scholarly journals Synergistic Mutations of LRP6 and WNT10A in Familial Tooth Agenesis

2021 ◽  
Vol 11 (11) ◽  
pp. 1217
Author(s):  
Kuan-Yu Chu ◽  
Yin-Lin Wang ◽  
Yu-Ren Chou ◽  
Jung-Tsu Chen ◽  
Yi-Ping Wang ◽  
...  
Keyword(s):  
Tooth Development ◽  
Wide Spectrum ◽  
Genetic Diagnosis ◽  
Dose Dependence ◽  
Tooth Agenesis ◽  
Missense Mutations ◽  
Craniofacial Anomalies ◽  
Loss Of Function ◽  
Missing Teeth ◽  
Digenic Inheritance

Familial tooth agenesis (FTA), distinguished by developmental failure of selected teeth, is one of the most prevalent craniofacial anomalies in humans. Mutations in genes involved in WNT/β-catenin signaling, including AXIN2 WNT10A, WNT10B, LRP6, and KREMEN1, are known to cause FTA. However, mutational interactions among these genes have not been fully explored. In this study, we characterized four FTA kindreds with LRP6 pathogenic mutations: p.(Gln1252*), p.(Met168Arg), p.(Ala754Pro), and p.(Asn1075Ser). The three missense mutations were predicted to cause structural destabilization of the LRP6 protein. Two probands carrying both an LRP6 mutant allele and a WNT10A variant exhibited more severe phenotypes, suggesting mutational synergism or digenic inheritance. Biallelic LRP6 mutations in a patient with many missing teeth further supported the dose-dependence of LRP6-associated FTA. Analysis of 21 FTA cases with 15 different LRP6 loss-of-function mutations revealed high heterogeneity of disease severity and a distinctive pattern of missing teeth, with maxillary canines being frequently affected. We hypothesized that various combinations of sequence variants in WNT-related genes can modulate WNT signaling activities during tooth development and cause a wide spectrum of tooth agenesis severity, which highlights the importance of exome/genome analysis for the genetic diagnosis of FTA in this era of precision medicine.

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

2021 ◽  
Vol 7 (7) ◽  
pp. eabf1798
Author(s):  
A. Murashima-Suginami ◽  
H. Kiso ◽  
Y. Tokita ◽  
E. Mihara ◽  
Y. Nambu ◽  
...  
Keyword(s):  
Tooth Development ◽  
Bmp Signaling ◽  
Tooth Agenesis ◽  
Tooth Regeneration ◽  
Missing Teeth ◽  
Morphogenetic Protein ◽  
Genetic Abnormalities ◽  
Direct Binding ◽  
Tooth Germs ◽  
Lipoprotein Receptor Related Protein

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.

scholarly journals An in vitro and computational validation of a novel loss-of-functional mutation in PAX9 associated with non-syndromic tooth agenesis

2022 ◽  
Author(s):  
Tanmoy Sarkara ◽  
Prashant Ranjan ◽  
Smitha Kanathur ◽  
Ankush Gupta ◽  
PARIMAL DAS
Keyword(s):  
Amino Acid Position ◽  
Binding Activity ◽  
Mutant Protein ◽  
Tooth Agenesis ◽  
Craniofacial Anomalies ◽  
Loss Of Function ◽  
Wild Type ◽  
Paired Domain ◽  
Computational Validation

Congenital tooth agenesis (CTA) is one of the most common craniofacial anomalies. Its frequency varies among different population depending upon the genetic heterogeneity. CTA could be of familial or sporadic and syndromic or non-syndromic. Five major genes are found to be associated with non-syndromic CTA namely, PAX9, MSX1, EDA1, AXIN2 and WNT10A. In this study, an India family with CTA was investigated and a novel c.336C>G variation was identified in the exon 3 of PAX9, leading to substitution of evolutionary conserved Cys with Trp at 112 amino acid position located at the functionally significant DNA binding paired domain region. Functional analysis revealed that p.Cys112Trp mutation did not prevent the nuclear localization although mutant protein had higher cytoplasmic retention. EMSA using e5 probe revealed that mutant protein was unable to bind with the paired-domain binding site. Subsequently, GST pull-down assay revealed lower binding activity of the mutant protein with its known interactor MSX1. Further RNA-sequencing of PAX9 over-expressed HEK293, identified two potential novel targets, WNT4 and WNT7b those are up-regulated by wild-type PAX9 but not by mutant. These in vitro results were consistent with the computational results. The in vitro and computational observations altogether suggest that c.336C>G (p.Cys112Trp) variation leads to loss-of-function of PAX9 leading to CTA in this family.

scholarly journals Prevalence of Hypodontia in the Permanent Dentition of Macedonian Population

