376 results on '"Harald Jüppner"'
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2. Kidney glycolysis serves as a mammalian phosphate sensor that maintains phosphate homeostasis
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Wen Zhou, Petra Simic, Iris Y. Zhou, Peter Caravan, Xavier Vela Parada, Donghai Wen, Onica L. Washington, Maria Shvedova, Kerry A. Pierce, Clary B. Clish, Michael Mannstadt, Tatsuya Kobayashi, Marc N. Wein, Harald Jüppner, and Eugene P. Rhee
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General Medicine - Published
- 2023
3. Bartter Syndrome Type 1 Due to Novel SLC12A1 Mutations Associated With Pseudohypoparathyroidism Type II
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Zentaro Kiuchi, Kandai Nozu, Kunimasa Yan, and Harald Jüppner
- Abstract
Bartter syndrome type 1 is caused by mutations in the solute carrier family 12 member 1 (SLC12A1), encoding the sodium-potassium-chloride cotransporter-2 (NKCC2). In addition to causing renal salt-losing tubulopathy, SLC12A1 mutations are known to cause nephrocalcinosis due to hypercalciuria, as well as failure to thrive associated with abnormal calcium and phosphorus homeostasis. We report a now 7-year-old Japanese girl with polyuria, hyponatremia, hypokalemia, and metabolic alkalosis, in whom compound heterozygous novel SLC12A1 mutations were identified. Elevated parathyroid hormone (PTH) levels were consistently noted after the age of 1 year in conjunction with gradually declining serum calcium and increasing serum phosphorus levels. To confirm suspected PTH-resistance, Ellsworth Howard tests were performed at the ages of 6 years 8 months and 6 years 10 months in the absence or presence of ibuprofen, respectively. Urinary adenosine 3′,5′-cyclic monophosphate excretion increased on both occasions in response to PTH(1-34) infusion suggesting pseudohypoparathyroidism type II. However, only during treatment with ibuprofen did PTH induce an almost normal phosphaturic response. The nonsteroidal anti-inflammatory drugs thus enhanced growth velocity, alleviated hypercalciuria, and increased PTH-stimulated urinary phosphorus excretion without significantly affecting renal function.
- Published
- 2023
4. Homozygous Ser-1 to Pro-1 mutation in parathyroid hormone identified in hypocalcemic patients results in secretion of a biologically inactive pro-hormone
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Patrick Hanna, Ashok Khatri, Shawn Choi, Severine Brabant, Matti L. Gild, Marie L. Piketty, Bruno Francou, Dominique Prié, John T. Potts, Roderick J. Clifton-Bligh, Agnès Linglart, Thomas J. Gardella, and Harald Jüppner
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Multidisciplinary - Abstract
Like other secreted peptides, nascent parathyroid hormone (PTH) is synthesized with a pre- and a pro-sequence (25 and 6 amino acids, respectively). These precursor segments are sequentially removed in parathyroid cells before packaging into secretory granules. Three patients from two unrelated families who presented during infancy with symptomatic hypocalcemia were found to have a homozygous serine (S) to proline (P) change affecting the first amino acid of the mature PTH. Unexpectedly, biological activity of synthetic [P1]PTH(1-34) was indistinguishable from that of unmodified [S1]PTH(1-34). However, in contrast to conditioned medium from COS-7 cells expressing prepro[S1]PTH(1-84), medium from cells expressing prepro[P1]PTH(1-84) failed to stimulate cAMP production despite similar PTH levels when measured by an intact assay that detects PTH(1-84) and large amino-terminally truncated fragments thereof. Analysis of the secreted, but inactive PTH variant led to the identification of pro[P1]PTH(−6 to +84). Synthetic pro[P1]PTH(−6 to +34) and pro[S1]PTH(−6 to +34) had much less bioactivity than the corresponding PTH(1-34) analogs. Unlike pro[S1]PTH(−6 to +34), pro[P1]PTH(−6 to +34) was resistant to cleavage by furin suggesting that the amino acid variant impairs preproPTH processing. Consistent with this conclusion, plasma of patients with the homozygous P1 mutation had elevated proPTH levels, as determined with an in-house assay specific for pro[P1]PTH(−6 to +84). In fact, a large fraction of PTH detected by the commercial intact assay represented the secreted pro[P1]PTH. In contrast, two commercial biointact assays that use antibodies directed against the first few amino acid residues of PTH(1-84) for capture or detection failed to detect pro[P1]PTH.
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- 2023
5. Expanding homogeneous culture of human primordial germ cell-like cells maintaining germline features without serum or feeder layers
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Mutsumi Kobayashi, Misato Kobayashi, Junko Odajima, Keiko Shioda, Young Sun Hwang, Kotaro Sasaki, Pranam Chatterjee, Christian Kramme, Richie E. Kohman, George M. Church, Amanda R. Loehr, Robert S. Weiss, Harald Jüppner, Joanna J. Gell, Ching C. Lau, and Toshi Shioda
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Male ,Induced Pluripotent Stem Cells ,Feeder Cells ,Obstetrics and Gynecology ,Cell Differentiation ,General Medicine ,Cell Biology ,Biochemistry ,Germ Cells ,Genetics ,Humans ,Female ,Cells, Cultured ,Developmental Biology - Abstract
In vitro expansion of human primordial germ cell-like cells (hPGCLCs), a pluripotent stem cell-derived PGC model, has proved challenging due to rapid loss of primordial germ cell (PGC)-like identity and limited cell survival/proliferation. Here, we describe long-term culture hPGCLCs (LTC-hPGCLCs), which actively proliferate in a serum-free, feeder-free condition without apparent limit as highly homogeneous diploid cell populations maintaining transcriptomic and epigenomic characteristics of hPGCLCs. Histone proteomics confirmed reduced H3K9me2 and increased H3K27me3 marks in LTC-hPGCLCs compared with induced pluripotent stem cells (iPSCs). LTC-hPGCLCs established from multiple human iPSC clones of both sexes were telomerase positive, senescence-free cells readily passaged with minimal cell death or deviation from the PGC-like identity. LTC-hPGCLCs are capable of differentiating to DAZL-positive M-spermatogonia-like cells in the xenogeneic reconstituted testis (xrTestis) organ culture milieu as well as efficiently producing fully pluripotent embryonic germ cell-like cells in the presence of stem cell factor and fibroblast growth factor 2. Thus, LTC-hPGCLCs provide convenient access to unlimited amounts of high-quality and homogeneous hPGCLCs.
- Published
- 2022
6. Progression of PTH Resistance in Autosomal Dominant Pseudohypoparathyroidism Type Ib Due to Maternal STX16 Deletions
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Zentaro Kiuchi, Harald Jüppner, Patrick Hanna, Robert C. Olney, Peter J. Tebben, Terry DeClue, Monica Reyes, and Anu Sharma
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Male ,Heterozygote ,medicine.medical_specialty ,Calcitriol ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,chemistry.chemical_element ,Context (language use) ,Syntaxin 16 ,Calcium ,Severity of Illness Index ,Biochemistry ,Exon ,Endocrinology ,Internal medicine ,medicine ,GNAS complex locus ,Humans ,Genetic Testing ,Prospective Studies ,Epigenetics ,Online Only Articles ,Pseudohypoparathyroidism ,biology ,business.industry ,Biochemistry (medical) ,Infant ,medicine.disease ,chemistry ,Parathyroid Hormone ,Child, Preschool ,Disease Progression ,biology.protein ,Female ,STX16 ,Maternal Inheritance ,business ,Gene Deletion ,Follow-Up Studies ,medicine.drug - Abstract
Context Maternally inherited STX16 deletions that cause loss of methylation at GNAS exon A/B and thereby reduce Gsα expression are the most frequent cause of autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP1B). Early identification of these disease-causing variants in the children of affected and unaffected female carriers would prompt treatment with calcium and calcitriol once parathyroid hormone (PTH) levels increase, thereby preventing hypocalcemia and associated complications. Objective This study aimed to determine when PTH and calcium abnormalities develop after birth if a STX16 deletion is inherited maternally. Methods Forty-four children of affected (n = 7) or unaffected (n = 7) females with a STX16 deletion were investigated for the presence of these variants. If a deletion was identified, measurement of PTH, calcium, phosphate, and thyrotropin (TSH) was advised. Results The STX16 deletion that causes AD-PHP1B was identified in 25 children. Pretreatment laboratory results were available for 19 of those cases. Elevated PTH levels were detected by 2 years of age, and these were progressively higher if laboratory testing was first performed after establishing the genetic defect later in life. Total serum calcium levels remained within normal limits until about 5 years of age. TSH levels showed no consistent rise over time. Conclusion Establishing whether a STX16 deletion is inherited from a female carrier of a disease-causing variant rapidly establishes the diagnosis of AD-PHP1B. Several years before overt hypocalcemia developed, PTH levels increased, thereby establishing the onset of PTH resistance. Our findings provide diagnostic guidance and when treatment with calcium and calcitriol should be considered in order to prevent hypocalcemia and associated sequelae.
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- 2021
7. Molecular Definition of Pseudohypoparathyroidism Variants
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Harald Jüppner
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musculoskeletal diseases ,0301 basic medicine ,medicine.medical_specialty ,Gs-alpha ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,030209 endocrinology & metabolism ,Biology ,Biochemistry ,Epigenesis, Genetic ,Loss of heterozygosity ,GNAS ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,cAMP ,Internal medicine ,Chromogranins ,GTP-Binding Protein alpha Subunits, Gs ,medicine ,GNAS complex locus ,Humans ,Epigenetics ,Pseudohypoparathyroidism ,phosphate ,Genetics ,Mini-Reviews ,calcium ,epigenetics ,TSH ,Biochemistry (medical) ,pseudohypoparathyroidism ,DNA Methylation ,medicine.disease ,parent-specific GNAS methylation ,030104 developmental biology ,Differentially methylated regions ,Molecular Diagnostic Techniques ,Uniparental Isodisomy ,STX16 ,biology.protein ,Pseudopseudohypoparathyroidism ,AcademicSubjects/MED00250 ,PTH - Abstract
Pseudohypoparathyroidism (PHP) and pseudopseudohypoparathyroidism (PPHP) are caused by mutations and/or epigenetic changes at the complex GNAS locus on chromosome 20q13.3 that undergoes parent-specific methylation changes at several differentially methylated regions (DMRs). GNAS encodes the alpha-subunit of the stimulatory G protein (Gsα) and several splice variants thereof. PHP type Ia (PHP1A) is caused by heterozygous inactivating mutations involving the maternal exons 1-13. Heterozygosity of these maternal GNAS mutations cause PTH-resistant hypocalcemia and hyperphosphatemia because paternal Gsα expression is suppressed in certain organs thus leading to little or no Gsα protein in the proximal renal tubules and other tissues. Besides biochemical abnormalities, PHP1A patients show developmental abnormalities, referred to as Albright’s hereditary osteodystrophy (AHO). Some, but not all of these AHO features are encountered also in patients affected by PPHP, who carry paternal Gsα-specific mutations and typically show no laboratory abnormalities. Autosomal dominant PHP type Ib (AD-PHP1B) is caused by heterozygous maternal deletions within GNAS or STX16, which are associated with loss of methylation at the A/B DMR alone or at all maternally methylated GNAS exons. Loss of methylation of exon A/B and the resulting biallelic expression of A/B transcript reduces Gsα expression thus leading to hormonal resistance. Epigenetic changes at all differentially methylated GNAS regions are also observed in sporadic PHP1B, which is the most frequent PHP1B variant. However, this disease variant remains unresolved at the molecular level, except for rare cases with paternal uniparental isodisomy or heterodisomy of chromosome 20q (patUPD20q).
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- 2021
8. Preferential Maternal Transmission of <scp> STX16‐GNAS </scp> Mutations Responsible for Autosomal Dominant Pseudohypoparathyroidism Type Ib ( <scp>PHP1B</scp> ): Another Example of Transmission Ratio Distortion
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Monica Reyes, Zentaro Kiuchi, and Harald Jüppner
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0301 basic medicine ,Genetics ,Mutation ,medicine.diagnostic_test ,Offspring ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Biology ,medicine.disease ,medicine.disease_cause ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine ,GNAS complex locus ,biology.protein ,Orthopedics and Sports Medicine ,Pseudopseudohypoparathyroidism ,STX16 ,Allele ,Pseudohypoparathyroidism ,Genetic testing - Abstract
Preferential transmission of a genetic mutation to the next generation, referred to as transmission ratio distortion (TRD), is well established for several dominant disorders, but underlying mechanisms remain undefined. Recently, TRD was reported for patients affected by pseudohypoparathyroidism type Ia or pseudopseudohypoparathyroidism. To determine whether TRD is observed also for autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP1B), we analyzed kindreds with the frequent 3-kb STX16 deletion or other STX16/GNAS mutations. If inherited from a female, these genetic defects lead to loss-of-methylation at exon A/B alone or at all three differentially methylated regions (DMR), resulting in parathyroid hormone (PTH)-resistant hypocalcemia and hyperphosphatemia and possibly resistance to other hormones. In total, we investigated 212 children born to 80 females who are unaffected carriers of a STX16/GNAS mutation (n = 47) or affected by PHP1B (n = 33). Of these offspring, 134 (63.2%) had inherited the genetic defect (p = .00012). TRD was indistinguishable for mothers with a STX16/GNAS mutation on their paternal (unaffected carriers) or maternal allele (affected). The mechanisms favoring transmission of the mutant allele remain undefined but are likely to include abnormalities in oocyte maturation. Search for mutations in available descendants of males revealed marginally significant evidence for TRD (p = .038), but these analyses are less reliable because many more offspring of males than females with a STX16/GNAS mutation were lost to follow-up (31 of 98 versus 6 of 218). This difference in follow-up is probably related to the fact that inheritance of a mutation from a male does not have clinical implications, whereas inheritance from an affected or unaffected female results in PHP1B. Lastly, affected PHP1B females had fewer descendants than unaffected carriers, but it remains unclear whether abnormal oocyte development or impaired actions of reproductive hormones are responsible. Our findings highlight previously not recognized aspects of AD-PHP1B that are likely to have implications for genetic testing and counseling. © 2020 American Society for Bone and Mineral Research (ASBMR).
