<i>GREM2</i> nucleotide variants and the risk of tooth agenesis

Mostowska, Adrianna; Biedziak, Barbara; Zadurska, Małgorzata; Bogdanowicz, Agnieszka; Olszewska, Aneta; Cieślińska, Katarzyna; Firlej, Ewa; Jagodzińśki, Paweł P.

doi:10.1111/odi.12793

Cited by 12 publications

(10 citation statements)

References 52 publications

(71 reference statements)

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“…GREM2 variants were suggested as likely pathogenic for tooth agenesis and other dental anomalies such as taurodontism and microdontia, although incomplete penetrance and variable expressivity even within the same families were reported . Our association findings also support a role for this gene in isolated tooth agenesis and tooth development.…”

Section: Discussionsupporting

confidence: 66%

Further evidence for the role of WNT10A, WNT10B and GREM2 as candidate genes for isolated tooth agenesis

Magruder

Carter

Williams

et al. 2018

Orthod Craniofacial Res

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Objective: To investigate the association of single nucleotide variants in the candidate genes WNT10A, WNT10B and GREM2 with isolated tooth agenesis. Setting and sample population:A total of 435 Caucasian individuals (88 cases with isolated tooth agenesis and 347 unrelated controls) were ascertained at the University of Texas Health Science Center at Houston School of Dentistry. Clinical and radiographic examination by orthodontists confirmed the diagnosis of tooth agenesis. Genetic evaluation excluded syndromic forms of tooth agenesis. Materials and methods: Saliva samples were collected as source of genomic DNA.Fourteen variants in/nearby WNT10A, WNT10B and GREM2 were genotyped to test for association with tooth agenesis. Genotyping was performed using TaqMan chemistry in a real-time polymerase chain reaction assay. Allelic and haplotype frequencies were compared among cases and controls using chi-square tests as implemented in PLINK v.1.06. Bonferroni correction was used and P ≤ 0.004 indicates statistical differences between groups.Results: Significant associations were found between individual SNPs and SNP combinations in WNT10A, WNT10B and GREM2 SNPs with isolated tooth agenesis (P < 0.004). Conclusion:Our findings further support a role for variants in WNT10A, WNT10Band GREM2 genes in the aetiology of isolated tooth agenesis. Functional studies are necessary to investigate the biological effects of these gene variants in tooth agenesis phenotypes. K E Y W O R D S association, GREM2, tooth agenesis, WNT10A, WNT10B S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section at the end of the article. How to cite this article: Magruder S, Carter E, Williams MA, English J, Akyalcin S, Letra A. Further evidence for the role of WNT10A, WNT10B and GREM2 as candidate genes for isolated tooth agenesis. Orthod Craniofac Res. 2018;21:258-263. https://doi.

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Section: Discussionsupporting

confidence: 66%

Further evidence for the role of WNT10A, WNT10B and GREM2 as candidate genes for isolated tooth agenesis

Magruder

Carter

Williams

et al. 2018

Orthod Craniofacial Res

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“…ATF1 , WNT10B and GREM2 were recently suggested as candidate genes for TA, 5,8,16 and replicated in independent studies 4,17,18 . In this study, we assessed the potential allele‐specific effects of the TA‐associated variants ATF1 rs11169552, WNT10B rs833843 and GREM2 rs1414655, located in the regulatory regions of their respective genes.…”

Section: Discussionmentioning

confidence: 94%

Functional characterization of ATF1, GREM2 AND WNT10B variants associated with tooth agenesis

