catalytic enzyme; 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 amelogenesis imperfecta	Role in metal ion transport
224300	Dysosteosclerosis	nk	Hypomineralized enamel (chalky), delayed eruption of primary teeth	nk
225410	Ehlers-danlos syndrome, type VII, autosomal recessive	ADAMTS2	Excises the N-propeptide of type I and type II procollagens. NPI enzyme is a metalloproteinase	Enzyme that excises the N-propeptide of type I, type II and type V procollagens
225500	Ellis-van creveld syndrome	EVC1; EVC2	Enamel hypoplasia, conical shaped teeth, premature eruption of primary teeth	nk
226440	Epidermolysis bullosa, late-onset localized junctional, with mental retardation	nk	Enamel hypoplasia	nk
226600	Epidermolysis bullosa dystrophica, autosomal recessive	COL7A1	Generalized enamel hypoplasia	Collagen beneath stratified squamous epithelia
226650	Epidermolysis bullosa, junctional, non-herlitz type	COL17A1;LAMA3; LAMB3;LAMC2; ITGB4	Enamel hypoplasia	Components of hemidesmosomes important for cell attachment
226670	Epidermolysis bullosa simplex with muscular dystrophy	PLEC1	Enamel hypoplasia	Intermediate filament-binding protein
226700	Epidermolysis bullosa, junctional, herlitz type	LAMA3; LAMB3; LAMC3	Enamel hypoplasia	Cell adhesion, signal transduction and differentiation of keratinocytes
226730	Epidermolysis bullosa junctionalis with pyloric atresia	ITGB4; ITGA6	Enamel hypoplasia	Transmembrane 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 enamel hypoplasia and nail defects	nk	Hypomineralized enamel	nk
240300	Autoimmune polyendocrine syndrome, type I; APS1	AIRE	Enamel hypoplasia	Autoimmune regulator gene and transcriptional activator
241510	Hypophosphatasia, childhood	ALPL	Enamel hypoplasia, odontohypophosphatasia	Membrane bound 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 herlitz EB	Cell adhesion ligand for integrins
251190	Microcephalic primordial dwarfism, toriello type	nk	Enamel hypoplasia	nk
253000	Morquio syndrome a	GALNS	Enamel hypoplasia; pitted and reduced thickness	Lysosomal enzyme involved in the catabolism of keratin and chondroitin sulfate
253010	Morquio syndrome b	GLB1	Enamel hypoplasia	Lysosomal enzyme
257850	Oculodentodigital dysplasia, autosomal recessive	GJA1	Enamel hypoplasia	codes CONNEXIN 43 a 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 rickets, type 1A	CYP27B1	Enamel discoloration permanent teeth	Catalytic enzyme
601539	Peroxisome Biogenesis Disorder	PEX1, PEX2, PEX26	Enamel hypoplasia	ATPase enzymes
270200	Sjogren-larsson syndrome	ALDH3A2	Enamel hypoplasia	Catalytic enzyme
275450	Trichoodontoonychial dysplasia	nk	Enamel hypoplasia, anodontia	nk
277440	Vitamin d-dependent rickets, type 2A; VDDR2A	VDR	Dental anomalies	Hormone receptor
601216	Platyspondyly with amelogenesis imperfecta	nk	Enamel hypoplasia and hypodontia, discolored enamel	nk
601701	Arthrogryposis and ectodermal dysplasia	nk	Enamel abnormalities	nk
604278	Renal tubular acidosis, proximal, with ocular abnormalities and mental retardation	SLC4A4	Enamel hypoplasia	Sodium bicarbonate cotransporter, regulator
605472	Usher syndrome, type IIC; USH2C	GPR98, PDZD7	Enamel hypoplasia	Transmembrane receptor
607626	Ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis	CLDN1	Enamel dysplasia	Claudin-1 is a tight-junction protein
610319	Rhizomelic dysplasia, scoliosis, and retinitis pigmentosa	nk	Amelogenesis imperfecta mentioned, hypomaturation	nk
611174	Hypertelorism, severe, with midface prominence, myopia, mental retardation, and bone fragility	IRX5	Enamel hypoplasia	Gene regulation; involved in several embryonic developmental processes
612783	Immune dysfunction with t-cell inactivation due to calcium entry defect 2	STIM1	Enamel defect	Calcium sensor that conveys the calcium load of the endoplasmic reticulum
X-linked				nk
302350	Nance-horan syndrome	NHS	Enamel hypoplasia, supernumerary teeth and screwdriver incisors	Vasopressin receptor
304800	Diabetes insipidus, nephrogenic, x-linked	AVPR2	Hypomineralized enamel	Endoplasmic reticulum transmembrane protein
305600	Focal dermal hypoplasia	PORCN	Enamel hypoplasia	transmembrane endopeptidase
307800	Hypophosphatemic rickets, x-linked dominant	PHEX	Enamel hypoplasia	Protease functioning in the signal protein activation
308205	Ichthyosis follicularis, atrichia, and photophobia syndrome	MBTPS2	Enamel dysplasia	Membrane-embedded zinc metalloprotease that activates signaling proteins
308205	Ifap syndrome with or without bresheck syndrome	MBTPS2	Enamel dysplasia	Phosphatase enzyme
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 aqueductal stenosis	nk	Enamel hypoplasia of the hypomaturation-hypocalcification type	Tumor suppressor by activation of GPTases
603641	Neuroendocrine carcinoma of salivary glands, sensorineural hearing loss, and enamel hypoplasia	nk	Enamel hypoplasia	Contiguous gene deletion syndrome; regulatory protein (inhibitor)
613254	Tuberous sclerosis 2	TSC2	Enamel hypoplasia	ECM secreted by ameloblasts
613675	Chromosome 17q11.2 deletion syndrome, 1.4-MB	17q11.2; NF1	Enamel hypoplasia	Transcription factor