2014 ◽  
Vol 18 (2) ◽  
pp. 93-98
Author(s):  
Darko Pop Acev ◽  
Julijana Gjorgova
Keyword(s):  
Tooth Development ◽  
Cross Sectional Study ◽  
Tooth Agenesis ◽  
Missing Teeth ◽  
Cross Sectional ◽  
Congenitally Missing Teeth ◽  
Albanian Population ◽  
Congenitally Missing ◽  
Missing Tooth ◽  
Functional Deficiency

SUMMARYHypodontia or tooth agenesis is a condition at which the patient is missing one or more teeth due to a failure of those teeth to develop. This is not only an aesthetic, but also a functional deficiency. The incidence of congenitally missing teeth depends on etiological factors that affect tooth development, as well as which dentition is concerned, sex or race and geographic distribution. The tooth agenesis is mostly seen in teeth that are formed last in a given class (lateral incisors, second premolars and third molars). The aim of this study was to calculate the prevalence of congenitally missing teeth in population of FYROM and, through a review of the literature, to compare these results to other populations in the world.For this purpose a retrospective, transversal and cross-sectional study was made, where dental history and anamnesis of 8160 patients (3671 males and 4489 females) were examined, as well as their panoramic radiographs. The patients were 8-18 years old. The data was statistically analyzed with programme Statistica 7.0. The prevalence of hypodontia population of FYROM was 7.52%. Most commonly congenitally missing tooth in patients with hypodontia was mandibular second premolar (35.5% left and 34.53% right). Tooth agenesis predominated in females and in ethnic Albanian population, without significance.

scholarly journals Hedgehog signalling regulates patterning of the murine and human dentitions through Gas1 co-receptor function

2020 ◽  
Author(s):  
Maisa Seppala ◽  
Beatrice Thivichon-Prince ◽  
Guilherme M. Xavier ◽  
Nina Shaffie ◽  
Indiya Sangani ◽  
...  
Keyword(s):  
Tooth Development ◽  
Human Subjects ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Supernumerary Teeth ◽  
Hedgehog Signalling ◽  
Shh Pathway ◽  
Tooth Number ◽  
Cranial Neural Crest Cells ◽  
Tooth Germs

ABSTRACTThe mammalian dentition exhibits wide numerical and morphological variation between different species. The regulation of dental pattern is achieved through complex reiterative molecular signalling interactions that occur through multiple stages of tooth development. We show that mice with loss-of-function in the Hedgehog co-receptor Gas1 have variation in size, morphology and number of teeth within the molar dentition. Specifically, premolar-like supernumerary teeth are present with high penetrance, arising through survival and continued development of vestigial tooth germs. We further demonstrate that Gas1 function in cranial neural crest cells is essential for the regulation of tooth number, acting to restrict Wnt signalling in vestigial tooth germs through facilitation of Shh signalling. Moreover, regulation of tooth number is independent of the additional Hedgehog co-receptors Cdon and Boc. Interestingly, further reduction of Shh pathway activity in a Gas1 mutant background leads to fusion of the molar field and ultimately, developmental arrest of tooth development rather than exacerbating the supernumerary phenotype. Finally, we demonstrate defective coronal morphology in the molar dentition of human subjects carrying GAS1 missense mutations, suggesting that regulation of Hedgehog signalling through GAS1 is also essential for normal patterning of the human dentition.

scholarly journals Failure of Tooth Development: Prevalence, Genetic Causes and Clinical Features

2021 ◽  
Author(s):  
Emilia Severin ◽  
George Gabriel Moldoveanu ◽  
Andreea Moldoveanu
Keyword(s):  
Tooth Development ◽  
Gene Mutations ◽  
Dental Arch ◽  
Tooth Agenesis ◽  
Missing Teeth ◽  
Related Quality ◽  
Wide Variability ◽  
Health Related ◽  
Clinical Consequences ◽  
Tooth Number

In dental practice may be encountered a wide variability in the clinical dental phenotype of tooth number. Failure of tooth development at the bud stage causes tooth agenesis and reduction in tooth number in the dental arch which involves various complications. Tooth agenesis is one of the most common developmental anomalies of human permanent dentition and tends to run in families, may aggregate within families, suggesting a genetic cause. Tooth agenesis can occur in association with a variety of craniofacial syndromes, but it is also found as an isolated trait (familial or sporadic). Other tooth anomalies, such as tooth shape and size, delayed eruption of teeth, malposition, short roots or taurodontism, have been noted in association with non-syndromic tooth agenesis as well. Both the deciduous and permanent dentitions may be affected by missing teeth. Variations in the number of missing teeth can be determined by a mutation in one gene, by mutations in multiple genes, induced by local or systemically acting environmental factor, caused by a combination of gene mutations and environmental factors acting together, or by damage to chromosomes. As the number of missing teeth increases, so does the severity of clinical consequences and the impact on oral health–related quality of life.