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- 2020
9. A Novel <scp> GNAS </scp> Duplication Associated With Loss‐of‐Methylation Restricted to Exon <scp>A/B</scp> Causes Pseudohypoparathyroidism Type <scp>Ib</scp> ( <scp>PHP1B</scp> )
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Harald Jüppner, Sayaka Kawashima, Johanna A. Pallotta, Monica Reyes, Maki Fukami, Masayo Kagami, and Dirk Schnabel
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0301 basic medicine ,Genetics ,biology ,Endocrinology, Diabetes and Metabolism ,Breakpoint ,030209 endocrinology & metabolism ,medicine.disease ,03 medical and health sciences ,Exon ,030104 developmental biology ,0302 clinical medicine ,Gene duplication ,GNAS complex locus ,biology.protein ,medicine ,Orthopedics and Sports Medicine ,Epigenetics ,Multiplex ligation-dependent probe amplification ,Allele ,Pseudohypoparathyroidism - Abstract
Pseudohypoparathyroidism type Ib (PHP1B) is characterized by resistance to parathyroid hormone (PTH) leading to hypocalcemia and hyperphosphatemia, and in some cases resistance toward additional hormones. Patients affected by this disorder all share a loss-of-methylation (LOM) at the differentially methylated GNAS exon A/B, which reduces expression of the stimulatory G protein α-subunit (Gsα) from the maternal allele. This leads in the proximal renal tubules, where the paternal GNAS allele does not contribute much to expression of this signaling protein, to little or no Gsα expression thereby causing PTH resistance. We now describe a PHP1B patient with a de novo genomic GNAS duplication of approximately 88 kb, which is associated with LOM restricted to exon A/B alone. Multiplex ligation-dependent probe amplification (MLPA), comparative genomic hybridization (CGH), and whole-genome sequencing (WGS) established that the duplicated DNA fragment extends from GNAS exon AS1 (telomeric breakpoint) to a small region between two imperfect repeats just upstream of LOC105372695 (centromeric breakpoint). Our novel duplication is considerably shorter than previously described duplications/triplications in that portion of chromosome 20q13 and it does not affect methylation at exons AS and XL. Based on these and previous findings, it appears plausible that the identified genomic abnormality disrupts in cis the actions of a transcript that is required for establishing or maintaining exon A/B methylation. Our findings extend the molecular causes of PHP1B and provide additional insights into structural GNAS features that are required for maintaining maternal Gsα expression and for preventing PTH-resistance. © 2020 American Society for Bone and Mineral Research (ASBMR).
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- 2020
10. Selective pharmacological inhibition of the sodium-dependent phosphate cotransporter NPT2a promotes phosphate excretion
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Jeonifer Garren, Hiroshi Saito, Valerie Clerin, Harald Jüppner, Janka Kisucka, Monica Reyes, Kevin J. Filipski, and An Hai Nguyen
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Male ,0301 basic medicine ,Nephrology ,medicine.medical_specialty ,Sodium-Phosphate Cotransporter Proteins, Type IIa ,Phosphates ,Rats, Sprague-Dawley ,Excretion ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Hyperphosphatemia ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Renal Insufficiency, Chronic ,Mice, Knockout ,Reabsorption ,General Medicine ,Phosphate ,medicine.disease ,Rats ,Fibroblast Growth Factors ,Fibroblast Growth Factor-23 ,030104 developmental biology ,Endocrinology ,chemistry ,030220 oncology & carcinogenesis ,Tumoral calcinosis ,N-Acetylgalactosaminyltransferases ,Cotransporter ,Kidney disease - Abstract
The sodium-phosphate cotransporter NPT2a plays a key role in the reabsorption of filtered phosphate in proximal renal tubules, thereby critically contributing to phosphate homeostasis. Inadequate urinary phosphate excretion can lead to severe hyperphosphatemia as in tumoral calcinosis and chronic kidney disease (CKD). Pharmacological inhibition of NPT2a may therefore represent an attractive approach for treating hyperphosphatemic conditions. The NPT2a-selective small-molecule inhibitor PF-06869206 was previously shown to reduce phosphate uptake in human proximal tubular cells in vitro. Here, we investigated the acute and chronic effects of the inhibitor in rodents and report that administration of PF-06869206 was well tolerated and elicited a dose-dependent increase in fractional phosphate excretion. This phosphaturic effect lowered plasma phosphate levels in WT mice and in rats with CKD due to subtotal nephrectomy. PF-06869206 had no effect on Npt2a-null mice, but promoted phosphate excretion and reduced phosphate levels in normophophatemic mice lacking Npt2c and in hyperphosphatemic mice lacking Fgf23 or Galnt3. In CKD rats, once-daily administration of PF-06869206 for 8 weeks induced an unabated acute phosphaturic and hypophosphatemic effect, but had no statistically significant effect on FGF23 or PTH levels. Selective pharmacological inhibition of NPT2a thus holds promise as a therapeutic option for genetic and acquired hyperphosphatemic disorders.
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- 2020
11. Actions of Parathyroid Hormone Ligand Analogues in Humanized PTH1R Knockin Mice
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Eileen J Daley, Sung-Hee Yoon, Monica Reyes, Michael Bruce, Daniel J Brooks, Mary Bouxsein, John T Potts, Henry M Kronenberg, Marc N Wein, Beate Lanske, Harald Jüppner, and Thomas J Gardella
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Parathyroid Hormone-Related Protein ,Mice, Transgenic ,Ligands ,Rats ,Mice, Inbred C57BL ,Mice ,Endocrinology ,Parathyroid Hormone ,Animals ,Receptors, Parathyroid Hormone ,Amino Acid Sequence ,Receptor, Parathyroid Hormone, Type 1 ,Signal Transduction ,Research Article - Abstract
Rodent models are commonly used to evaluate parathyroid hormone (PTH) and PTH-related protein (PTHrP) ligands and analogues for their pharmacologic activities and potential therapeutic utility toward diseases of bone and mineral ion metabolism. Divergence, however, in the amino acid sequences of rodent and human PTH receptors (rat and mouse PTH1Rs are 91% identical to the human PTH1R) can lead to differences in receptor-binding and signaling potencies for such ligands when assessed on rodent vs human PTH1Rs, as shown by cell-based assays in vitro. This introduces an element of uncertainty in the accuracy of rodent models for performing such preclinical evaluations. To overcome this potential uncertainty, we used a homologous recombination-based knockin (KI) approach to generate a mouse (in-host strain C57Bl/6N) in which complementary DNA encoding the human PTH1R replaces a segment (exon 4) of the murine PTH1R gene so that the human and not the mouse PTH1R protein is expressed. Expression is directed by the endogenous mouse promoter and hence occurs in all biologically relevant cells and tissues and at appropriate levels. The resulting homozygous hPTH1R-KI (humanized) mice were healthy over at least 10 generations and showed functional responses to injected PTH analog peptides that are consistent with a fully functional human PTH1R in target bone and kidney cells. The initial evaluation of these mice and their potential utility for predicting behavior of PTH analogues in humans is reported here.
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- 2022
12. Functional Properties of Two Distinct PTH1R Mutants Associated With Either Skeletal Defects or Pseudohypoparathyroidism
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Ignacio Portales‐Castillo, Thomas Dean, Ashok Khatri, Harald Jüppner, and Thomas J Gardella
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Endocrinology, Diabetes and Metabolism ,Orthopedics and Sports Medicine - Abstract
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
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- 2022
13. Nephropathic Cystinosis: A Distinct Form of CKD–Mineral and Bone Disorder that Provides Novel Insights into the Regulation of FGF23
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Rachel I Gafni, William A. Gahl, Macarena Jiménez, Harald Jüppner, Myles Wolf, Galina Nesterova, Barbara Gales, Luis F de Castro, Michael T. Collins, Isidro B. Salusky, Mary Scott Roberts, Pablo Florenzano, Carlos Ferreira, Sri Harsha Tella, Katherine Wesseling-Perry, and Daniela Markovich
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,Urinary system ,Cystinosis ,Disease ,urologic and male genital diseases ,Gastroenterology ,Phosphates ,Young Adult ,Clinical Research ,Chronic kidney disease-mineral and bone disorder ,Nephropathic Cystinosis ,Internal medicine ,Lysosomal storage disease ,Homeostasis ,Humans ,Medicine ,Vitamin D ,Child ,Wasting ,Chronic Kidney Disease-Mineral and Bone Disorder ,business.industry ,Fanconi syndrome ,General Medicine ,medicine.disease ,female genital diseases and pregnancy complications ,Fibroblast Growth Factors ,Fibroblast Growth Factor-23 ,Nephrology ,Child, Preschool ,Renal physiology ,Female ,medicine.symptom ,business - Abstract
Background The rare lysosomal storage disease nephropathic cystinosis presents with renal Fanconi syndrome that evolves in time to CKD. Although biochemical abnormalities in common causes of CKD-mineral and bone disorder have been defined, it is unknown if persistent phosphate wasting in nephropathic cystinosis is associated with a biochemical mineral pattern distinct from that typically observed in CKD-mineral and bone disorder. Methods We assessed and compared determinants of mineral homeostasis in patients with nephropathic cystinosis across the predialysis CKD spectrum to these determinants in age- and CKD stage-matched patients, with causes of CKD other than nephropathic cystinosis. Results The study included 50 patients with nephropathic cystinosis-related CDK and 97 with CKD from other causes. All major aspects of mineral homeostasis were differentially effected in patients with CKD stemming from nephropathic cystinosis versus other causes. Patients with nephropathic cystinosis had significantly lower percent tubular reabsorption of phosphate and fibroblast growth factor-23 (FGF23) at all CKD stages, and lower blood phosphate in CKD stages 3-5. Linear regression analyses demonstrated lower FGF23 levels in nephropathic cystinosis participants at all CKD stages when corrected for eGFR and age, but not when adjusted for serum phosphate. Conclusions Nephropathic cystinosis CKD patients have mineral abnormalities that are distinct from those in CKD stemming from other causes. Persistently increased urinary phosphate excretion maintains serum phosphate levels within the normal range, thus protecting patients with nephropathic cystinosis from elevations of FGF23 during early CKD stages. These findings support the notion that phosphate is a significant driver of increased FGF23 levels in CKD and that mineral abnormalities associated with CKD are likely to vary depending on the underlying renal disease.