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.

Figure.

The putative protein function of gene products affecting enamel indicated that extracellular matrix proteins and enzymes accounted for about 30% of conditions, about 20% were regulatory proteins or transcription factors, and about 14% were transmembrane or other proteins.

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 keratin and chondroitin sulfate	Enamel hypoplasia; pitted and reduced thickness
GLB1	Unknown	Enamel hypoplasia
CYP27B1	Catalytic enzyme forming biologically active vitamin D	Enamel discoloration permanent teeth
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 differentiation of keratinocytes	Enamel hypoplasia
GJA1	Codes CONNEXIN 43 a major protein of gap junctions	Enamel hypoplasia
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 of activities, including mitogenesis, angiogenesis, and wound healing	Enamel dysplasia, peg shaped lateral incisors
FGF3	Growth factor associated with mitogenic and cell survival activities	Enlarged canines and molars
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 present during maturation stage	Enamel hypoplasia, hypodontia
3.7-Mb deletion 17p11.2; RAI1	Unknown	Enamel hypoplasia
	Unknown	Enamel hypomineralization
AIRE	Unknown	Enamel hypoplasia
TSC2	Unknown	Enamel hypoplasia
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 formation	Enamel hypoplasia
PITX2; FOXC1	Bicoid class of homeodomain transcription factors	Enamel hypoplasia, conical and misshapen teeth, hypodontia
TP63	Regulates expression of genes important to enamel formation	Enamel hypoplasia and hypodontia
DLX3	Regulates expression of genes important to enamel formation	Enamel hypoplasia
Transmembrane protein
COL7A1	May play role in ameloblast differentiation interactions	Enamel hypoplasia
COL17A1; LAMA3; LAMB3; LAMC2	Components of hemidesmosomes important for cell attachment	Enamel hypoplasia
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 the endoplasmic reticulum	Enamel hypoplasia
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-binding phosphoprotein	Enamel dysplasia
FAM20A	Kinase that phosphorylates proteins important to amelogenesis	Enamel hypoplasia
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.

There were multiple conditions with the term amelogenesis imperfecta identified in the search. The conditions including the term amelogenesis involved nonsyndromic enamel conditions, traditionally referred to as amelogenesis imperfectas, and syndromic conditions affecting tissues or organs in addition to the enamel phenotype (Table 1). Syndromes with an associated enamel phenotype had a variety of other manifestations involving the brain, eyes, kidney, skin, and other tissues and organs depending on the condition. Delineation of hereditary enamel defects as nonsyndromic and syndromic conditions can be problematic due to overlapping phenotypes and multiple listings for disorders caused by allelic mutations (e.g., DLX3 mutations). Here we present these conditions separately in the tables, as this classification approach is still recognized by most clinicians and this is how the conditions are presented in OMIM.

Discussion

The number and functional diversity of genes associated with hereditary enamel defects and the molecular pathways involved is not surprising given the complexity of enamel development. Despite the diversity of molecular defects, the most common phenotype described in our OMIM query was enamel hypoplasia. The specific enamel phenotype is often not described in any detail in OMIM or in the manuscripts reviewed from PubMed. It is not surprising that alterations in a variety of pathways can lead to a phenotype of enamel hypoplasia given the sensitivity and exquisite regulation of the amelogenesis processes. Future studies directed at detailed phenotype characterization of hereditary enamel defects will provide clues regarding the role of genes, proteins, and pathways involved in enamel formation.

The classification of developmental enamel defects has been reviewed and modified for more than 70 years. A 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 understating 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 nonsyndromic amelogenesis imperfecta). These 10 genes allow molecular diagnosis of the majority of amelogenesis imperfecta cases; however, there remain individuals with enamel defects that have as yet to be identified genetic mutations that cause the amelogenesis imperfecta phenotype (Wright et al. 2011). One of the genes listed on OMIM as an amelogenesis imperfecta with gingival fibromatosis (OMIM 614253), FAM20A, is now known to be causative of enamel-renal syndrome (OMIM 204690; Wang et al. 2014). These 2 conditions are listed separately on OMIM but appear to be the same entity. In some conditions, such as Kolschutters-Tonz syndrome (OMIM 226750, gene ROGDI), the enamel phenotype appears quite similar to the hypomineralized forms of amelogenesis imperfecta (Schossig et al. 2012). The pathologic mechanism of this neurologic condition and function of the ROGDI gene product remain unknown, but one could speculate that the causative gene is expressed by ameloblasts and that its protein plays a critical role in enamel biomineralization. While the genes are known for many hereditary enamel defects, the protein function and specific mechanisms involved with these conditions remain poorly understood. Future classification of hereditary enamel defects should include organization around the phenotype, mode of inheritance, molecular defect, and protein function and its role in enamel formation or pathologic mechanism. Such a classification system would provide a robust organizational approach that would offer a logical and informative clustering of the diverse hereditary enamel conditions.