A Rare Case of Congenital Missing Mandibular Second Molar: Report and Review of Literature

2020 ◽  
Author(s):  
Deepashri H Kambalimath
Keyword(s):  
Tooth Development ◽  
Rare Condition ◽  
Review Of Literature ◽  
Indian Literature ◽  
Missing Teeth ◽  
Second Molar ◽  
The World ◽  
Mandibular Second Molar ◽  
Sporadic Cases ◽  
Genetic And Environmental Factors

Congenital missing permanent second molar is an extremely rare condition. Non syndromic mandibular second molar agenesis associated with other anomalies has occasionally been reported in literature, but isolated sporadic cases are rarely observed. Number of interactions between genetic and environmental factors during the process of tooth development might be the causative etiology for agenesis. This report presents an isolated case of hypodontia with absence of bilateral mandibular second molar agenesis in a healthy 18 year old female patient is presented and literature review on prevalence of most missing teeth with incidence of missing second molar in various regions of the world and in various regions of Indian continent is presented. No such case has been reported in Indian literature so far.

scholarly journals Alterations in ZnT1 expression and function lead to impaired intracellular zinc homeostasis in cancer

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Adrian Israel Lehvy ◽  
Guy Horev ◽  
Yarden Golan ◽  
Fabian Glaser ◽  
Yael Shammai ◽  
...  
Keyword(s):  
Malignant Tumors ◽  
Zinc Homeostasis ◽  
Healthy Population ◽  
Missense Mutations ◽  
Protein Alignment ◽  
Loss Of Function ◽  
Intracellular Zinc ◽  
Dismal Prognosis ◽  
Zinc Levels ◽  
And Function

Abstract Zinc is vital for the structure and function of ~3000 human proteins and hence plays key physiological roles. Consequently, impaired zinc homeostasis is associated with various human diseases including cancer. Intracellular zinc levels are tightly regulated by two families of zinc transporters: ZIPs and ZnTs; ZIPs import zinc into the cytosol from the extracellular milieu, or from the lumen of organelles into the cytoplasm. In contrast, the vast majority of ZnTs compartmentalize zinc within organelles, whereas the ubiquitously expressed ZnT1 is the sole zinc exporter. Herein, we explored the hypothesis that qualitative and quantitative alterations in ZnT1 activity impair cellular zinc homeostasis in cancer. Towards this end, we first used bioinformatics to analyze inactivating mutations in ZIPs and ZNTs, catalogued in the COSMIC and gnomAD databases, representing tumor specimens and healthy population controls, respectively. ZnT1, ZnT10, ZIP8, and ZIP10 showed extremely high rates of loss of function mutations in cancer as compared to healthy controls. Analysis of the putative functional impact of missense mutations in ZnT1-ZnT10 and ZIP1-ZIP14, using homologous protein alignment and structural predictions, revealed that ZnT1 displays a markedly increased frequency of predicted functionally deleterious mutations in malignant tumors, as compared to a healthy population. Furthermore, examination of ZnT1 expression in 30 cancer types in the TCGA database revealed five tumor types with significant ZnT1 overexpression, which predicted dismal prognosis for cancer patient survival. Novel functional zinc transport assays, which allowed for the indirect measurement of cytosolic zinc levels, established that wild type ZnT1 overexpression results in low intracellular zinc levels. In contrast, overexpression of predicted deleterious ZnT1 missense mutations did not reduce intracellular zinc levels, validating eight missense mutations as loss of function (LoF) mutations. Thus, alterations in ZnT1 expression and LoF mutations in ZnT1 provide a molecular mechanism for impaired zinc homeostasis in cancer formation and/or progression.

scholarly journals Genetic Causes of Oculocutaneous Albinism in Pakistani Population

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 492
Author(s):  
Zureesha Sajid ◽  
Sairah Yousaf ◽  
Yar M. Waryah ◽  
Tauqeer A. Mughal ◽  
Tasleem Kausar ◽  
...  
Keyword(s):  
Genetic Interaction ◽  
Genetic Diagnosis ◽  
Underlying Disease ◽  
Oculocutaneous Albinism ◽  
Disease Etiology ◽  
Locus Heterogeneity ◽  
Pathogenic Variants ◽  
Digenic Inheritance ◽  
Inbred Populations ◽  
Pathological Variant

