The third family with Eiken syndrome

Jacob, Prince; Soni, Jai Prakash; Mortier, Geert; Girisha, Katta M.

doi:10.1111/cge.13601

Cited by 8 publications

(17 citation statements)

References 3 publications

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“…The finding that PFE occurs in both the patients with the V204E mutation and with the Eiken syndrome mutations (17,18) is consistent with a deficiency of the mutant PTH1R in responding to PTHrP during tooth development. (15,16) Tooth eruption and skeletal formation are coordinated processes that require paracrine and autocrine signaling dependent in part on local concentrations of PTHrP.…”

Section: Discussionsupporting

confidence: 59%

“…1 B , C , Table 1 ). On the PTH1R‐R186H mutant, the maximum response to PTH( 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ) was moderately higher than that observed on PTH1R‐WT (Emax = 118% ± 4%, p = 0.002, Table 1 ), whereas the potency of the response tended to be slightly (approximately threefold) weaker than that of the ligand on PTH1R‐WT. The reason for the increase in Emax is not clear, because the patient phenotype predicts a deficiency in responsiveness to PTH, which is at least suggested by the trend toward reduced potency.…”

Section: Resultsmentioning

confidence: 99%

“…5 C , Table 2 ). The relative responses induced by PTH(1‐28) and PTHrP( 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ) on PTH1R‐R186H therefore differed from those obtained on this mutant receptor with the intact peptides, as the Emax of the response to PTH(1‐34) was increased by ~18% and potency tended to be approximately threefold weaker, whereas the response to PTHrP(1‐36) was unchanged for efficacy and approximately twofold stronger in potency. These differences suggest that residues in the 29–34 and 29–36 regions of PTH(1‐34) and PTHrP(1‐36), respectively, can modulate the impact that the R186H mutation located in TM1 of the receptor has on the overall ligand interaction process.…”

Section: Resultsmentioning

confidence: 99%

“…( 13 , 14 , 15 , 16 ) Eiken skeletal dysplasia is a rare skeletal condition of delayed ossification that is linked to homozygous PTH1R mutations, and, in two of the three reported families, occurs with PFE. ( 1 , 17 , 18 ) Of interest, patients with Eiken syndrome or PFE are not reported to have defects in maintaining calcium and phosphate homeostasis, nor to have changes in blood levels of PTH, findings which suggest that the developmental pathways regulated by paracrine‐acting PTHrP are more sensitive to the effects of the PTH1R mutations identified in PFE and Eiken syndrome than are the homeostatic pathways that are regulated by endocrine‐acting PTH.…”

Section: Introductionmentioning

confidence: 99%

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Functional Properties of Two Distinct PTH1R Mutants Associated With Either Skeletal Defects or Pseudohypoparathyroidism

et al. 2022

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Consistent with a vital role of parathyroid hormone (PTH) receptor type 1 (PTH1R) in skeletal development, homozygous loss‐of‐function PTH1R mutations in humans results in neonatal lethality (Blomstrand chondrodysplasia), whereas such heterozygous mutations cause a primary failure of tooth eruption (PFE). Despite a key role of PTH1R in calcium and phosphate homeostasis, blood mineral ion levels are not altered in such cases of PFE. Recently, two nonlethal homozygous PTH1R mutations were identified in two unrelated families in which affected members exhibit either dental and skeletal abnormalities (PTH1R‐V204E) or hypocalcemia and hyperphosphatemia (PTH1R‐R186H). Arg186 and Val204 map to the first transmembrane helix of the PTH1R, and thus to a critical region of this class B G protein‐coupled receptor. We used cell‐based assays and PTH and PTH‐related protein (PTHrP) ligand analogs to assess the impact of the R186H and V204E mutations on PTH1R function in vitro. In transiently transfected HEK293 cells, PTH1R‐R186H mediated cyclic adenosine monophosphate (cAMP) responses to PTH(1‐34) and PTHrP(1‐36) that were of comparable potency to those observed on wild‐type PTH1R (PTH1R‐WT) (half maximal effective concentrations [EC50s] = 0.4nM to 1.2nM), whereas the response‐maxima were significantly reduced for the PTH1R‐V204E mutant (maximum effect [Emax] = 81%–77% of PTH1R‐WT, p ≤ 0.004). Antibody binding to an extracellular hemagglutinin (HA) tag was comparable for PTH1R‐R186H and PTH1R‐WT, but was significantly reduced for PTH1R‐V204E (maximum binding level [Bmax] = 44% ± 11% of PTH1R‐WT, p = 0.002). The potency of cAMP signaling induced by a PTH(1‐11) analog was reduced by ninefold and threefold, respectively, for PTH1R‐R186H and PTH1R‐V204E, relative to PTH1R‐WT, and a PTH(1‐15) radioligand analog that bound adequately to PTH1R‐WT exhibited little or no specific binding to either mutant receptor. The data support a general decrease in PTH1R surface expression and/or function as a mechanism for PFE and a selective impairment in PTH ligand affinity as a potential PTH1R‐mutation‐based mechanism for pseudohypoparathyroidism. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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Section: Discussionsupporting