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- 2020
14. Recommendations for Diagnosis and Treatment of Pseudohypoparathyroidism and Related Disorders: An Updated Practical Tool for Physicians and Patients
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Serap Turan, Eileen M. Shore, Murat Bastepe, Olaf Hiort, Agnès Linglart, Francesca Elli, Roberto Bufo, Guiomar Perez de Nanclares, Michael A. Levine, Beatriz Lecumberri, M. Carola Zillikens, Rebeca Rodado, Vrinda Saraff, Ashley H. Shoemaker, Luisa De Sanctis, Guillemette Devernois, Gianpaolo De Filippo, Aurora Garcia Ramirez, Philip Murray, Susanne Thiele, Outi Mäkitie, Lars Rejnmark, Regina Matsunaga Martin, Manasori Minagawa, Timothee Choplin, Emily L. Germain-Lee, Giovanna Mantovani, Peter Kamenický, Harald Jüppner, Lionel Groussin, Nina Knight, Elvire Le Norcy, Anya Rothenbuhler, Neveen A. T. Hamdy, Robert J. Pignolo, David Monk, Thomas Eggermann, Caroline Silve, Arrate Pereda, Gabriel Á. Martos-Moreno, S Faisal Ahmed, Philip Woods, Patrick Hanna, Erasmus MC other, Internal Medicine, Mantovani, Giovanna, Bastepe, Murat, Monk, David, De Sanctis, Luisa, Thiele, Susanne, Ahmed, S. Faisal, Bufo, Roberto, Choplin, Timothee, De Filippo, Gianpaolo, Devernois, Guillemette, Eggermann, Thomas, Elli, Francesca M., Garcia Ramirez, Aurora, Germain-Lee, Emily L., Groussin, Lionel, Hamdy, Neveen A. T., Hanna, Patrick, Hiort, Olaf, Jueppner, Harald, Kamenicky, Peter, Knight, Nina, Le Norcy, Elvire, Lecumberri, Beatriz, Levine, Michael A., Maekitie, Outi, Martin, Regina, Martos-Moreno, Gabriel Angel, Minagawa, Manasori, Murray, Philip, Pereda, Arrate, Pignolo, Robert, Rejnmark, Lars, Rodado, Rebeca, Rothenbuhler, Anya, Saraff, Vrinda, Shoemaker, Ashley H., Shore, Eileen M., Silve, Caroline, Turan, Serap, Woods, Philip, Zillikens, M. Carola, Perez de Nanclares, Guiomar, Linglart, Agnes, HUS Children and Adolescents, Clinicum, Lastentautien yksikkö, Children's Hospital, University of Helsinki, and Helsinki University Hospital Area
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Pediatrics ,Endocrinology, Diabetes and Metabolism ,Acrodysostosis ,Psychological intervention ,Type 2 diabetes ,Ossification ,Parathyroid hormone ,STIMULATORY G-PROTEIN ,0302 clinical medicine ,Endocrinology ,3123 Gynaecology and paediatrics ,Diagnosis ,SKELETAL RESPONSIVENESS ,Medicine ,Child ,Subclinical infection ,030219 obstetrics & reproductive medicine ,Brachydactyly ,Calcium and phosphate metabolism ,Management ,3. Good health ,IDENTIFIES PDE4D MUTATIONS ,Pseudohypoparathyroidism ,Practice Guidelines as Topic ,INCREASED PREVALENCE ,medicine.symptom ,Bone disorders ,Consensus ,Treatment ,Adult ,Transition to Adult Care ,medicine.medical_specialty ,Genetic counseling ,PARATHYROID-HORMONE ,PROGRESSIVE OSSEOUS HETEROPLASIA ,030209 endocrinology & metabolism ,HORMONE-RELEASING-HORMONE ,Short stature ,Article ,03 medical and health sciences ,PSEUDO-PSEUDOHYPOPARATHYROIDISM ,Hypothyroidism ,Humans ,Dwarfism, Pituitary ,ALBRIGHT HEREDITARY OSTEODYSTROPHY ,business.industry ,ENERGY-EXPENDITURE ,medicine.disease ,Diabetes Mellitus, Type 2 ,Pediatrics, Perinatology and Child Health ,business - Abstract
Patients affected by pseudohypoparathyroidism (PHP) or related disorders are characterized by physical findings that may include brachydactyly, a short stature, a stocky build, early-onset obesity, ectopic ossifications, and neurodevelopmental deficits, as well as hormonal resistance most prominently to parathyroid hormone (PTH). In addition to these alterations, patients may develop other hormonal resistances, leading to overt or subclinical hypothyroidism, hypogonadism and growth hormone (GH) deficiency, impaired growth without measurable evidence for hormonal abnormalities, type 2 diabetes, and skeletal issues with potentially severe limitation of mobility. PHP and related disorders are primarily clinical diagnoses. Given the variability of the clinical, radiological, and biochemical presentation, establishment of the molecular diagnosis is of critical importance for patients. It facilitates management, including prevention of complications, screening and treatment of endocrine deficits, supportive measures, and appropriate genetic counselling. Based on the first international consensus statement for these disorders, this article provides an updated and ready-to-use tool to help physicians and patients outlining relevant interventions and their timing. A life-long coordinated and multidisciplinary approach is recommended, starting as far as possible in early infancy and continuing throughout adulthood with an appropriate and timely transition from pediatric to adult care.
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- 2020
15. A novel deletion involving the first GNAS exon encoding Gs alpha causes PHP1A without methylation changes at exon A/B
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Devon Campbell, Monica Reyes, Sare Betul Kaygusuz, Saygın Abali, Tulay Guran, Abdullah Bereket, Masayo Kagami, Serap Turan, Harald Jüppner, Acibadem University Dspace, and Campbell D., Reyes M., Kaygusuz S. B., Abalı S., Güran T., Bereket A., Kagami M., Turan S., Jüppner H.
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Male ,Physiology ,Endocrinology, Diabetes and Metabolism ,Medicine (miscellaneous) ,PROTEIN ,Sağlık Bilimleri ,Parathyroid hormone ,Pediatrics ,Clinical Medicine (MED) ,TIP, GENEL & DAHİLİ ,GTP-Binding Protein alpha Subunits, Gs ,Gsα ,Klinik Tıp (MED) ,Albright hereditary osteodystrophy ,MEDICINE, GENERAL & INTERNAL ,Klinik Tıp ,Exons ,General Medicine ,Tıp ,General Health Professions ,Medicine ,Epigenetics ,PEDİATRİ ,Family Practice ,Pseudohypoparathyroidism type Ia (PHP1A) ,Histology ,Gs-alpha ,PSEUDOHYPOPARATHYROIDISM ,Phosphate ,Assessment and Diagnosis ,Pathophysiology ,Article ,Çocuk Sağlığı ve Hastalıkları ,Child Health and Diseases ,Health Sciences ,Chromogranins ,Internal Medicine ,Humans ,GNAS methylation ,Pediatric Endocrinology and Metabolism ,Internal Medicine Sciences ,Fundamentals and Skills ,Gs alpha ,Dahili Tıp Bilimleri ,DNA Methylation ,CLINICAL MEDICINE ,CYCLASE ,GENE ,Pediatrics, Perinatology and Child Health ,Calcium ,Pediatrik Endokrinoloji ve Metabolizma - Abstract
Individuals affected by pseudohypoparathyroidism type 1A (PHP1A) display hyperphosphatemia and hypocalcemia despite elevated PTH levels, as well as features of Albright Hereditary Osteodystrophy (AHO). PHP1A is caused by variants involving the maternal GNAS exons 1-13 encoding the stimulatory G protein alpha-subunit (Gs alpha). MLPA and aCGH analysis led in a male PHP1A patient to identification of a de novo 1284-bp deletion involving GNAS exon 1. This novel variant overlaps with a previously identified 1438-bp deletion in another PHP1A patient (ref. Li et al. (2020) {[}13], patient 2) that extends from the exon 1 promoter into the up-stream intronic region. This latter deletion is associated with reduced methylation at GNAS exon A/B, i.e. the differentially methylated region (DMR) that is demethylated in most pseudohypoparathyroidism type 1B (PHP1B) patients. In contrast, genomic DNA from our patient revealed no evidence for an epigenetic GNAS defect as determined by MS-MLPA and pyrosequencing. These findings thus reduce the region, which, in addition to other nucleotide sequences telomeric of exon A/B, may undergo histone modifications or interacts with transcription factors and possibly as-yet unknown proteins that are required for establishing the maternal methylation imprints at this site. Taken together, nucleotide deletions or changes within an approximately 1300-bp region telomeric of exon A/B could be a cause of PHP1B variants with complete or incomplete loss-of-methylation at the exon A/B DMR. In addition, when investigating patients with suspected PHP1A, MLPA should be considered to search for structural abnormalities within this difficult to analyze genomic region comprising GNAS exon 1.
- Published
- 2022
16. Shortened Fingers and Toes: GNAS Abnormalities are Not the Only Cause
- Author
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Harald Jüppner, Monica Reyes, and Caroline Silve
- Subjects
musculoskeletal diseases ,0301 basic medicine ,medicine.medical_specialty ,Gs alpha subunit ,Cyclic AMP-Dependent Protein Kinase RIalpha Subunit ,Endocrinology, Diabetes and Metabolism ,Acrodysostosis ,Parathyroid hormone ,030105 genetics & heredity ,Article ,Fingers ,03 medical and health sciences ,Chondrocytes ,Endocrinology ,Internal medicine ,Heterotrimeric G protein ,Chromogranins ,GTP-Binding Protein alpha Subunits, Gs ,Internal Medicine ,medicine ,GNAS complex locus ,Humans ,Growth Plate ,Receptor ,PRKAR1A ,Receptor, Parathyroid Hormone, Type 1 ,biology ,Chemistry ,Parathyroid Hormone-Related Protein ,General Medicine ,Toes ,medicine.disease ,Cyclic AMP-Dependent Protein Kinases ,Cyclic Nucleotide Phosphodiesterases, Type 3 ,Cyclic Nucleotide Phosphodiesterases, Type 4 ,Musculoskeletal Abnormalities ,030104 developmental biology ,biology.protein ,Haploinsufficiency ,hormones, hormone substitutes, and hormone antagonists - Abstract
The PTH/PTHrP receptor (PTHR1) mediates the actions of parathyroid hormone (PTH) and PTH-related peptide (PTHrP) by coupling this G protein-coupled receptor (GPCR) to the alpha-subunit of the heterotrimeric stimulatory G protein (Gsα) and thereby to the formation of cAMP. In growth plates, PTHrP-dependent activation of the cAMP/PKA second messenger pathway prevents the premature differentiation of chondrocytes into hypertrophic cells resulting in delayed growth plate closure. Heterozygous mutations in GNAS, the gene encoding Gsα, lead to a reduction in cAMP levels in growth plate chondrocytes that is sufficient to cause shortening of metacarpals and/or -tarsals, i. e. typical skeletal aspects of Albright’s Hereditary Osteodystrophy (AHO). However, heterozygous mutations in other genes, including those encoding PTHrP, PRKAR1A, PDE4D, and PDE3A, can lead to similar or even more pronounced acceleration of skeletal maturation that is particularly obvious in hands and feet, and reduces final adult height. Genetic mutations other than those resulting in Gsα haploinsufficiency thus reduce intracellular cAMP levels in growth plate chondrocytes to a similar extent and thereby accelerate skeletal maturation.
- Published
- 2019
17. OR21-3 Spatial Signaling Bias of a Gain-of-Function PTH1R Mutant Associated with Delayed Ossification in Eiken Syndrome
- Author
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Thomas Dean, Thomas Gardella, Harald Jüppner, Sophia Savransky, Jean-Pierre Vilardaga, and Ignacio Portales-Castillo
- Subjects
Endocrinology, Diabetes and Metabolism - Abstract
Skeletal development is orchestrated by the interaction of the parathyroid hormone related peptide (PTHrP) with the parathyroid hormone receptor type 1 (PTH1R). Knock-out or severe deficiency of either PTH1R or PTHrP by homozygous loss-of-function mutations results in premature hypertrophy of chondrocytes and accelerated bone mineralization, leading to neonatal death. In contrast, patients with a heterozygous gain-of-function PTH1R mutation (H223R, T410P/R or I458K/R) present with Jansen metaphyseal chondrodysplasia (JMC), characterized by delayed bone mineralization, hypercalcemia, hypercalciuria and hypophosphatemia. Eiken syndrome is also characterized by markedly delayed bone mineralization but lacks the biochemical abnormalities of JMC. Eiken syndrome has been described for three unrelated families, in which there are one of three homozygous PTH1R mutations: R485X, E35K or Y134S. As the functional properties of these PTH1R mutants have not been studied, we assessed their characteristics in cell-based assays. GS22A cells (HEK293/Glosensor) were transiently transfected to express the WT or a mutant PTH1R. Cell surface expression levels assessed by extracellular HA tag-directed immunofluorescence flow cytometry and normalized to PTH1R-WT (100%) were 50% for PTH1R-R485X, 90% for PTH1R-E35K and 20% for PTH1R-Y134S. Dynamic cAMP measurements via the Glosensor reporter revealed that the basal activities of PTH1R-R485X and PTH1R-E35K were 7-fold and 1.5-fold higher than that of PTH1R-WT (p0.05). Intracellular calcium signaling assessed by changes in FURA2 fluorescence after PTHrP(1-36) (100 nM) addition was more robust with PTH1R-R485X than for PTH1R-WT (AUCs over 2.5 mins. = 606±9 vs 551±10, p=0.0074) and similar to PTH1R-WT with PTH1R-E35K and PTH1R-Y134S (p ≥0.2). Both basal and agonist-activated cAMP signaling by the R485X mutant were reduced by addition of a dTrp12-PTHrP(7-36) antagonist/inverse agonist analog. Fluorescence microscopy of HEK293/βarrestin2YFP (GBR24) cells stimulated with TMRPTH(1-34) revealed a clear association of βarrestin2YFP with PTH1R-WT, as well as with PTH1R-E35K and PTH1R-Y134S in internalized complexes, but no such association with PTH1R-R485X. Nevertheless, over-expression of βarrestin2YFP in GS22A cells markedly reduced basal and ligand-stimulated cAMP generation by PTH1R-R485X, consistent with a residual capacity of PTH1R-485X to bind βarrestin2. Treatment with the endocytosis inhibitor Dyngo4A in GS22A cells transfected with PTH1R-R485X completely blocked TMRPTH(1-34) internalization assessed by fluorescent microscopy, and enhanced ∼5-fold the cAMP response potency to PTH(1-34) vs DMSO treatment. In contrast, treatment with Dyngo4A did not increase PTH(1-34) cAMP potency in the PTH1R-WT. Collectively these results suggest that PTH1R-R485X signals via cAMP predominantly from the cell surface. The data reveal distinct functional properties for the three PTH1R mutants associated with Eiken syndrome and suggest a novel correlation between excessive PTH1R cAMP signaling due to impaired βarrestin-mediated internalization and a delay in ossification. Presentation: Monday, June 13, 2022 11:30 a.m. - 11:45 a.m.