Melanin pigment helps protect our body from broad wavelength solar radiation and skin cancer. Among other pigmentation disorders in humans, albinism is reported to manifest in both syndromic and nonsyndromic forms as well as with varying inheritance patterns. Oculocutaneous albinism (OCA), an autosomal recessive nonsyndromic form of albinism, presents as partial to complete loss of melanin in the skin, hair, and iris. OCA has been known to be caused by pathogenic variants in seven different genes, so far, according to all the currently published population studies. However, the detection rate of alleles causing OCA varies from 50% to 90%. One of the significant challenges of uncovering the pathological variant underlying disease etiology is inter- and intra-familial locus heterogeneity. This problem is especially pertinent in highly inbred populations. As examples of such familial locus heterogeneity, we present nine consanguineous Pakistani families with segregating OCA due to variants in one or two different known albinism-associated genes. All of the identified variants are predicted to be pathogenic, which was corroborated by several in silico algorithms and association with diverse clinical phenotypes. We report an individual affected with OCA carries heterozygous, likely pathogenic variants in TYR and OCA2, raising the question of a possible digenic inheritance. Altogether, our study highlights the significance of exome sequencing for the complete genetic diagnosis of inbred families and provides the ramifications of potential genetic interaction and digenic inheritance of variants in the TYR and OCA2 genes.

Independent regulation of Dlx2 expression in the epithelium and mesenchyme of the first branchial arch

Development ◽  
2000 ◽  
Vol 127 (2) ◽  
pp. 217-224 ◽  
Author(s):  
B.L. Thomas ◽  
J.K. Liu ◽  
J.L. Rubenstein ◽  
P.T. Sharpe
Keyword(s):  
Tooth Development ◽  
Branchial Arch ◽  
Oral Epithelium ◽  
Upstream Sequence ◽  
Loss Of Function ◽  
Signalling Molecules ◽  
Molar Teeth ◽  
Overlapping Domains ◽  
Upper Molar

Dlx2, a member of the distal-less gene family, is expressed in the first branchial arch, prior to the initiation of tooth development, in distinct, non-overlapping domains in the mesenchyme and the epithelium. In the mesenchyme Dlx2 is expressed proximally, whereas in oral epithelium it is expressed distally. Dlx2 has been shown to be involved in the patterning of the murine dentition, since loss of function of Dlx1 and Dlx2 results in early failure of development of upper molar teeth. We have investigated the regulation of Dlx2 expression to determine how the early epithelial and mesenchymal expression boundaries are maintained, to help to understand the role of these distinct expression domains in patterning of the dentition. Transgenic mice produced with a lacZ reporter construct, containing 3.8 kb upstream sequence of Dlx2, led to the mapping of regulatory regions driving epithelial but not mesenchymal expression in the first branchial arch. We show that the epithelial expression of Dlx2 is regulated by planar signalling by BMP4, which is coexpressed in distal oral epithelium. Mesenchymal expression is regulated by a different mechanism involving FGF8, which is expressed in the overlying epithelium. FGF8 also inhibits expression of Dlx2 in the epithelium by a signalling pathway that requires the mesenchyme. Thus, the signalling molecules BMP4 and FGF8 provide the mechanism for maintaining the strict epithelial and mesenchymal expression domains of Dlx2 in the first arch.

scholarly journals MEN4 and CDKN1B mutations: the latest of the MEN syndromes

2017 ◽  
Vol 24 (10) ◽  
pp. T195-T208 ◽  
Author(s):  
Rami Alrezk ◽  
Fady Hannah-Shmouni ◽  
Constantine A Stratakis
Keyword(s):  
Tumor Suppressor ◽  
Neuroendocrine Tumors ◽  
Pituitary Adenomas ◽  
Wide Spectrum ◽  
Susceptibility Gene ◽  
Germline Mutations ◽  
Suppressor Gene ◽  
Loss Of Function ◽  
Putative Tumor Suppressor

Multiple endocrine neoplasia (MEN) refers to a group of autosomal dominant disorders with generally high penetrance that lead to the development of a wide spectrum of endocrine and non-endocrine manifestations. The most frequent among these conditions is MEN type 1 (MEN1), which is caused by germline heterozygous loss-of-function mutations in the tumor suppressor geneMEN1. MEN1 is characterized by primary hyperparathyroidism (PHPT) and functional or nonfunctional pancreatic neuroendocrine tumors and pituitary adenomas. Approximately 10% of patients with familial or sporadic MEN1-like phenotype do not haveMEN1mutations or deletions. A novel MEN syndrome was discovered, initially in rats (MENX), and later in humans (MEN4), which is caused by germline mutations in the putative tumor suppressorCDKN1B. The most common phenotype of the 19 established cases of MEN4 that have been described to date is PHPT followed by pituitary adenomas. Recently, somatic or germline mutations inCDKN1Bwere also identified in patients with sporadic PHPT, small intestinal neuroendocrine tumors, lymphoma and breast cancer, demonstrating a novel role forCDKN1Bas a tumor susceptibility gene for other neoplasms. In this review, we report on the genetic characterization and clinical features of MEN4.

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