confidence: 59%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Functional Properties of Two Distinct PTH1R Mutants Associated With Either Skeletal Defects or Pseudohypoparathyroidism

et al. 2022

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“…Biallelic hypomorphic alleles in the PTH/PTHrP receptor are the molecular cause of Eiken syndrome, a very rare skeletal dysplasia with delayed bone ossification, epiphyseal abnormalities with dysplasia and supernumerary epiphyses, and disturbed bone remodeling (Jacob et al 2019).…”

Section: Applicationmentioning

confidence: 99%

Parathyroid Hormone Receptor

Kopp

2021

Encyclopedia of Pathology

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The primary receptor for parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP) is the PTH/PTHrP receptor, which is also designated as PTH1 receptor (PTH1R). The PTH/PTHrP receptor is a member of the Gprotein-coupled seven transmembrane receptor family (GPCR). In response to ligand binding, it activates several intracellular pathways, among them the Gsαadenylyl cyclaseprotein kinase A (PKA) signaling cascade.

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Identification of a novel heterozygous PTH1R variant in a Chinese family with incomplete penetrance

Wang,

Zhao,

Zhang

et al. 2023

Molec Gen & Gen Med

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BackgroundMutations in PTH1R are associated with Jansen‐type metaphyseal chondrodysplasia (JMC), Blomstrand osteochondrodysplasia (BOCD), Eiken syndrome, enchondroma, and primary failure of tooth eruption (PFE). Inheritance of the PTH1R gene can be either autosomal dominant or autosomal recessive, indicating the complexity of the gene. Our objective was to identify the phenotypic differences in members of a family with a novel PTH1R mutation.MethodsThe proband was a 13‐year, 6‐month‐old girl presenting with short stature, abnormal tooth eruption, skeletal dysplasia, and midface hypoplasia. The brother and father of the proband presented with short stature and abnormal tooth eruption. High‐throughput sequencing was performed on the proband, and the variant was confirmed in the proband and other family members by Sanger sequencing. Amino acid sequence alignment was performed using ClustalX software. Three‐dimensional structures were analyzed and displayed using the I‐TASSER website and PyMOL software.ResultsHigh‐throughput genome sequencing and Sanger sequencing validation showed that the proband, her father, and her brother all carried the PTH1R (NM_000316) c.1393G>A (p.E465K) mutation. The c.1393G>A (p.E465K) mutation was novel, as it has not been reported in the literature database. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, the p.E465K variant was considered to have uncertain significance. Biological information analysis demonstrated that this identified variant was highly conserved and highly likely pathogenic.ConclusionsWe identified a novel heterozygous mutation in the PTH1R gene leading to clinical manifestations with incomplete penetrance that expands the spectrum of known PTH1R mutations.

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The third family with Eiken syndrome

Cited by 8 publications

References 3 publications

Functional Properties of Two Distinct PTH1R Mutants Associated With Either Skeletal Defects or Pseudohypoparathyroidism

Functional Properties of Two Distinct PTH1R Mutants Associated With Either Skeletal Defects or Pseudohypoparathyroidism

Parathyroid Hormone Receptor

Identification of a novel heterozygous PTH1R variant in a Chinese family with incomplete penetrance

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