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- 2022
18. Chronic Kidney Disease–Mineral and Bone Disorders
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Ignacio Portales-Castillo, Elaine W. Yu, Harald Jüppner, and Sagar U. Nigwekar
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business.industry ,Medicine ,Physiology ,business ,medicine.disease ,Kidney disease - Published
- 2021
19. Obesity and Gα
- Author
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Harald, Jüppner
- Subjects
Humans ,Obesity - Published
- 2021
20. Obesity and Gα(s) Variants
- Author
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Harald Jüppner
- Subjects
musculoskeletal diseases ,Genetics ,Gs alpha subunit ,biology ,business.industry ,General Medicine ,medicine.disease ,Obesity ,Article ,Exon ,GNAS complex locus ,biology.protein ,medicine ,business ,G alpha subunit ,Genetic association - Abstract
Mendes de Oliveira and colleagues now report in the Journal that variants in GNAS exons that encode the stimulatory G-protein alpha subunit (Gαs) have a strong genetic association with severe obesi...
- Published
- 2021
21. A Distinct Variant of Pseudohypoparathyroidism (PHP) First Characterized Some 41 Years Ago Is Caused by the 3‐kb STX16 Deletion
- Author
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Monica Reyes, Zentaro Kiuchi, Harald Jüppner, and Arnold S. Brickman
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Endocrinology, Diabetes and Metabolism ,PARATHYROID‐RELATED DISORDERS ,Parathyroid hormone ,Diseases of the musculoskeletal system ,Biology ,Exon ,CELL/TISSUE SIGNALING ,ENDOCRINE PATHWAYS ,medicine ,GNAS complex locus ,Orthopedics and Sports Medicine ,Osteodystrophy ,Epigenetics ,Allele ,Pseudohypoparathyroidism ,Genetics ,Orthopedic surgery ,DISORDERS OF CALCIUM/PHOSPHATE METABOLISM ,Original Articles ,medicine.disease ,EPIGENETICS ,RC925-935 ,biology.protein ,STX16 ,Original Article ,PTH/Vit D/FGF23 ,GENETIC RESEARCH ,RD701-811 - Abstract
In 1980, Farfel and colleagues (NEJM, 1980;303:237–42) provided first evidence for two distinct variants of pseudohypoparathyroidism (PHP) that present with hypocalcemia and impaired parathyroid hormone (PTH)‐stimulated urinary cAMP and phosphate excretion, either in the presence or absence of Albright's hereditary osteodystrophy (AHO). An “abnormal allele” and an “unexpressed allele” were considered as underlying defects, predictions that turned out to be correct for both forms of PHP. Patients affected by the first variant (now referred to as PHP1A) were later shown to be carriers of inactivating mutations involving the maternal GNAS exons encoding Gsα. Patients affected by the second variant (now referred to as PHP1B) were shown in the current study to carry a maternal 3‐kb STX16 deletion, the most frequent cause of autosomal dominant PHP1B, which is associated with loss of methylation at GNAS exon A/B that reduces or abolishes maternal Gsα expression. However, the distinct maternal mutations leading to either PHP1A or PHP1B are disease‐causing only because paternal Gsα expression in the proximal renal tubules is silenced, ie, “unexpressed.” Our findings resolve at the molecular level carefully conducted investigations reported some 41 years ago that had provided first clues for the existence of two distinct PHP variants. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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- 2021
22. High frequency of paternal iso or heterodisomy at chromosome 20 associated with sporadic pseudohypoparathyroidism 1B
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Marie-Laure Kottler, Matthieu Decamp, Nadia Coudray, Céline Ballandonne, Claire Bracquemart, Cindy Colson, Nicolas Gruchy, Hervé Mittre, Arnaud Molin, Harald Jüppner, Rieko Takatani, Nicolas Richard, Service de Génétique [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Œstrogènes, reproduction, cancer (OeReCa), Chiba University Hospital, Endocrine Unit, and Massachusetts General Hospital [Boston]
- Subjects
Adult ,Male ,0301 basic medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,Histology ,Physiology ,Endocrinology, Diabetes and Metabolism ,Chromosomes, Human, Pair 20 ,030209 endocrinology & metabolism ,Biology ,Article ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Gene Frequency ,GNAS complex locus ,medicine ,Humans ,Epigenetics ,Allele ,Imprinting (psychology) ,Pseudohypoparathyroidism ,Genetics ,Methylation ,Uniparental Disomy ,medicine.disease ,030104 developmental biology ,Differentially methylated regions ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,biology.protein ,Female ,Chromosome 20 - Abstract
International audience; Pseudohypoparathyroidism 1B (PHP1B) is caused by maternal epigenetic defects in the imprinted GNAS cluster. PHP1B can follow an autosomal dominant mode of inheritance or occur sporadically (spor-PHP1B). These latter patients present broad methylation changes of two or more differentially methylated regions (DMR) that, when mimicking the paternal allele, raises the suspicious of the occurrence of paternal uniparental disomy of chromosome 20 (upd(20)pat). A cohort of 33 spor-PHP1B patients was screened for upd(20)pat using comparative genomic hybridization with SNP-chip. Methylation analyses were assessed by methylation specific-multiplex ligation-dependent probe amplification. Upd(20)pat was identified in 6 patients, all exhibiting typical paternal methylation pattern compared to normal controls, namely a complete loss of methylation of GNAS A/B:TSS-DMR, negligible methylation at GNAS-AS1 :TSS-DMR and GNAS-XL:Ex1-DMR and complete gain of methylation at GNAS-NESP:TSS-DMR. The overall frequency of upd(20) is 18% in our cohort when searched considering both severe and partial loss of imprinting. However, twenty five patients displayed severe methylation pattern and the upd(20)pat frequency reaches 24% when searching in this group. Consequently, up to day, upd(20)pat is the most common anomaly than other genetic alterations in spor-PHP1B patients. Upd(20)pat occurrence is not linked to the parental age in contrast to upd(20)mat, strongly associated with an advanced maternal childbearing age. This study provides criteria to guide further investigations for upd(20)pat needed for an adequate genetic counseling.
- Published
- 2019
23. Pseudohypoparathyroidism
- Author
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Agnès Linglart, Michael A. Levine, and Harald Jüppner
- Subjects
Adult ,0301 basic medicine ,Endocrinology, Diabetes and Metabolism ,Drug Resistance ,030209 endocrinology & metabolism ,Article ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Endocrinology ,Parathyroid Hormone ,Pseudohypoparathyroidism ,Humans ,Bone Diseases ,Child - Abstract
Pseudohypoparathyroidism (PHP) refers to a heterogeneous group of uncommon, yet related metabolic disorders that are characterized by impaired activation of the Gsα/cAMP/PKA signaling pathway by parathyroid hormone (PTH) and other hormones that interact with Gsa-coupled receptors. Proximal renal tubular resistance to PTH and thus hypocalcemia and hyperphosphatemia, frequently in presence of brachydactyly, ectopic ossification, early-onset obesity, or short stature are common features of PHP. Registries and large cohorts of patients are needed to conduct clinical and genetic research, to improve the still limited knowledge regarding the underlying disease mechanisms, and allow the development of novel therapies.
- Published
- 2018
24. Lack of GNAS Remethylation During Oogenesis May Be a Cause of Sporadic Pseudohypoparathyroidism Type Ib
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Myrto Frangos, Chhavi Agarwal, Angelo Milioto, Peter J. Tebben, Patrick Hanna, Giovanna Mantovani, Monica Reyes, Giedre Grigelioniene, Verónica Mericq, Daniel Zeve, Zentaro Kiuchi, Serap Turan, Isidro B. Salusky, Any Chen, Harald Jüppner, and Svetlana Ten
- Subjects
Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Clinical Biochemistry ,Context (language use) ,Biology ,Biochemistry ,Intracytoplasmic sperm injection ,Endocrinology ,Oogenesis ,Internal medicine ,medicine ,GNAS complex locus ,Chromogranins ,GTP-Binding Protein alpha Subunits, Gs ,Humans ,Epigenetics ,Online Only Articles ,Pseudohypoparathyroidism ,Retrospective Studies ,Assisted reproductive technology ,In vitro fertilisation ,Biochemistry (medical) ,DNA Methylation ,medicine.disease ,biology.protein ,STX16 - Abstract
Context Pseudohypoparathyroidism type Ib (PHP1B) is characterized by hypocalcemia and hyperphosphatemia due to parathyroid hormone resistance in the proximal renal tubules. Maternal pathogenic STX16/GNAS variants leading to maternal epigenetic GNAS changes impair expression of the stimulatory G protein alpha-subunit (Gsα) thereby causing autosomal dominant PHP1B. In contrast, genetic defects responsible for sporadic PHP1B (sporPHP1B) remain mostly unknown. Objective Determine whether PHP1B encountered after in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) causes GNAS remethylation defects similar to those in sporPHP1B. Design Retrospective analysis. Results Nine among 36 sporPHP1B patients investigated since 2000, all with loss of methylation (LOM) at the 3 maternal GNAS differentially methylated regions (DMRs) and gain of methylation at the paternal NESP DMR, had been conceived through IVF or ICSI. Besides abnormal GNAS methylation, IVF/ICSI PHP1B cases revealed no additional imprinting defects. Three of these PHP1B patients have dizygotic twins, and 4 have IVF/ICSI-conceived siblings, all with normal GNAS methylation; 2 unaffected younger siblings were conceived naturally. Conclusion Sporadic and IVF/ICSI-conceived PHP1B patients revealed indistinguishable epigenetic changes at all 4 GNAS DMRs, thus suggesting a similar underlying disease mechanism. Given that remethylation at the 3 maternal DMRs occurs during oogenesis, male factors are unlikely to cause LOM postfertilization. Instead, at least some of the sporPHP1B variants could be caused by a defect or defects in an oocyte-expressed gene that is required for fertility and for re-establishing maternal GNAS methylation imprints. It remains uncertain, however, whether the lack of GNAS remethylation alone and the resulting reduction in Gsα expression is sufficient to impair oocyte maturation.
- Published
- 2021
25. Author response for 'A distinct variant of pseudohypoparathyroidism ( PHP ) first characterized some 41 years ago is caused by the 3‐kb STX16 deletion'
- Author
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null Zentaro Kiuchi, null Monica Reyes, null Arnold S. Brickman, and null Harald Jüppner
- Published
- 2021
26. A Novel Familial PHP1B Variant With Incomplete Loss of Methylation at GNAS-A/B and Enhanced Methylation at GNAS-AS2
- Author
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Brigitte Delemer, Patrick Hanna, Agnès Linglart, Bruno Francou, and Harald Jüppner
- Subjects
0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,030209 endocrinology & metabolism ,Context (language use) ,Biology ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Internal medicine ,medicine ,GNAS complex locus ,Chromogranins ,GTP-Binding Protein alpha Subunits, Gs ,Humans ,Allele ,Child ,Pseudohypoparathyroidism ,Clinical Research Article ,Biochemistry (medical) ,Methylation ,DNA Methylation ,Middle Aged ,medicine.disease ,Molecular biology ,genomic DNA ,030104 developmental biology ,chemistry ,biology.protein ,STX16 ,Female ,Transcription Initiation Site ,DNA - Abstract
Context Pseudohypoparathyroidism type 1B (PHP1B), also referred to as inactivating PTH/PTHrP signaling disorder (iPPSD), is characterized by proximal renal tubular resistance to parathyroid hormone (PTH) leading to hypocalcemia, hyperphosphatemia, and elevated PTH values. Autosomal dominant PHP1B (AD-PHP1B) with loss of methylation at the maternal GNAS A/B:TSS-DMR (transcription start site-differentially methylated region) alone can be caused by maternal deletions involving STX16. Objective Characterize a previously not reported AD-PHP1B family with loss of methylation at GNAS A/B:TSS-DMR, but without evidence for a STX16 deletion on the maternal allele and assess GNAS-AS2:TSS-DMR methylation. Methods DNA from 24 patients and 10 controls were investigated. AD-PHP1B patients without STX16 deletion from a single family (n = 5), AD-PHP1B patients with STX16 deletion (n = 9), sporPHP1B (n = 10), unaffected controls (n = 10), patUPD20 (n = 1), and matUPD20 (n = 1). Methylation and copy number analyses were performed by pyrosequencing, methylation-sensitive multiplex ligation-dependent probe amplification, and multiplex ligation-dependent probe amplification. Results Molecular cloning of polymerase chain reaction–amplified, bisulfite-treated genomic DNA from healthy controls revealed evidence for 2 distinct GNAS-AS2:TSS-DMR subdomains, named AS2-1 and AS2-2, which showed 16.0 ± 2.3% and 31.0 ± 2.2% methylation, respectively. DNA from affected members of a previously not reported AD-PHP1B family without the known genetic defects revealed incomplete loss of methylation at GNAS A/B:TSS-DMR, normal methylation at the 3 well-established maternal and paternal DMRs, and, surprisingly, increased methylation at AS2-1 (32.9 ± 3.5%), but not at AS2-2 (30.5 ± 2.9%). Conclusion The distinct methylation changes at the novel GNAS-AS2:TSS-DMR will help characterize further different PHP1B/iPPSD3 variants and will guide the search for underlying genetic defects, which may provide novel insights into the mechanisms underlying GNAS methylation.
