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 18 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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“…Congenital tooth agenesis is one of the most common anomalies in human development, which is highly heritable and observed in the general population with racial/ethnic difference in prevalence of 0.08–0.16%. 1–3 It has been identified some homeodomain transcription factor cording genes as genetic causes of isolated tooth agenesis, such as MSX1 [OMIM 142983], 4 and PAX9 [OMIM 167416]. 5 In addition to these homeoprotein transcription factors, haploinsufficiency of WNT signaling-related molecules including wingless-type MMTV integration site family, member 10A ( WNT10A ) [OMIM150400], 6–8 the axis inhibitor 2 ( AXIN2 ) [OMIM 608015], 9 and low-density lipoprotein receptor-related protein 6 ( LRP6 ) [OMIM 616724] cause human tooth agenesis.…”

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confidence: 99%

WNT10A variants isolated from Japanese patients with congenital tooth agenesis

et al. 2017

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It has been reported that dozens of WNT10A variants are associated with human isolated tooth agenesis, however, little is known about the precise phenotypes. In 50 Japanese patients with severe congenital tooth agenesis, we identified 11 patients with WNT10A variants. Comparing phenotypes between the tooth agenesis patients carrying the wild-type and variants of WNT10A, we revealed that the development of lateral incisors is relatively susceptive to insufficiency of WNT/β-catenin signaling.

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

Cited by 18 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

WNT10A variants isolated from Japanese patients with congenital tooth agenesis

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