In silico and functional evaluation of <i><scp>PTH</scp>1R</i> mutations found in patients with primary failure of eruption (<scp>PFE</scp>)

Hendricks, Heather; Bencharit, Sompop; Seaman, William T.; Frazier‐Bowers, Sylvia A.

doi:10.1111/ocr.12160

Cited by 7 publications

(7 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…While substitution of Arg-147 in the extracellular domain of the receptor partially affected binding of PTH 1-34 and cAMP production, the substitution of Arg-383 with Gln (R383Q) had little effect on the binding of the ligand. The partial suppression of cAMP production in HeLa cells with R383Q-PTH1R is considered to be due to other reasons, such as possible alteration in G-protein binding (Hendricks et al 2017).…”

Section: Discussionmentioning

confidence: 99%

Functional Analysis of PTH1R Variants Found in Primary Failure of Eruption

et al. 2020

View full text Add to dashboard Cite

Although many variants of the parathyroid hormone 1 receptor (PTH1R) gene are known to be associated with primary failure of eruption (PFE), the mechanisms underlying the link remains poorly understood. We here performed functional analyses of PTH1R variants reported in PFE patients—namely, 356C>T (P119L), 395C>T (P132L), 439C>T (R147C), and 1148G>A (R383Q)—using HeLa cells with a lentiviral vector-mediated genetic modification. Two particular variants, P119L and P132L, had severe reduction in a level of N-linked glycosylation when compared with wild-type PTH1R, whereas the other 2 showed modest alteration. PTH1R having P119L or P132L showed marked decrease in the affinity to PTH1-34, which likely led to severely impaired cAMP accumulation upon stimulation in cells expressing these mutants, highlighting the importance of these 2 amino acid residues for ligand-mediated proper functioning of PTH1R. To further gain insights into PTH1R functions, we established the induced pluripotent stem cell (iPSC) lines from a patient with PFE and the heterozygous P132L mutation. When differentiated into osteoblastic-lineage cells, PFE-iPSCs showed no abnormality in mineralization. The mRNA expression of RUNX2, SP7, and BGLAP, the osteoblastic differentiation-related genes, and that of PTH1R were augmented in both PFE-iPSC-derived cells and control iPSC-derived cells in the presence of bone morphogenetic protein 2. Also, active vitamin D3 induced the expression of RANKL, a major key factor for osteoclastogenesis, equally in osteoblastic cells derived from control and PFE-iPSCs. In sharp contrast, exposure to PTH1-34 resulted in no induction of RANKL mRNA expression in the cells expressing P132L variant PTH1R, consistent with the idea that a type of heterozygous PTH1R gene mutation would spoil PTH-dependent response in osteoblasts. Collectively, this study demonstrates a link between PFE-associated genetic alteration and causative functional impairment of PTH1R, as well as a utility of iPSC-based disease modeling for future elucidation of pathogenesis in genetic disorders, including PFE.

show abstract

Section: Discussionmentioning

confidence: 99%

Functional Analysis of PTH1R Variants Found in Primary Failure of Eruption

et al. 2020

View full text Add to dashboard Cite

show abstract

“…The proband was a 13-year-old young man with an incomplete eruption of the right upper anterior tooth (11,12,13), resulting in a signi cant open-bite. His left rst molar 26 partially erupted.…”

Section: Case Presentationmentioning

confidence: 99%

“…The clinical examination revealed that the right maxillary anterior teeth of the proband (11,12,13) were below the occlusion plane, forming an open-bite of 4mm. The eruption height of the left maxillary rst molar (26) was slightly insu cient.…”

Section: Clinical Analysis Of the Probandmentioning

confidence: 99%

“…

Case presentationThe proband was a 13-year-old young man with an incomplete eruption of the right upper anterior tooth (11,12,13), resulting in a signi cant open-bite. His left rst molar 26 partially erupted.

…”

mentioning

confidence: 99%

See 1 more Smart Citation

Identification of a novel PTH1R variant in a family with primary failure of eruption

Zha¹,

Yu³

et al. 2023

Preprint

View full text Add to dashboard Cite

Background This work aimed to report a small family of Primary Failure of Eruption(PFE) with a novel PTH1R variant. One of the patients has a rare clinical phenotype of the anterior tooth involved only.Case presentation The proband was a 13-year-old young man with an incomplete eruption of the right upper anterior tooth(11,12,13), resulting in a significant open-bite. His left first molar 26 partially erupted. Family history revealed that the proband's 12-year-old brother and father also had teeth eruption disorders. Genetic testing found a novel PTH1R variant (c.1325-1336del), which has never been reported before. The diagnosis of PFE was based on clinical and radiographic characteristics and the result of genetic testing. Bioinformatic analysis predicted this variant would result in the truncation of the G protein-coupled receptor encoded by the PTH1R, affecting its structure and function.Conclusion A novel PTH1R variant identified through whole-exome sequencing further expands the mutation spectrum of PFE. Patients in this family have different phenotypes, which reflects the characteristics of variable phenotypic expression of PFE.

show abstract

“…The etiology of missing teeth, that is, a disturbance of tooth development (i.e., tooth agenesis or disturbance of tooth eruption), especially of the permanent teeth, remains unknown. The etiology of tooth agenesis includes genetic factors, environmental factors, or a combination thereof [9,10,11,12], while the etiology of a disturbance of tooth eruption may include systemic factors, local factors, as well as genetic factors [13,14,15,16]. For example, prolonged retention of a deciduous tooth due to failure of deciduous tooth resorption, abnormal an eruptive path, the presence of a supernumerary tooth, or anomalous position of a tooth (e.g., tilting, displacement, transmigration), can disturb the eruption of permanent teeth.…”

Section: Introductionmentioning

confidence: 99%

Association between Maternal Smoking during Pregnancy and Missing Teeth in Adolescents

Kang¹,

Yasuda²,

Ogawa³

et al. 2019

IJERPH

View full text Add to dashboard Cite

Tooth agenesis and disturbance of tooth eruption is the most prevalent oral defect, and is possibly caused by the interaction of genetic and environmental factors. We hypothesized that prenatal factors may affect tooth development. The objective of this study was to examine whether smoking during pregnancy was associated with missing teeth in the offspring during adolescence. The study population comprised pregnant women and their children registered (N = 1052) at Koshu city, Japan. When the expectant mothers visited the city office for pregnancy registration, a survey was conducted to ascertain their lifestyle habits. Data on missing teeth in the children were obtained from the compulsory dental health checkup during junior high school years. Multivariate logistic regression models were fitted to assess the association between missing teeth and lifestyle habits. A total of 772 children were studied. The prevalence of missing teeth in these children was 4.9%. Children whose mothers smoked six cigarettes or more per day were 4.59 (95% CI: 1.07–19.67) times more likely to present with missing teeth than those children whose mothers did not smoke, after adjustment for possible confounders. Our findings indicate that smoking during pregnancy can be a risk factor for missing teeth in the offspring.

show abstract

In silico and functional evaluation of PTH1R mutations found in patients with primary failure of eruption (PFE)

Cited by 7 publications

References 16 publications

Functional Analysis of PTH1R Variants Found in Primary Failure of Eruption

Functional Analysis of PTH1R Variants Found in Primary Failure of Eruption

Identification of a novel PTH1R variant in a family with primary failure of eruption

Association between Maternal Smoking during Pregnancy and Missing Teeth in Adolescents

Contact Info

Product

Resources

About