- Published
- 2020
27. GNAS, PDE4D, and PRKAR1A Mutations and GNAS Methylation Changes Are Not a Common Cause of Isolated Early-Onset Severe Obesity Among Finnish Children
- Author
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Petra Loid, Minna Pekkinen, Monica Reyes, Taina Mustila, Heli Viljakainen, Harald Jüppner, Outi Mäkitie, HUS Children and Adolescents, Children's Hospital, University of Helsinki, Helsinki University Hospital Area, CAMM - Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, Research Programs Unit, Clinicum, Department of Food and Nutrition, and Lastentautien yksikkö
- Subjects
musculoskeletal diseases ,PSEUDOHYPOPARATHYROIDISM ,030204 cardiovascular system & hematology ,Pediatrics ,GNAS ,03 medical and health sciences ,0302 clinical medicine ,3123 Gynaecology and paediatrics ,030225 pediatrics ,GNAS complex locus ,Medicine ,Missense mutation ,Multiplex ligation-dependent probe amplification ,Epigenetics ,Pseudohypoparathyroidism ,2. Zero hunger ,Genetics ,biology ,business.industry ,lcsh:RJ1-570 ,lcsh:Pediatrics ,Brief Research Report ,G protein-cAMP-signaling ,acrodysostosis ,medicine.disease ,3. Good health ,Differentially methylated regions ,Pediatrics, Perinatology and Child Health ,biology.protein ,childhood-onset obesity ,STX16 ,Median body ,business - Abstract
Context: Pseudohypoparathyroidism type Ia (PHP1A) is caused by inactivating mutations involving GNAS exons 1–13, encoding the alpha-subunit of the stimulatory G protein (Gsα). Particularly PHP1A, but also other disorders involving the Gsα-cAMP-signaling pathway, have been associated with early-onset obesity. Thus, patients with mutations in the genes encoding PDE4D and PRKAR1A can also be obese. Furthermore, epigenetic GNAS changes, as in pseudohypoparathyroidism type Ib (PHP1B), can lead to excessive weight.Objective: Search for genetic variants in GNAS, PDE4D, and PRKAR1A and for methylation alterations at the GNAS locus in Finnish subjects with isolated severe obesity before age 10 years.Methods: Next generation sequencing to identify pathogenic variants in the coding exons of GNAS, PDE4D, and PRKAR1A; Multiplex Ligation-dependent Probe Amplification (MLPA) and methylation-sensitive MLPA (MS-MLPA) to search for deletions in GNAS and STX16, and for epigenetic changes at the four differentially methylated regions (DMR) within GNAS.Results: Among the 88 subjects (median age 13.8 years, median body mass index Z-score +3.9), we identified one rare heterozygous missense variant of uncertain significance in the XL exon of GNAS in a single patient. We did not identify clearly pathogenic variants in PDE4D and PRKAR1A, and no GNAS methylation changes were detected by MS-MLPA.Conclusions: Our results suggest that coding GNAS mutations or methylation changes at the GNAS DMRs, or coding mutations in PDE4D and PRKAR1A are not common causes of isolated childhood obesity in Finland.
- Published
- 2020
28. Immunohistochemicaf evidence of parathyroid hormone-related protein in human parathyroid tissue
- Author
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Jonas Rastad, Gunnel Bjerneroth, Göran Åkerström, Harald Jüppner, Claes Juhlin, Per Hellman, and Peter Ridefelt
- Subjects
medicine.medical_specialty ,Hyperparathyroidism ,Pathology ,Parathyroid hormone-related protein ,business.industry ,Endocrinology, Diabetes and Metabolism ,Parathyroid hormone ,General Medicine ,Parathyroid chief cell ,medicine.disease ,Pathology and Forensic Medicine ,Endocrinology ,Parathyroid carcinoma ,Internal medicine ,Monoclonal ,medicine ,Immunohistochemistry ,business ,hormones, hormone substitutes, and hormone antagonists ,Immunostaining - Abstract
Immunohistochemical staining for parathyroid hormone-related protein (PTHrp) was investigated on cryosections of 17 normal-sized human parathyroid glands, 47 adenomatous and hyperplastic glands of hypercalcemic patients with primary or uremic hyperparathyroidism, and 5 metastases of parathyroid carcinoma. Utilizing a polyclonal antiserum recognizing aminoterminal PTHrp, approximately two-thirds of the normal and enlarged glands but none of the parathyroid carcinomas demonstrated a conspicuous immunostaining. The extent and intensity of the reactivity varied between the glands even of individual patients. The staining was found in chief and oxyphilic parathyroid cells, and studies of cell suspensions substantiated that the immunoreaction was present also on the surface of the parathyroid cells. Reduced PTHrp expression in the functionally more dedifferentiated parathyroid tissue was suggested by comparison of the normal (i.e., suppressed) and adenomatous parathyroid tissue from the individual patients and by parallel stainings with the monoclonal El1 antibody, which recognizes a calcium sensor involved in the regulation of parathyroid hormone release. The findings substantiate a functional role for PTHrp in euparathyroid and hyperparathyroid individuals.
- Published
- 2020
29. Glycerol-3-phosphate is an FGF23 regulator derived from the injured kidney
- Author
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Marta Christov, Petra Simic, Andrew M. Tager, David B. Sykes, Sushrut S. Waikar, Clary B. Clish, Wenhan Chang, Robert E. Gerszten, Najihah Aziz, Jerold Chun, Eugene P. Rhee, Ian H. de Boer, Bryan Kestenbaum, Wondong Kim, David E. Leaf, Ravi Thadhani, Debby Ngo, Zhiqiang Cheng, Paola Divieti Pajevic, Harald Jüppner, Kerry A. Pierce, Nicolas Govea, Sammy Elmariah, Wen Zhou, and Marc N. Wein
- Subjects
0301 basic medicine ,Nephrology ,Fibroblast growth factor 23 ,Male ,Glycerol ,Kidney Disease ,urologic and male genital diseases ,Kidney ,Medical and Health Sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Bone disease ,Chronic kidney disease ,Receptors ,Lysophosphatidic acid ,Homeostasis ,2.1 Biological and endogenous factors ,Aetiology ,Receptors, Lysophosphatidic Acid ,Mice, Knockout ,Chemistry ,Acute kidney injury ,General Medicine ,Acute Kidney Injury ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Glycerophosphates ,Bone Biology ,Female ,Research Article ,medicine.medical_specialty ,Knockout ,Immunology ,Renal and urogenital ,Lysophosphatidic Acid ,Cell Line ,Phosphates ,03 medical and health sciences ,Internal medicine ,medicine ,Metabolomics ,Animals ,Humans ,LPAR1 ,medicine.disease ,Fibroblast Growth Factors ,stomatognathic diseases ,Fibroblast Growth Factor-23 ,030104 developmental biology ,Endocrinology ,Renal phosphate excretion - Abstract
Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that controls blood phosphate levels by increasing renal phosphate excretion and reducing 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D] production. Disorders of FGF23 homeostasis are associated with significant morbidity and mortality, but a fundamental understanding of what regulates FGF23 production is lacking. Because the kidney is the major end organ of FGF23 action, we hypothesized that it releases a factor that regulates FGF23 synthesis. Using aptamer-based proteomics and liquid chromatography–mass spectrometry–based (LC-MS–based) metabolomics, we profiled more than 1600 molecules in renal venous plasma obtained from human subjects. Renal vein glycerol-3-phosphate (G-3-P) had the strongest correlation with circulating FGF23. In mice, exogenous G-3-P stimulated bone and bone marrow FGF23 production through local G-3-P acyltransferase–mediated (GPAT-mediated) lysophosphatidic acid (LPA) synthesis. Further, the stimulatory effect of G-3-P and LPA on FGF23 required LPA receptor 1 (LPAR1). Acute kidney injury (AKI), which increases FGF23 levels, rapidly increased circulating G-3-P in humans and mice, and the effect of AKI on FGF23 was abrogated by GPAT inhibition or Lpar1 deletion. Together, our findings establish a role for kidney-derived G-3-P in mineral metabolism and outline potential targets to modulate FGF23 production during kidney injury.
- Published
- 2020
30. List of Contributors
- Author
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David Abraham, Maria Almeida, Elena Ambrogini, Andrew Arnold, Bence Bakos, Clemens Bergwitz, Daniel D. Bikle, John P. Bilezikian, Neil Binkley, Alessandro Bisello, L.F. Bonewald, George Bou-Gharios, Roger Bouillon, Mary L. Bouxsein, Brendan F. Boyce, Steven Boyd, Maria Luisa Brandi, David B. Burr, Laura M. Calvi, Ernesto Canalis, Xu Cao, Geert Carmeliet, Thomas O. Carpenter, Wenhan Chang, Shek Man Chim, Shilpa Choudhary, Sylvia Christakos, Yong-Hee Patricia Chun, Cristiana Cipriani, Roberto Civitelli, Thomas L. Clemens, Michael T. Collins, Caterina Conte, Mark S. Cooper, Jillian Cornish, Serge Cremers, Bess Dawson-Hughes, Benoit de Crombrugghe, Hector F. DeLuca, David W. Dempster, Matthew T. Drake, Patricia Ducy, Frank H. Ebetino, Klaus Engelke, Reinhold G. Erben, David R. Eyre, Charles R. Farber, Marina Feigenson, Mathieu Ferron, Pablo Florenzano, Francesca Fontana, Brian L. Foster, Peter A. Friedman, Seiji Fukumoto, Laura W. Gamer, Thomas J. Gardella, Patrick Garnero, Harry K. Genant, Francesca Giusti, Andy Göbel, David Goltzman, Jeffrey P. Gorski, James Griffith, R. Graham G Russell, Kurt D. Hankenson, Fadil M. Hannan, Stephen E. Harris, Iris R. Hartley, Christine Hartmann, Robert P. Heaney, Geoffrey N. Hendy, Matthew J. Hilton, Lorenz C. Hofbauer, Gill Holdsworth, Yi-Hsiang Hsu, David M. Hudson, Marja Hurley, Karl L. Insogna, Robert L. Jilka, Mark L. Johnson, Rachelle W. Johnson, Glenville Jones, Stefan Judex, Harald Jüppner, Ivo Kalajzic, Gérard Karsenty, Hua Zhu Ke, Sundeep Khosla, Douglas P. Kiel, J. Klein-Nulend, Frank C. Ko, Yasuhiro Kobayashi, Martin Konrad, Paul J. Kostenuik, Christopher S. Kovacs, Richard Kremer, Venkatesh Krishnan, Henry M. Kronenberg, Peter A. Lakatos, Uri A. Liberman, Joseph A. Lorenzo, Conor C. Lynch, Karen M. Lyons, Y. Linda Ma, Christa Maes, Michael Mannstadt, Stavros Manolagas, Robert Marcus, David E. Maridas, Pierre J. Marie, Francesca Marini, Jasna Markovac, T. John Martin, Brya G. Matthews, Antonio Maurizi, Sasan Mirfakhraee, Sharon M. Moe, David G. Monroe, Carolina A. Moreira, Ralph Müller, David S. Musson, Teruyo Nakatani, Dorit Naot, Nicola Napoli, Tally Naveh-Many, Edward F. Nemeth, Thomas L. Nickolas, Michael S. Ominsky, Noriaki Ono, David M. Ornitz, Nicola C. Partridge, Vihitaben S. Patel, J. Wesley Pike, Carol Pilbeam, Lori Plum, John T. Potts, J. Edward Puzas, Tilman D. Rachner, Audrey Rakian, Rubie Rakian, Nora E. Renthal, Julie A. Rhoades (Sterling), Mara Riminucci, Scott J. Roberts, Pamela Gehron Robey, Michael J. Rogers, G. David Roodman, Clifford J. Rosen, Vicki Rosen, David W. Rowe, Janet Rubin, Clinton T. Rubin, Karl P. Schlingmann, Ego Seeman, Markus J. Seibel, Chris Sempos, Dolores M. Shoback, Caroline Silve, Justin Silver, Natalie A. Sims, Frederick R. Singer, Joseph P. Stains, Steve Stegen, Paula H. Stern, Gaia Tabacco, Istvan Takacs, Naoyuki Takahashi, Donovan Tay, Anna Teti, Rajesh V. Thakker, Ryan E. Tomlinson, Francesco Tonelli, Dwight A. Towler, Elena Tsourdi, Chia-Ling Tu, Nobuyuki Udagawa, Connie M. Weaver, Marc N. Wein, Lee S. Weinstein, MaryAnn Weis, Michael P. Whyte, Bart O. Williams, Xin Xu, Shoshana Yakar, Yingzi Yang, Stefano Zanotti, and Hong Zhou
- Published
- 2020
31. Genetic disorders caused by mutations in the parathyroid hormone/parathyroid hormone–related peptide receptor, its ligands, and downstream effector molecules
- Author
-
Caroline Silve and Harald Jüppner
- Subjects
Ion homeostasis ,Parathyroid hormone receptor ,Chemistry ,Effector ,Parathyroid hormone ,Receptor ,hormones, hormone substitutes, and hormone antagonists ,Protein kinase C ,Cell biology ,G protein-coupled receptor ,Bone remodeling - Abstract
The parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor (PTHR1) is a G-protein-coupled receptor (GPCR) that mediates the actions of PTH and PTHrP through at least two distinct second-messenger pathways, cAMP/PKA and IP3/Ca++/PKC. PTHR1 thus has several different biological functions including the PTH-dependent regulation of calcium and phosphate homeostasis and bone turnover, and in addition to numerous other roles, the PTHrP-dependent differentiation of growth plate chondrocytes and thus bone elongation. Consequently, mutations affecting PTHR1, its two ligands, or the proteins involved in downstream signaling can be the cause of several different disorders affecting mineral ion homeostasis, growth plate biology, and bone and tooth development. Rare human disorders affecting these organ systems were shown to be caused by genetic defects in PTHR1, GNAS, PRKAR1A, PDE4D, PDE3A, and HDAC4 and thus have provided novel insights into the underlying regulatory mechanisms.
