Dental agenesis is the most common developmental anomaly in humans and is frequently associated with several other oral abnormalities. Whereas the incidence of missing teeth may vary considerably depending on dentition, gender, and demographic or geographic profiles, distinct patterns of agenesis have been detected in the permanent dentition. These frequently involve the last teeth of a class to develop (I2, P2, M3) suggesting a possible link with evolutionary trends. Hypodontia can either occur as an isolated condition (non-syndromic hypodontia) involving one (80% of cases), a few (less than 10%) or many teeth (less than 1%), or can be associated with a systemic condition or syndrome (syndromic hypodontia), essentially reflecting the genetically and phenotypically heterogeneity of the condition. Based on our present knowledge of genes and transcription factors that are involved in tooth development, it is assumed that different phenotypic forms are caused by different genes involving different interacting molecular pathways, providing an explanation not only for the wide variety in agenesis patterns but also for associations of dental agenesis with other oral anomalies. At present, the list of genes involved in human non-syndromic hypodontia includes not only those encoding a signaling molecule (TGFA) and transcription factors (MSX1 and PAX9) that play critical roles during early craniofacial development, but also genes coding for a protein involved in canonical Wnt signaling (AXIN2), and a transmembrane receptor of fibroblast growth factors (FGFR1). Our objective was to review the current literature on the molecular mechanisms that are responsible for selective dental agenesis in humans and to present a detailed overview of syndromes with hypodontia and their causative genes. These new perspectives and future challenges in the field of identification of possible candidate genes involved in dental agenesis are discussed.

Dental agenesis: genetic and clinical perspectives

Tooth agenesis or hypodontia, failure to develop all normally developing teeth, is one of the most common developmental anomalies in man. Common forms, including third molar agenesis and hypodontia of one or more of the incisors and premolars, constitute the great majority of cases. They typically affect those teeth that develop latest in each tooth class and these teeth are also most commonly affected in more severe and rare types of tooth agenesis. Specific vulnerability of the last developing teeth suggests that agenesis reflects quantitative defects during dental development. So far molecular genetics has revealed the genetic background of only rare forms of tooth agenesis. Mutations in MSX1, PAX9, AXIN2 and EDA have been identified in familial severe agenesis (oligodontia) and mutations in many other genes have been identified in syndromes in which tooth agenesis is a regular feature. Heterozygous loss of function mutations in many genes reduce the gene dose, whereas e.g. in hypohidrotic ectodermal dysplasia (EDA) the complete inactivation of the partially redundant signaling pathway reduces the signaling centers. Although these mechanisms involve quantitative disturbances, the phenotypes associated with mutations in different genes indicate that in addition to an overall reduction of odontogenic potential, tooth class-specific and more complex mechanisms are also involved. Although several of the genes so far identified in rare forms of tooth agenesis are being studied as candidate genes of common third molar agenesis and incisor and premolar hypodontia, it is plausible that novel genes that contribute to these phenotypes will also become identified.

Genetic basis of tooth agenesis

The focus of this work is to highlight the most recent advances in the understanding of cleft lip and palate occurrence. Information regarding research on long-term outcomes, genes and their interactions with other genes, and gene-environment interactions is compiled to provide the reader with a critical and up-to-date overview on the current knowledge of the etiology of cleft lip and palate. Recent epidemiological evidence strongly suggests that individuals born with clefts have a shorter lifespan and may have a higher incidence of cancer and psychological disorders. IRF6 has been shown to be an important contributor to cleft lip and palate, but the functional variant leading to the defect has not yet been defined. Inactivation of MSX1 and genes in the FGF family has also been shown to lead to cleft lip and palate. In addition, missense mutations in several candidate genes may cause cleft lip and palate, but definitive evidence regarding the biological consequences of these mutations is yet to be unraveled. Maternal cigarette smoking increases the risk of a baby born with clefts, in particular when the mother carries the GSTT1-null variants. The latest approaches in cleft research include the analysis of several additional phenotypical features of the population, with the goal of increasing the statistical power of genetics studies.

Unraveling Human Cleft Lip and Palate Research

The genetic basis of inherited anomalies of the teeth: Part 1: Clinical and molecular aspects of non-syndromic dental disorders

Tooth agenesis may originate from either genetic or environmental factors. Genetically determined hypodontic disorders appear as isolated features or as part of a syndrome. Msx1, Pax9, and Axin2 are involved in non-syndromic hypodontia, while genes such as Shh, Pitx2, Irf6, and p63 are considered to participate in syndromic genetic disorders, which include tooth agenesis. In dentistry, artificial tooth implants represent a common solution to tooth loss problems; however, molecular dentistry offers promising solutions for the future. In this paper, the genetic and molecular bases of non-syndromic and syndromic hypodontia are reviewed, and the advantages and disadvantages of tissue engineering in the clinical treatment of tooth agenesis are discussed.

Tooth Agenesis: from Molecular Genetics to Molecular Dentistry

We sincerely thank the family members who participated in this study. The Pakistan Science Foundation provided the support necessary for M.A. to visit the family members. This work was supported, in part, by National Institutes of Health–National Human Genome Research Institute grant HG-00008 (to J.O.) and by a grant from the National Institutes of Health–National Institute of Arthritis, Musculoskeletal and Skin Diseases, Skin Disease Research Center (to J.O. and A.M.C.).

A locus for autosomal recessive hypodontia with associated dental anomalies maps to chromosome 16q12.1.

Tooth agenesis constitutes the most common anomaly of dental development in humans. In the majority of familial cases of hypodontia alone or in association with other anomalies, the mode of inheritance is autosomal dominant. In the present study, we have identified two distantly related consanguineous Pakistani kindreds with an autosomal recessive form of oligodontia with associated dental anomalies. Locus in this case has been mapped on chromosome 4p16.1–p16.3. The maximum two-point LOD score of 2.85 (θ=0.0) was obtained at markers D4S2925 and D4S2285. A maximum multipoint LOD score exceeding 4 was obtained at the same markers. Recombination events observed in affected individuals localized the disease locus between markers D4S412 and D4S2935, spanning a 9.24-cM region on chromosome 4p16.1–p16.3. Sequence analysis of candidate gene MSX1 revealed a novel recessive missense mutation resulting in substitution of alanine to threonine amino acid (p. A219T), located in the MSX1 homeodomain, which is important for DNA binding and protein–protein interaction. The mutation, p. A219T, is the first recessive mutation identified in MSX1.

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A novel missense mutation in MSX1 underlies autosomal recessive oligodontia with associated dental anomalies in Pakistani families

Thonus garhwaliensis sp.n. has 107-1.13mm long body; a = 28–29; b = 3.7–4.0. c = 66–11; V == 56–59; odontostyle = 15–16 μm; odontophore = 18–19 μm; spicules = 37–38 μm long, 10 closely spaced ventromedian supplements and a short hemispheroid tail. T. cylindricus is reported for the first time from India.

Mahmud Haider

Papers

A locus for autosomal recessive hypodontia with associated dental anomalies maps to chromosome 16q12.1.

A novel missense mutation in MSX1 underlies autosomal recessive oligodontia with associated dental anomalies in Pakistani families

A new and a known species of Thonus Thorne, 1974 (Aporcelaimidae: Dorylaimida) from India