Many genetic alterations affect development of epithelial derivatives and can have associated alterations in dental formation, as the oral epithelium is critical to tooth bud initiation. A classic example is the ectodermal dysplasias that are frequently associated with hypodontia and, in some cases, enamel defects (e.g., ectrodactyly, ectodermal dysplasia, and cleft lip/palate; OMIM 604292). Genes that are critical for early tooth formation events, such as invagination and proliferation of the oral epithelium, can result in hypodontia or missing teeth. Such is indeed the case with x-linked hypohidrotic ectodermal dysplasias (OMIM 305100). Mutations affecting genes involving the WNT pathway can be associated with both hypodontia and enamel hypoplasia characterized by thin or pitted enamel (e.g., focal dermal hypoplasia; OMIM 305600; Wang et al. 2007). Because of these genes’ roles in epithelium development, they are associated with many developmental perturbations of ectodermally derived appendages. Table 1 lists those OMIM conditions and the known genes and their purported protein functions related to epithelial growth and development (e.g., KIND1, PORCN, TP63).

Numerous other critical developmental pathways affect epithelium and are associated with enamel defects. For example, the WNT10A, TP63, PORCN, and DLX3 genes are all associated with syndromes that have abnormal ectodermal appendage development and can have defective enamel formation (Price et al. 1998; Adaimy et al. 2007; Wang et al. 2007; Koster 2010). Given that the genes and gene products can be interactive (PORCN and WNT, TP63 and DLX3), it is not surprising that similar developmental defects and phenotypes might occur. Mutations in the PORCN gene are associated with the focal dermal hypoplasia syndrome (OMIM 305600). Focal dermal hypoplasia syndrome is known to have a marked enamel hypoplasia phenotype, but the OMIM description only notes hypoplastic teeth (Murakami et al. 2011). Genetic mutations affecting epithelial integrity can also be associated with developmental enamel defects (e.g., laminin 5; Aberdam et al. 1994). Maintaining an intact sheath of ameloblasts is essential for controlling the microenvironment critical for enamel biomineralization. The ameloblasts control the enamel matrix microenvironment’s ion content, pH, and water content through the expression of numerous genes. Some of these genes are associated with enamel defects, such as the CFTR gene, which codes for the cystic fibrosis conductance transmembrane regulator (Ferrazzano et al. 2012). Mutations in CFTR cause cystic fibrosis (OMIM 219700), and although enamel defects are reported in about half of affected individuals (Ferrazzano et al. 2012), an enamel phenotype is not described in the OMIM database. Not only is this ion channel critical as a chloride ion channel, but it also plays a role in pH modulation (Arquitt et al. 2002). Humans with SLC4A4 mutations (codes for electrogenic sodium base transporter—an important pH regulator; OMIM 3604278) have abnormal enamel development. Recent animal studies indicate that mutations in this gene are associated with proximal tubular acidosis resulting in a systemic acidosis that secondarily causes the defective enamel formation (Wen et al. 2014). This is another example of a genetic mutation secondarily causing an enamel malformation (e.g., systemic acidosis). Nephrogenic diabetes insipidus (OMIM 304800; gene mutations in AVPR2) is associated with a fluorotic enamel phenotype that occurs secondarily to the inability of the renal collecting duct to respond to antidiuretic hormone and the resulting polyuria and polydipsia (Klein 1975).

The list of genes associated with enamel defects has grown tremendously over the past decade. The molecular pathways involved in the development of enamel defects are diverse, and the functionality of the genes and gene products is heterogeneous. Syndrome-associated enamel defects are caused by many genes that affect other tissues, including eye, kidney, brain, and skin, to name just a few. Identification of the genes associated with developmental defects of enamel has been extremely informative in helping advance our knowledge of the molecular control of enamel formation and how genes and gene products can have diverse functions in different tissues. Review of the OMIM database reveals that the phenotype characterization of enamel defects is incomplete and future studies providing more detailed phenotypic evaluation of enamel malformations are needed. Advancing our understanding of the enamel phenotypes, protein function, and developmental pathways will assist in developing a logical and more useful classification system of hereditary enamel disorders.

Author Contributions

J.T. Wright, I.A. Carrion, contributed to conception, design, and data analysis, drafted and critically revised the manuscript; C. Morris, contributed to conception, design, and data analysis, drafted the manuscript. All authors gave final approval and agree to be accountable for all aspects of the work.