- Published
- 2020
32. Receptors for parathyroid hormone and parathyroid hormone–related protein
- Author
-
John T. Potts, Harald Jüppner, and Thomas J. Gardella
- Subjects
Parathyroid hormone-related protein ,Endosome ,Parathyroid hormone receptor ,Mineral metabolism ,Parathyroid hormone ,Gene rearrangement ,Biology ,Ligand (biochemistry) ,Receptor ,Cell biology - Abstract
This chapter describes the molecular biology of the parathyroid hormone receptor type 1 (PTHR1), specifically at the level of ligand binding and signal activation mechanisms. It begins with the basic protein architecture of the PTHR1, viewed particularly in the light of the X-ray crystal and cryo-electron microscopy structures that have emerged for several related class B G-protein-coupled receptors. The evolutionary history of the PTHR1 and its ligands is then outlined, from ancient origins in early chordates through the gene rearrangement events that led to the diversified receptor subtypes seen in various vertebrate lineages, as well the possibility for other receptors for C-terminal portions of parathyroid hormone and parathyroid hormone–related protein. Focus then turns to specific mechanisms of binding and activation at the PTHR1, and how new developing concepts of ligand-dependent conformational selectivity, temporal bias, and endosomal signaling are suggesting unique opportunities for new therapeutic ligand development. Disease-causing mutations in the PTHR1 are then discussed in terms of their impact on basic mechanisms, and finally presented are the recent advances in small-molecule ligand discovery for the PTHR1. In all, the chapter aims to sharpen awareness of progress made in defining how the PTHR1 functions and how it might be better targeted for the treatment of bone and mineral metabolism diseases.
- Published
- 2020
33. Phosphate homeostasis disorders
- Author
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Marta Christov and Harald Jüppner
- Subjects
0301 basic medicine ,Fibroblast growth factor 23 ,Hypophosphatemia ,Endocrinology, Diabetes and Metabolism ,Biology ,Kidney ,Bone and Bones ,Phosphates ,03 medical and health sciences ,Endocrinology ,medicine ,Homeostasis ,Humans ,Klotho ,Effector ,PHEX ,Kidney metabolism ,Phosphorus Metabolism Disorders ,medicine.disease ,DMP1 ,Cell biology ,Fibroblast Growth Factors ,Fibroblast Growth Factor-23 ,030104 developmental biology ,Ion homeostasis ,Metabolic Networks and Pathways - Abstract
Our understanding of the regulation of phosphate balance has benefited tremendously from the molecular identification and characterization of genetic defects leading to a number of rare inherited or acquired disorders affecting phosphate homeostasis. The identification of the key phosphate-regulating hormone, fibroblast growth factor 23 (FGF23), as well as other molecules that control its production, such as the glycosyltransferase GALNT3, the endopeptidase PHEX, and the matrix protein DMP1, and molecules that function as downstream effectors of FGF23 such as the longevity factor Klotho and the phosphate transporters NPT2a and NPT2c, has permitted us to understand the complex interplay that exists between the kidneys, bone, parathyroid, and gut. Such insights from genetic disorders have allowed not only the design of potent targeted treatment of FGF23-dependent hypophosphatemic conditions, but also provide clinically relevant observations related to the dysregulation of mineral ion homeostasis in health and disease.
- Published
- 2018
34. Parathyroid Hormone
- Author
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Thomas J. Gardella, Robert A. Nissenson, and Harald Jüppner
- Published
- 2018
35. Hypoparathyroidism
- Author
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Tamara Vokes, Mishaela R. Rubin, Karen K. Winer, Michael Mannstadt, Natalie E. Cusano, Harald Jüppner, and John P. Bilezikian
- Published
- 2018
36. Pseudohypoparathyroidism
- Author
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Agnès Linglart, Michael A. Levine, and Harald Jüppner
- Published
- 2018
37. Genetic and Epigenetic Defects at the GNAS Locus Lead to Distinct Patterns of Skeletal Growth but Similar Early-Onset Obesity
- Author
-
Daniele Tessaris, Alessia Usardi, Guiomar Perez de Nanclares, Giovanna Mantovani, Virginie Grybek, Luisa De Sanctis, Susanne Thiele, Anya Rothenbuhler, Arrate Pereda, Peter Kamenicky, Léa C. Tran, Agnès Linglart, Marie Laure Kottler, Léa Linglart, Francesca Elli, Harald Jüppner, Bruno Francou, Ashley H. Shoemaker, Javier Errea, and Patrick Hanna
- Subjects
0301 basic medicine ,medicine.medical_specialty ,biology ,business.industry ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Overweight ,medicine.disease ,Obesity ,Short stature ,Accelerated Growth ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Endocrinology ,Internal medicine ,medicine ,GNAS complex locus ,biology.protein ,Orthopedics and Sports Medicine ,Pseudopseudohypoparathyroidism ,medicine.symptom ,business ,Haploinsufficiency ,Pseudohypoparathyroidism - Abstract
Pseudohypoparathyroidism type 1A (PHP1A), pseudoPHP (PPHP), and PHP type 1B (PHP1B) are caused by maternal and paternal GNAS mutations and abnormal methylation at maternal GNAS promoter(s), respectively. Adult PHP1A patients are reportedly obese and short, whereas most PPHP patients are born small. In addition to parathyroid hormone (PTH) resistance, PHP1A and PHP1B patients may display early-onset obesity. Because early-onset and severe obesity and short stature are daily burdens for PHP1A patients, we aimed at improving knowledge on the contribution of the GNAS transcripts to fetal and postnatal growth and fat storage. Through an international collaboration, we collected growth and weight data from birth until adulthood for 306 PHP1A/PPHP and 220 PHP1B patients. PHP1A/PPHP patients were smaller at birth than healthy controls, especially PPHP (length Z-score: PHP1A -1.1 ± 1.8; PPHP -3.0 ± 1.5). Short stature is observed in 64% and 59% of adult PHP1A and PPHP patients. PHP1B patients displayed early postnatal overgrowth (height Z-score at 1 year: 2.2 ± 1.3 and 1.3 ± 1.5 in autosomal dominant and sporadic PHP1B) followed by a gradual decrease in growth velocity resulting in normal adult height (Z-score for both: -0.4 ± 1.1). Early-onset obesity characterizes GNAS alterations and is associated with significant overweight and obesity in adults (bodey mass index [BMI] Z-score: 1.4 ± 2.6, 2.1 ± 2.0, and 1.4 ± 1.9 in PPHP, PHP1A, and PHP1B, respectively), indicating that reduced Gsα expression is a contributing factor. The growth impairment in PHP1A/PPHP may be due to Gsα haploinsufficiency in the growth plates; the paternal XLαs transcript likely contributes to prenatal growth; for all disease variants, a reduced pubertal growth spurt may be due to accelerated growth plate closure. Consequently, early diagnosis and close follow-up is needed in patients with GNAS defects to screen and intervene in case of early-onset obesity and decreased growth velocity. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).
- Published
- 2018
38. Discovery of Orally Bioavailable Selective Inhibitors of the Sodium-Phosphate Cotransporter NaPi2a (SLC34A1)
- Author
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Samit Kumar Bhattacharya, Aaron C. Smith, Paula M. Loria, Kevin J. Filipski, Kun Song, Edward L. Conn, Yan Weng, Markus Boehm, Matthew F. Sammons, Harald Jüppner, Andre Shavnya, Jane Panteleev, Janice A. Brown, Valerie Clerin, and Carie Facemire
- Subjects
0301 basic medicine ,Kidney ,urogenital system ,Urinary system ,Organic Chemistry ,Transporter ,Pharmacology ,Phosphate ,Biochemistry ,Bioavailability ,Excretion ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Drug Discovery ,medicine ,Cotransporter ,Hormone - Abstract
[Image: see text] Sodium-phosphate cotransporter 2a, or NaPi2a (SLC34A1), is a solute-carrier (SLC) transporter located in the kidney proximal tubule that reabsorbs glomerular-filtered phosphate. Inhibition of NaPi2a may enhance urinary phosphate excretion and correct maladaptive mineral and hormonal derangements associated with increased cardiovascular risk in chronic kidney disease–mineral and bone disorder (CKD-MBD). To date, only nonselective NaPi inhibitors have been described. Herein, we detail the discovery of the first series of selective NaPi2a inhibitors, resulting from optimization of a high-throughput screening hit. The oral PK profile of inhibitor PF-06869206 (6f) in rodents allows for the exploration of the pharmacology of selective NaPi2a inhibition.
- Published
- 2018
39. FGF23 and Left Ventricular Hypertrophy in Children with CKD
- Author
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Susan L. Furth, Aisha Betoko, Harald Jüppner, Bradley A. Warady, Mark Mitsnefes, Myles Wolf, Michael F. Schneider, Anthony A. Portale, and Isidro B. Salusky
- Subjects
Male ,medicine.medical_specialty ,Adolescent ,Epidemiology ,030232 urology & nephrology ,030204 cardiovascular system & hematology ,Kidney ,urologic and male genital diseases ,Critical Care and Intensive Care Medicine ,Left ventricular hypertrophy ,Severity of Illness Index ,Ventricular Function, Left ,Muscle hypertrophy ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Interquartile range ,Internal medicine ,Prevalence ,medicine ,Humans ,Prospective Studies ,Renal Insufficiency, Chronic ,Risk factor ,Child ,Transplantation ,Ventricular Remodeling ,business.industry ,Age Factors ,Original Articles ,Odds ratio ,Prognosis ,medicine.disease ,Confidence interval ,Up-Regulation ,Fibroblast Growth Factors ,Fibroblast Growth Factor-23 ,Nephrology ,North America ,Cardiology ,Female ,Hypertrophy, Left Ventricular ,business ,Body mass index ,Biomarkers ,Glomerular Filtration Rate ,Kidney disease - Abstract
Background and Objectives High plasma concentration of fibroblast growth factor 23 (FGF23) is a risk factor for left ventricular hypertrophy (LVH) in adults with CKD, and induces myocardial hypertrophy in experimental CKD. We hypothesized that high FGF23 levels associate with a higher prevalence of LVH in children with CKD. Design, setting, participants, & measurements We performed echocardiograms and measured plasma C-terminal FGF23 concentrations in 587 children with mild-to-moderate CKD enrolled in the Chronic Kidney Disease in Children (CKiD) study. We used linear and logistic regression to analyze the association of plasma FGF23 with left ventricular mass index (LVMI) and LVH (LVMI ≥95th percentile), adjusted for demographics, body mass index, eGFR, and CKD-specific factors. We also examined the relationship between FGF23 and LVH by eGFR level. Results Median age was 12 years (interquartile range, 8–15) and eGFR was 50 ml/min per 1.73 m2 (interquartile range, 38–64). Overall prevalence of LVH was 11%. After adjustment for demographics and body mass index, the odds of having LVH was higher by 2.53 (95% confidence interval, 1.28 to 4.97; P Conclusions Plasma FGF23 concentration ≥170 RU/ml is an independent predictor of LVH in children with eGFR≥45 ml/min per 1.73 m2.
- Published
- 2017
40. A novel deletion involving GNAS exon 1 causes PHP1A and further refines the region required for normal methylation at exon A/B
- Author
-
Nese Ersoz Gulcelik, Murat Bastepe, Monica Reyes, Anara Karaca, and Harald Jüppner
- Subjects
Adult ,musculoskeletal diseases ,0301 basic medicine ,Histology ,Physiology ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Article ,03 medical and health sciences ,Exon ,0302 clinical medicine ,Chromogranins ,GTP-Binding Protein alpha Subunits, Gs ,GNAS complex locus ,Humans ,Genetics ,biology ,Intron ,Exons ,Methylation ,DNA Methylation ,Molecular biology ,Pedigree ,030104 developmental biology ,Differentially methylated regions ,CpG site ,Pseudohypoparathyroidism ,DNA methylation ,biology.protein ,Female ,STX16 ,Gene Deletion - Abstract
GNAS exons 1–13 encode the biallelically expressed alpha-subunit of the stimulatory G protein (Gαs). Additional transcripts derived from this locus use alternative first exons that undergo parent-specific methylation, thus allowing transcription only from the non-modified allele. Pseudohypoparathyroidism type Ia (PHP1A) is characterized by Albright's Hereditary Osteodystrophy (AHO) and resistance to multiple hormones; this disorder is caused by maternal inactivating mutations involving Gαs exons. In contrast, pseudohypoparathyroidism type Ib (PHP1B) is characterized mostly by resistance to PTH and often mild TSH resistance, usually without AHO features. The autosomal dominant variant of PHP1B (AD-PHP1B) is caused by maternal deletions in GNAS or STX16 that reduce Gαs expression through loss-of-methylation at GNAS exon A/B alone or at multiple differentially methylated regions (DMR). Several large maternal deletions involve not only GNAS exons 1–13, but also one or several GNAS DMRs, thus causing PHP1A combined with apparent GNAS epigenetic changes that are indistinguishable from those observed in PHP1B. Some of these deletions include a large CpG island extending from exon A/B to the intron between GNAS exons 1 and 2, but there is no evidence for parent-specific exon 1 methylation. We now describe a family in which the female proband and her daughter presented with hypocalcemia, elevated PTH levels, shortened metacarpals, and obesity, but without obvious neurocognitive abnormalities. A maternally inherited 2015-bp deletion that includes GNAS exon 1was identified thereby establishing the diagnosis of PHP1A. The centromeric deletion breakpoint is located 178 bp upstream of exon 1, yet no methylation changes were observed at exon A/B. This novel deletion therefore refines further the region between exon A/B and exon 1 that is critical for establishing or maintaining normal methylation at GNAS exon A/B. 1.