Williams

Zeng

Chiquet

et al. 2021

Orthod Craniofacial Res

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Objective To determine the functional effects of ATF1, WNT10B and GREM2 gene variants identified in individuals with tooth agenesis (TA). Settings and sample population Stem cells from human exfoliated deciduous teeth (SHED) were used as an in vitro model system to test the effect of TA‐associated variants. Materials and methods Plasmid constructs containing reference and mutant alleles for ATF1 rs11169552, WNT10B rs833843 and GREM2 rs1414655 variants were transfected into SHED for functional characterization of variants. Allele‐specific changes in gene transcription activity, protein expression, cell migration and proliferation, and expression of additional tooth development genes (MSX1, PAX9 and AXIN2) were evaluated. Data analyses were performed using Student's t‐test. P‐values ≤ .05 were considered statistically significant. Results Mutant variants resulted in significantly decreased transcriptional activity of respective genes (P < 0.05), although no changes in protein localization were noted. Expression of MSX1 was significantly decreased in ATF1‐ and GREM2‐mutant cells, whereas PAX9 or AXIN2 mRNA expression was not significantly altered. Mutant WNT10B had no significant effect on the expression of additional TA genes. ATF1‐ and GREM2‐mutant cells presented increased cell migration. Cell proliferation was also affected with all three mutant alleles. Conclusions Our results demonstrate that ATF1, WNT10B and GREM2 mutant alleles have modulatory effects on gene/protein function that may contribute to TA.

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“…Human genome-wide association studies (GWAS) identified GREM2 variants associated with developmental disorders and disease, such as bone function and bone mass associated with osteoporosis, atrial fibrillation, and tooth agenesis (9)(10)(11)(12)(13). A Grem2 -/mouse line was previously developed as part of a high-throughput mouse knockout and phenotyping project (14).…”

Section: Introductionmentioning

confidence: 99%

“…GREM2 tightly associates with heparin through a protein binding domain outside of the BMP binding domain, which limits or downregulates BMP signaling, thus enhancing the inhibitory activity of GREM2 on BMPs (2,8). Human genome-wide association studies (GWAS) identified GREM2 variants associated with developmental disorders and disease, such as bone function and bone mass associated with osteoporosis, atrial fibrillation, and tooth agenesis (9)(10)(11)(12)(13). A Grem2 -/mouse line was previously developed as part of a high-throughput mouse knockout and phenotyping project (14).…”

Section: Introductionmentioning

confidence: 99%

Deletion ofGremlin-2alters estrous cyclicity and disrupts female fertility in mice

Rydze

Patton

Salazar-Torralba

et al. 2020

Preprint

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Members of the differential screening-selected gene aberrative in neuroblastoma (DAN) protein family are developmentally conserved extracellular binding proteins that antagonize bone morphogenetic protein (BMP) signaling. This protein family includes the Gremlin proteins, GREM1 and GREM2, which are known to have key functions during embryogenesis and adult physiology. While BMPs play essential roles in adult female reproductive physiology, the role of the DAN family in ovarian function is less understood. We generated mice null for Grem2 to study its role in female fertility in addition to screening patients with primary ovarian insufficiency for variants in GREM2. Grem2-/- mice are viable and female Grem2-/- mice have diminished fecundity and irregular estrous cycles. This is accompanied by reduced serum levels of anti-Müllerian hormone, a marker of the ovarian reserve, in adult mice. Alterations in ovarian expression of inhibin and activin subunit genes, which are required for regulation of the hypothalamic-pituitary-ovarian (HPO) axis, were identified. While Grem2 mRNA transcript was not detected in the pituitary, Grem2 was expressed in the hypothalami of wild type female mice. Additionally, screening 106 women with primary ovarian insufficiency identified one individual with a heterozygous variant in GREM2 that lies within the predicted BMP-GREM2 interface. In total, these data suggest that Grem2 is necessary for female fecundity by playing a novel role in regulating the HPO axis and possibly contributing to female reproductive disease.

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GREM2 nucleotide variants and the risk of tooth agenesis

Abstract: Our study confirmed that GREM2 is a candidate gene for tooth agenesis, which mutations can explain, however, only a small fraction of the genetic contribution to the pathogenesis of this anomaly.

Cited by 12 publications

References 52 publications

Further evidence for the role of WNT10A, WNT10B and GREM2 as candidate genes for isolated tooth agenesis

Further evidence for the role of WNT10A, WNT10B and GREM2 as candidate genes for isolated tooth agenesis

Functional characterization of ATF1, GREM2 AND WNT10B variants associated with tooth agenesis

Deletion ofGremlin-2alters estrous cyclicity and disrupts female fertility in mice

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