Genetic epidemiology of tooth agenesis in Japan: a population‐ and family‐based study

Machida, Junichiro; Nishiyama, Takeshi; Kishino, Hirohisa; Yamaguchi, Satoru; Kimura, Masashi; Shibata, Akio; Terada, Tadashi; Kamamoto, Munefumi; Yamamoto, Kara; Makino, Shinya; Miyachi, Hitoshi; Shimozato, Kazuo; Tokita, Yoshihito

doi:10.1111/cge.12456

Cited by 19 publications

(17 citation statements)

References 8 publications

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“…[1][2][3] Isolated oligodontia can be a heritable developmental abnormality with a 0.1% prevalence. 4 It is often linked to a mutation in genes encoding transcriptional factors involved in early steps of odontogenesis (MSX1, PAX9, AXIN2, IRF6), or components of ectodysplasin signaling (EDA, EDAR, EDARADD) or Wnt signaling pathways (WNT10A, LRP5/6).…”

Section: Introductionmentioning

confidence: 99%

Dental and extra‐oral clinical features in 41 patients with WNT10A gene mutations: A multicentric genotype–phenotype study

et al. 2017

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WNT10A gene encodes a canonical wingless pathway signaling molecule involved in cell fate specification as well as morphogenetic patterning of the developing ectoderm, nervous system, skeleton, and tooth. In patients, WNT10A mutations are responsible for ectodermal-derived pathologies including isolated hypo-oligodontia, tricho-odonto-onycho-dermal dysplasia and Schöpf-Schulz-Passarge syndrome (SSPS). Here we describe the dental, ectodermal, and extra-ectodermal phenotypic features of a cohort of 41 patients from 32 unrelated families. Correlations with WNT10A molecular status (heterozygous carrier, compound heterozygous, homozygous) and patient's phenotypes were performed. Mild to severe oligodontia was observed in all patients bearing biallelic WNT10A mutations. However, patients with compound heterozygous mutations presented no significant difference in phenotypes compared with homozygous individuals. Anomalies in tooth morphology were frequently observed with heterozygous patients displaying hypodontia. No signs of SSPS, especially eyelids cysts, were detected in our cohort. Interestingly, extra-ectodermal signs consisted of skeletal, neurological and vascular anomalies, the latter suggesting a wider phenotypic spectrum associated with WNT10A mutations. Indeed, the Wnt pathway plays a crucial role in skeletal development, lipid metabolism, and neurogenesis, potentially explaining patient's clinical manifestations.

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Section: Introductionmentioning

confidence: 99%

Dental and extra‐oral clinical features in 41 patients with WNT10A gene mutations: A multicentric genotype–phenotype study

et al. 2017

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“…Tooth agenesis is classified into two subtypes according to the number of missing teeth: hypodontia (one to five missing teeth, excluding the third molar) and oligodontia (six or more missing teeth, excluding the third molar). Recently, we reported that the prevalences of these two subtypes in the Japanese population are 6.8% (hypodontia) and 0.1% (oligodontia) and that the sibling recurrence risks are 25.0% and 43.8%, respectively, suggesting that the severe phenotype, oligodontia, may be mostly transmitted in a dominant fashion [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

An Aberrant Splice Acceptor Site Due to a Novel Intronic Nucleotide Substitution in MSX1 Gene Is the Cause of Congenital Tooth Agenesis in a Japanese Family

et al. 2015

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Congenital tooth agenesis is caused by mutations in the MSX1, PAX9, WNT10A, or AXIN2 genes. Here, we report a Japanese family with nonsyndromic tooth agenesis caused by a novel nucleotide substitution in the intronic region between exons 1 and 2 of the MSX1 gene. Because the mutation is located 9 bp before exon 2 (c.452-9G>A), we speculated that the nucleotide substitution would generate an abnormal splice site. Using cDNA analysis of an immortalized patient blood cell, we confirmed that an additional 7-nucleotide sequence was inserted at the splice junction between exons 1 and 2 (c.451_452insCCCTCAG). The consequent frameshift generated a homeodomain-truncated MSX1 (p.R151fsX20). We then studied the subcellular localization of truncated MSX1 protein in COS cells, and observed that it had a whole cell distribution more than a nuclear localization, compared to that of wild-type protein. This result suggests a deletion of the nuclear localization signal, which is mapped to the MSX1 homeodomain. These results indicate that this novel intronic nucleotide substitution is the cause of tooth agenesis in this family. To date, most MSX1 variants isolated from patients with tooth agenesis involve single amino acid substitutions in the highly conserved homeodomain or deletion mutants caused by frameshift or nonsense mutations. We here report a rare case of an intronic mutation of the MSX1 gene responsible for human tooth agenesis. In addition, the missing tooth patterns were slightly but significantly different between an affected monozygotic twin pair of this family, showing that epigenetic or environmental factors also affect the phenotypic variations of missing teeth among patients with nonsyndromic tooth agenesis caused by an MSX1 haploinsufficiency.

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“…Interactions involving positive and negative loops among bone morphogenetic protein (BMP), fibroblast growth factors, Sonic hedgehog, and Wnt pathways regulate the morphogenesis of individual teeth (1,4). While the number of teeth is usually strictly controlled in individual species (5), it can increase or decrease congenitally in about 1% of individuals (6)(7)(8). Conditions of decreases and increases in the usual number of teeth are called tooth agenesis and supernumerary teeth, respectively.…”

Section: Introductionmentioning

confidence: 99%

Anti–USAG-1 therapy for tooth regeneration through enhanced BMP signaling

et al. 2021

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Uterine sensitization–associated gene-1 (USAG-1) deficiency leads to enhanced bone morphogenetic protein (BMP) signaling, leading to supernumerary teeth formation. Furthermore, antibodies interfering with binding of USAG-1 to BMP, but not lipoprotein receptor–related protein 5/6 (LRP5/6), accelerate tooth development. Since USAG-1 inhibits Wnt and BMP signals, the essential factors for tooth development, via direct binding to BMP and Wnt coreceptor LRP5/6, we hypothesized that USAG-1 plays key regulatory roles in suppressing tooth development. However, the involvement of USAG-1 in various types of congenital tooth agenesis remains unknown. Here, we show that blocking USAG-1 function through USAG-1 knockout or anti–USAG-1 antibody administration relieves congenital tooth agenesis caused by various genetic abnormalities in mice. Our results demonstrate that USAG-1 controls the number of teeth by inhibiting development of potential tooth germs in wild-type or mutant mice missing teeth. Anti–USAG-1 antibody administration is, therefore, a promising approach for tooth regeneration therapy.

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Genetic epidemiology of tooth agenesis in Japan: a population‐ and family‐based study

Cited by 19 publications

References 8 publications

Dental and extra‐oral clinical features in 41 patients with WNT10A gene mutations: A multicentric genotype–phenotype study

Dental and extra‐oral clinical features in 41 patients with WNT10A gene mutations: A multicentric genotype–phenotype study

An Aberrant Splice Acceptor Site Due to a Novel Intronic Nucleotide Substitution in MSX1 Gene Is the Cause of Congenital Tooth Agenesis in a Japanese Family

Anti–USAG-1 therapy for tooth regeneration through enhanced BMP signaling

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