- Published
- 2017
41. Mice maintain predominantly maternal Gαs expression throughout life in brown fat tissue (BAT), but not other tissues
- Author
-
Olta Tafaj, Ugur M. Ayturk, Steven Hann, Matthew L. Warman, and Harald Jüppner
- Subjects
Male ,musculoskeletal diseases ,0301 basic medicine ,medicine.medical_specialty ,Histology ,Gs alpha subunit ,Physiology ,Endocrinology, Diabetes and Metabolism ,Adipose tissue ,030209 endocrinology & metabolism ,Locus (genetics) ,Biology ,Article ,Mice ,03 medical and health sciences ,Exon ,0302 clinical medicine ,Adipose Tissue, Brown ,Internal medicine ,Brown adipose tissue ,Chromogranins ,GTP-Binding Protein alpha Subunits, Gs ,medicine ,GNAS complex locus ,Animals ,Allele ,Alleles ,Promoter ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Gene Expression Regulation ,biology.protein ,Female - Abstract
The murine Gnas (human GNAS) locus gives rise to Gαs and different splice variants thereof. The Gαs promoter is not methylated thus allowing biallelic expression in most tissues. In contrast, the alternative first Gnas/GNAS exons and their promoters undergo parent specific methylation, which limits transcription to the non-methylated allele. Pseudohypoparathyroidism type Ia (PHP1A) or type Ib (PHP1B) are caused by heterozygous maternal GNAS mutations suggesting that little or no Gαs is derived in some tissues from the non-mutated paternal GNAS thereby causing hormonal resistance. Previous data had indicated that Gαs is mainly derived from the maternal Gnas allele in brown adipose tissue (BAT) of newborn mice, yet it is biallelically expressed in adult BAT. This suggested that paternal Gαs expression is regulated by an unknown factor(s) that varies considerably with age. To extend these findings, we now used a strain-specific SNP in Gnas exon 11 (rs13460569) for evaluation of parent-specific Gαs expression through the densitometric quantification of BanII-digested RT-PCR products and digital droplet PCR (ddPCR). At all investigated ages, Gαs transcripts were derived in BAT predominantly from the maternal Gnas allele, while kidney and liver showed largely biallelic Gαs expression. Only low or undetectable levels of other paternally Gnas-derived transcripts were observed, making it unlikely that these are involved in regulating paternal Gαs expression. Our findings suggest that a cis-acting factor could be implicated in reducing paternal Gαs expression in BAT and presumably in proximal renal tubules, thereby causing PTH-resistance if the maternal GNAS/Gnas allele is mutated.
- Published
- 2017
42. Case 17-2017
- Author
-
Ryan W. Carroll, Harald Jüppner, Michelle Katz, and Elahna Paul
- Subjects
Male ,0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Thyrotropin ,030209 endocrinology & metabolism ,Article ,Drooling ,Diagnosis, Differential ,03 medical and health sciences ,0302 clinical medicine ,Swallowing ,Humans ,Medicine ,Burping ,Vitamin D ,Phosphorus blood ,Hypocalcemia ,business.industry ,Diagnostic test ,Phosphorus ,Fear ,Vitamins ,General Medicine ,Emergency department ,DNA Methylation ,medicine.disease ,Deglutition ,Airway Obstruction ,030104 developmental biology ,Pseudohypoparathyroidism ,Anesthesia ,Calcium ,medicine.symptom ,business ,Choking - Abstract
A 14-year-old boy was seen in the emergency department because he had a fear of choking while swallowing that had lasted for 2 days. On examination, he was alert and appeared to be anxious, with involuntary burping and drooling. Diagnostic tests were performed.
- Published
- 2017
43. A Large Inversion InvolvingGNASExon A/B and All Exons Encoding Gsα Is Associated With Autosomal Dominant Pseudohypoparathyroidism Type Ib (PHP1B)
- Author
-
Marja Ala-Houhala, Pasi I Nevalainen, Jesper Eisfeldt, Outi Mäkitie, Monica Reyes, Olta Tafaj, Giedre Grigelioniene, Harald Jüppner, Daniel Nilsson, Rieko Takatani, Anna Lindstrand, Angelo Molinaro, Susanne Thiele, and Marie-Laure Kottler
- Subjects
musculoskeletal diseases ,0301 basic medicine ,Genetics ,Proband ,biology ,Endocrinology, Diabetes and Metabolism ,Haplotype ,Locus (genetics) ,medicine.disease ,03 medical and health sciences ,Exon ,030104 developmental biology ,medicine ,GNAS complex locus ,biology.protein ,Orthopedics and Sports Medicine ,STX16 ,Pseudohypoparathyroidism ,Chromosomal inversion - Abstract
Pseudohypoparathyroidism type Ib (PHP1B) is characterized primarily by resistance to parathyroid hormone (PTH) and thus hypocalcemia and hyperphosphatemia, in most cases without evidence for Albright hereditary osteodystrophy (AHO). PHP1B is associated with epigenetic changes at one or several differentially-methylated regions (DMRs) within GNAS, which encodes the α-subunit of the stimulatory G protein (Gsα) and splice variants thereof. Heterozygous, maternally inherited STX16 or GNAS deletions leading to isolated loss-of-methylation (LOM) at exon A/B alone or at all maternal DMRs are the cause of autosomal dominant PHP1B (AD-PHP1B). In this study, we analyzed three affected individuals, the female proband and her two sons. All three revealed isolated LOM at GNAS exon A/B, whereas the proband's healthy maternal grandmother and uncle showed normal methylation at this locus. Haplotype analysis was consistent with linkage to the STX16/GNAS region, yet no deletion could be identified. Whole-genome sequencing of one of the patients revealed a large heterozygous inversion (1,882,433 bp). The centromeric breakpoint of the inversion is located 7,225 bp downstream of GNAS exon XL, but its DMR showed no methylation abnormality, raising the possibility that the inversion disrupts a regulatory element required only for establishing or maintaining exon A/B methylation. Because our three patients presented phenotypes consistent with PHP1B, and not with PHP1A, the Gsα promoter is probably unaffected by the inversion. Our findings expand the spectrum of genetic mutations that lead to LOM at exon A/B alone and thus biallelic expression of the transcript derived from this alternative first GNAS exon. © 2017 American Society for Bone and Mineral Research.
- Published
- 2017
44. Acute Parathyroid Hormone Injection Increases C-Terminal but Not Intact Fibroblast Growth Factor 23 Levels
- Author
-
Olena Andrukhova, Seham M. Rabadi, Braden Corbin, Julia M. Hum, Marta Christov, Akira Maeda, Reinhold G. Erben, Vanessa M. Knab, Pu Ni, Harald Jüppner, and Kenneth E. White
- Subjects
Male ,0301 basic medicine ,Fibroblast growth factor 23 ,medicine.medical_specialty ,Parathyroid hormone ,030209 endocrinology & metabolism ,Fibroblast growth factor ,Osteocytes ,Bone and Bones ,Injections ,Protein kinase C signaling ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Protein Domains ,In vivo ,Internal medicine ,medicine ,Animals ,Cyclic adenosine monophosphate ,Protein kinase A ,Furin ,Cells, Cultured ,Mice, Knockout ,biology ,Peptide Fragments ,Fibroblast Growth Factors ,Mice, Inbred C57BL ,Fibroblast Growth Factor-23 ,stomatognathic diseases ,030104 developmental biology ,chemistry ,Parathyroid Hormone ,biology.protein ,Female ,Special Section: Metabolism in Endocrine Health and Disease - Abstract
The acute effects of parathyroid hormone (PTH) on fibroblast growth factor 23 (FGF23) in vivo are not well understood. After a single subcutaneous PTH (1–34) injection (50 nmol/kg) in mice, FGF23 levels were assessed in plasma using assays that measure either intact alone (iFGF23) or intact/C-terminal FGF23 (cFGF23). Furthermore, FGF23 messenger RNA (mRNA) and protein levels were assessed in bone. In addition, we examined the effects of PTH treatment on FGF23 production in vitro using differentiated calvarial osteocyte-like cells. cFGF23 levels increased by three- to fivefold within 2 hours following PTH injection, which returned to baseline by 4 hours. In contrast, iFGF23 levels remained unchanged for the first 2 hours, yet declined to ∼60% by 6 hours and remained suppressed before returning to baseline after 24 hours. Using homozygous mice for an autosomal dominant hypophosphatemic rickets–FGF23 mutation or animals treated with a furin inhibitor, we showed that cFGF23 and iFGF23 levels increased equivalently after PTH injection. These findings are consistent with increased FGF23 production in bone, yet rapid cleavage of the secreted intact protein. Using primary osteocyte-like cell cultures, we showed that PTH increased FGF23 mRNA expression through cyclic adenosine monophosphate/protein kinase A, but not inositol triphosphate/protein kinase C signaling; PTH also increased furin protein levels. In conclusion, PTH injection rapidly increases FGF23 production in bone in vivo and in vitro. However, iFGF23 is rapidly degraded. At later time points through an unidentified mechanism, a sustained decrease in FGF23 production occurs.
- Published
- 2017
45. Jansen Metaphyseal Chondrodysplasia due to Heterozygous H223R-PTH1R Mutations With or Without Overt Hypercalcemia
- Author
-
Dhanya Yesodharan, Craig B. Langman, Eduardo Fernandez-Rebollo, Sheela Nampoothiri, Thomas J. Gardella, Eric T. Rush, and Harald Jüppner
- Subjects
musculoskeletal diseases ,Male ,0301 basic medicine ,medicine.medical_specialty ,Pathology ,Metaphyseal chondrodysplasia ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Parathyroid hormone ,Context (language use) ,Osteochondrodysplasias ,medicine.disease_cause ,Biochemistry ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Endocrinology ,Internal medicine ,medicine ,Humans ,Family history ,Receptor, Parathyroid Hormone, Type 1 ,Sanger sequencing ,Mutation ,Parathyroid hormone receptor ,business.industry ,fungi ,Biochemistry (medical) ,food and beverages ,Infant ,Original Articles ,030206 dentistry ,medicine.disease ,Pedigree ,030104 developmental biology ,Parathyroid Hormone ,Dysplasia ,Child, Preschool ,Hypercalcemia ,symbols ,Female ,business ,hormones, hormone substitutes, and hormone antagonists - Abstract
Jansen's metaphyseal chondrodysplasia (JMC) is a rare skeletal dysplasia characterized by abnormal endochondral bone formation and typically severe hypercalcemia despite normal/low levels of PTH. Five different heterozygous activating PTH/PTHrP receptor (PTH1R) mutations that change one of three different amino acid residues are known to cause JMC.Establishing the diagnosis of JMC during infancy or early childhood can be challenging, especially in the absence of family history and/or overt hypercalcemia. We therefore sought to provide radiographic findings supporting this diagnosis early in life.Three patients, a mother and her two sons, had radiographic evidence for JMC. However, obvious hypercalcemia and suppressed PTH levels were encountered only in both affected children. Sanger sequencing and endonuclease (SphI) digestion of PCR-amplified genomic DNA were performed to search for the H223R-PTH1R mutation.The heterozygous H223R mutation was identified in all three affected individuals. Surprisingly, however, the now 38-year-old mother was never overtly hypercalcemic and was therefore not diagnosed until her sons were found to be affected by JMC at the ages of 28 months and 40 days, respectively. The presented radiographic findings at different ages will help diagnose other infants/toddlers suspected of having JMC.The H223R mutation is typically associated with profound hypercalcemia despite low/normal PTH levels. However, the findings presented herein show that overt hypercalcemia is not always encountered in JMC, even if caused by this relatively frequent mutation, which is similar to observations with other PTH1R mutations that show less constitutive activity.
- Published
- 2016
46. Salt-inducible kinases dictate parathyroid hormone 1 receptor action in bone development and remodeling
- Author
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Maureen J O'Meara, Daniel J. Brooks, Janaina S. Martins, Ugur M. Ayturk, Hiroshi Noda, Rebecca Berdeaux, Wanida Ono, Marc Foretz, Christopher J Janton, Christian D. Castro, Marc N. Wein, Mizuki Nagata, Thomas J. Gardella, Shigeki Nishimori, Ruslan I. Sadreyev, Henry M. Kronenberg, Harald Jüppner, Mary L. Bouxsein, Murat Cetinbas, Michael Bruce, Instituto Nacional de Pesquisas da Amazônia (INPA), University of Adelaide, Orthopedic Biomechanics Laboratory (BIDMC), Beth Israel Deaconess Medical Center [Boston] (BIDMC), Harvard Medical School [Boston] (HMS)-Harvard Medical School [Boston] (HMS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Endocrine Unit, Massachusetts General Hospital [Boston], Beth Israel Deaconess Medical Center [Boston] (BIDMC)-Harvard Medical School [Boston] (HMS), Endocrine Unit, Department of Medicine, and Pediatric Neprology Unit, and MassGeneral Hospital for Children
- Subjects
Male ,0301 basic medicine ,Bone disease ,Parathyroid hormone ,Mice ,0302 clinical medicine ,Endocrinology ,Bone cell ,Phosphorylation ,Receptor ,Mice, Knockout ,Extracellular Matrix Proteins ,Kinase ,Bone development ,General Medicine ,Protein-Tyrosine Kinases ,[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,Phenotype ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM] ,Cell biology ,Histone ,Parathyroid Hormone ,030220 oncology & carcinogenesis ,Bone Biology ,Bone Remodeling ,hormones, hormone substitutes, and hormone antagonists ,Research Article ,Protein Serine-Threonine Kinases ,Biology ,Osteocytes ,03 medical and health sciences ,Chondrocytes ,medicine ,Animals ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,Cell Proliferation ,Receptor, Parathyroid Hormone, Type 1 ,G protein-coupled receptor ,Osteoblasts ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,Hypertrophy ,medicine.disease ,Osteoclast/osteoblast biology ,030104 developmental biology ,Animals, Newborn ,Mutation ,biology.protein ,Transcriptome ,Gene Deletion - Abstract
International audience; The parathyroid hormone 1 receptor (PTH1R) mediates the biologic actions of parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP). Here, we showed that salt-inducible kinases (SIKs) are key kinases that control the skeletal actions downstream of PTH1R and that this GPCR, when activated, inhibited cellular SIK activity. Sik gene deletion led to phenotypic changes that were remarkably similar to models of increased PTH1R signaling. In growth plate chondrocytes, PTHrP inhibited SIK3, and ablation of this kinase in proliferating chondrocytes rescued perinatal lethality of PTHrP-null mice. Combined deletion of Sik2 and Sik3 in osteoblasts and osteocytes led to a dramatic increase in bone mass that closely resembled the skeletal and molecular phenotypes observed when these bone cells express a constitutively active PTH1R that causes Jansen's metaphyseal chondrodysplasia. Finally, genetic evidence demonstrated that class IIa histone deacetylases were key PTH1R-regulated SIK substrates in both chondrocytes and osteocytes. Taken together, our findings establish that SIK inhibition is central to PTH1R action in bone development and remodeling. Furthermore, this work highlights the key role of cAMP-regulated SIKs downstream of GPCR action.
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- 2019
47. An Inverse Agonist Ligand of the PTH Receptor Partially Rescues Skeletal Defects in a Mouse Model of Jansen's Metaphyseal Chondrodysplasia
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Monica Reyes, Ernestina Schipani, Mary L. Bouxsein, Janaina S. Martins, Thomas Dean, Hiroshi Noda, Jun Guo, Michael Armanini, Ashok Khatri, Daniel J. Brooks, John T. Potts, Harald Jüppner, Marie B. Demay, and Thomas J. Gardella
- Subjects
Genetically modified mouse ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Dwarfism ,Mice, Transgenic ,Ligands ,Osteochondrodysplasias ,Article ,Bone remodeling ,Mice ,Skeletal disorder ,In vivo ,Internal medicine ,medicine ,Inverse agonist ,Animals ,Orthopedics and Sports Medicine ,Receptor ,Receptor, Parathyroid Hormone, Type 1 ,Chemistry ,Parathyroid hormone receptor ,medicine.disease ,Jansen's metaphyseal chondrodysplasia ,Fibroblast Growth Factor-23 ,Endocrinology ,Parathyroid Hormone - Abstract
Jansen's metaphyseal chondrodysplasia (JMC) is a rare disease of bone and mineral ion physiology that is caused by activating mutations in PTHR1. Ligand-independent signaling by the mutant receptors in cells of bone and kidney results in abnormal skeletal growth, excessive bone turnover, and chronic hypercalcemia and hyperphosphaturia. Clinical features further include short stature, limb deformities, nephrocalcinosis, and progressive losses in kidney function. There is no effective treatment option available for JMC. In previous cell-based assays, we found that certain N-terminally truncated PTH and PTHrP antagonist peptides function as inverse agonists and thus can reduce the high rates of basal cAMP signaling exhibited by the mutant PTHR1s of JMC in vitro. Here we explored whether one such inverse agonist ligand, [Leu11 ,dTrp12 ,Trp23 ,Tyr36 ]-PTHrP(7-36)NH2 (IA), can be effective in vivo and thus ameliorate the skeletal abnormalities that occur in transgenic mice expressing the PTHR1-H223R allele of JMC in osteoblastic cells via the collagen-1α1 promoter (C1HR mice). We observed that after 2 weeks of twice-daily injection and relative to vehicle controls, the IA analog resulted in significant improvements in key skeletal parameters that characterize the C1HR mice, because it reduced the excess trabecular bone mass, bone marrow fibrosis, and levels of bone turnover markers in blood and urine. The overall findings provide proof-of-concept support for the notion that inverse agonist ligands targeted to the mutant PTHR1 variants of JMC can have efficacy in vivo. Further studies of such PTHR1 ligand analogs could help open paths toward the first treatment option for this debilitating skeletal disorder. © 2019 American Society for Bone and Mineral Research.
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- 2019
48. Prolonged Pharmacokinetic and Pharmacodynamic Actions of a Pegylated Parathyroid Hormone (1-34) Peptide Fragment
- Author
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Ashok Khatri, Akira Maeda, Jun Guo, Thomas J. Gardella, John T. Potts, and Harald Jüppner
- Subjects
0301 basic medicine ,chemistry.chemical_classification ,Kidney ,medicine.medical_specialty ,Calcitriol ,Chemistry ,Endocrinology, Diabetes and Metabolism ,Parathyroid hormone ,030209 endocrinology & metabolism ,Peptide ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Endocrinology ,In vivo ,Internal medicine ,PEGylation ,medicine ,Orthopedics and Sports Medicine ,Receptor ,medicine.drug ,Hormone - Abstract
Polyethylene glycol (PEG) addition can prolong the pharmacokinetic and pharmacodynamic actions of a bioactive peptide in vivo, in part by impeding rates of glomerular filtration. For parathyroid hormone (PTH) peptides, pegylation could help in exploring the actions of the hormone in the kidney; e.g., in dissecting the relative roles that filtered versus blood-borne PTH play in regulating phosphate transport. It could also lead to potential alternate forms of treatment for hypoparathyroidism. We thus synthesized the fluorescent pegylated PTH derivative [Lys13 (tetramethylrhodamine {TMR}), Cys35 (PEG-20,000 Da)]PTH(1-35) (PEG-PTHTMR ) and its non-pegylated counterpart [Lys13 (TMR), Cys35 ]PTH(1-35) (PTHTMR ) and assessed their properties in cells and in mice. In PTHR1-expressing HEK-293 cells, PEG-PTHTMR and PTHTMR exhibited similar potencies for inducing cAMP signaling, whereas when injected into mice, the pegylated analog persisted much longer in the circulation (>24 hours versus ∼ 1 hour) and induced markedly more prolonged calcemic and phosphaturic responses than did the non-pegylated control. Fluorescence microscopy analysis of kidney sections obtained from the injected mice revealed much less PEG-PTHTMR than PTHTMR on the luminal brush-border surfaces of renal proximal tubule cells (PTCs), on which PTH regulates phosphate transporter function, whereas immunostained phosphorylated PKA substrate, a marker of cAMP signaling, was increased to similar extents for the two ligands and for each, was localized to the basolateral portion of the PTCs. Pegylation of a bioactive PTH peptide thus led to prolonged pharmacokinetic/pharmacodynamic properties in vivo, as well as to new in vivo data that support a prominent role for PTH action at basolateral surfaces of renal proximal tubule cells. © 2016 American Society for Bone and Mineral Research.
- Published
- 2016
49. Impaired growth and intracranial calcifications in autosomal dominant hypocalcemia caused by a GNA11 mutation
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Monica Reyes, Sirpa Tenhola, Harald Jüppner, Outi Mäkitie, Raimo Voutilainen, and Sanna Toiviainen-Salo
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Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Hypoparathyroidism ,Endocrinology, Diabetes and Metabolism ,Hypercalciuria ,Mutation, Missense ,030209 endocrinology & metabolism ,Reference range ,medicine.disease_cause ,Asymptomatic ,Short stature ,Article ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Internal medicine ,medicine ,Humans ,Missense mutation ,Child ,Calcium metabolism ,Mutation ,Hypocalcemia ,business.industry ,Calcinosis ,General Medicine ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,GTP-Binding Protein alpha Subunits ,Urinary calcium ,Pedigree ,030104 developmental biology ,Calcium ,Female ,medicine.symptom ,Nephrocalcinosis ,Tomography, X-Ray Computed ,business - Abstract
Objective Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia and inappropriately low PTH concentrations. ADH type 1 is caused by activating mutations in the calcium-sensing receptor (CASR), a G-protein-coupled receptor signaling through α11 (Gα11) and αq (Gαq) subunits. Heterozygous activating mutations in GNA11, the gene encoding Gα11, underlie ADH type 2. This study describes disease characteristics in a family with ADH caused by a gain-of-function mutation in GNA11. Design A three-generation family with seven members (3 adults, 4 children) presenting with ADH. Methods Biochemical parameters of calcium metabolism, clinical, genetic and brain imaging findings were analyzed. Results Sanger sequencing revealed a heterozygous GNA11 missense mutation (c.1018G>A, p.V340M) in all seven hypocalcemic subjects, but not in the healthy family members (n=4). The adult patients showed clinical symptoms of hypocalcemia, while the children were asymptomatic. Plasma ionized calcium ranged from 0.95 to 1.14mmol/L, yet plasma PTH was inappropriately low for the degree of hypocalcemia. Serum 25OHD was normal. Despite hypocalcemia 1,25(OH)2D and urinary calcium excretion were inappropriately in the reference range. None of the patients had nephrocalcinosis. Two adults and one child (of the two MRI scanned children) had distinct intracranial calcifications. All affected subjects had short stature (height s.d. scores ranging from −3.4 to −2.3 vs −0.5 in the unaffected children). Conclusions The identified GNA11 mutation results in biochemical abnormalities typical for ADH. Additional features, including short stature and early intracranial calcifications, cosegregated with the mutation. These findings may indicate a wider role for Gα11 signaling besides calcium regulation.
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- 2016
50. Fibroblast Growth Factor 23 and Risk of CKD Progression in Children
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Shari Messinger, Susan L. Furth, Anthony A. Portale, Harald Jüppner, Myles Wolf, Isidro B. Salusky, Bradley A. Warady, and Farzana Perwad
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Male ,medicine.medical_specialty ,Adolescent ,Epidemiology ,medicine.medical_treatment ,030232 urology & nephrology ,Urology ,Renal function ,030204 cardiovascular system & hematology ,urologic and male genital diseases ,Critical Care and Intensive Care Medicine ,Risk Assessment ,03 medical and health sciences ,0302 clinical medicine ,Renal Dialysis ,Risk Factors ,Interquartile range ,Internal medicine ,medicine ,Humans ,Prospective Studies ,Renal Insufficiency, Chronic ,Vitamin D ,Risk factor ,Child ,Prospective cohort study ,Dialysis ,Transplantation ,business.industry ,Hazard ratio ,Phosphorus ,Original Articles ,medicine.disease ,Kidney Transplantation ,Confidence interval ,Fibroblast Growth Factors ,Fibroblast Growth Factor-23 ,stomatognathic diseases ,Endocrinology ,Parathyroid Hormone ,Nephrology ,Disease Progression ,Female ,business ,Follow-Up Studies ,Glomerular Filtration Rate ,Kidney disease - Abstract
Background and objectives Plasma fibroblast growth factor 23 (FGF23) concentrations increase early in the course of CKD in children. High FGF23 levels associate with progression of CKD in adults. Whether FGF23 predicts CKD progression in children is unknown. Design, setting, participants, & measurements We tested the hypothesis that high plasma FGF23 is an independent risk factor for CKD progression in 419 children, aged 1–16 years, enrolled in the Chronic Kidney Disease in Children (CKiD) cohort study. We measured plasma FGF23 concentrations at baseline and determined GFR annually using plasma disappearance of iohexol or the CKiD study estimating equation. We analyzed the association of baseline FGF23 with risk of progression to the composite end point, defined as start of dialysis or kidney transplantation or 50% decline from baseline GFR, adjusted for demographics, baseline GFR, proteinuria, other CKD-specific factors, and other mineral metabolites. Results At enrollment, median age was 11 years [interquartile range (IQR), 8–15], GFR was 44 ml/min per 1.73 m 2 (IQR, 33–57), and FGF23 was 132 RU/ml (IQR, 88–200). During a median follow-up of 5.5 years (IQR, 3.5–6.6), 32.5% of children reached the progression end point. Higher FGF23 concentrations were independently associated with higher risk of the composite outcome (fully adjusted hazard ratio, 2.52 in the highest versus lowest FGF23 tertile; 95% confidence interval, 1.44 to 4.39, P =0.002; fully adjusted hazard ratio, 1.33 per doubling of FGF23; 95% confidence interval, 1.13 to 1.56, P =0.001). The time to progression was 40% shorter for participants in the highest compared with the lowest FGF23 tertile. In contrast, serum phosphorus, vitamin D metabolites, and parathyroid hormone did not consistently associate with progression in adjusted analyses. Conclusions High plasma FGF23 is an independent risk factor for CKD progression in children.
- Published
- 2016
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