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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 9 3052-3057
Copyright © 1999 by The Endocrine Society

Original Studies

A Novel Parathyroid Hormone (PTH)/PTH-Related Peptide Receptor Mutation in Jansen’s Metaphyseal Chondrodysplasia1

E. Schipani, C. Langman, J. Hunzelman, M. Le Merrer, K. Y. Loke, M. J. Dillon, C. Silve and H. Jüppner

Endocrine Unit, Department of Medicine (E.S., J.H., H.J.), and Children’s Service (H.J.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114; INSERM, U-426, Faculté de Médicine, Xavier Bichat (C.S.), and INSERM U-393, Hôpital Necker Enfants Malades (M.L.M.), Paris, Cedex 18 75870, France; the Department of Pediatrics, National University Hospital (K.Y.L.), Singapore 119074; Great Ormond Street Hospital for Children (M.J.D.), London, United Kingdom WC1N 3JH; and the Division of Nephrology, Children’s Memorial Hospital (C.L.), Chicago, Illinois 60614

Address all correspondence and requests for reprints to: Dr. E. Schipani, Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114. E-mail: schipani{at}helix.mgh.harvard.edu


   Abstract
Top
 Abstract
Introduction
 Case Reports
 Materials and Methods
 Results and Discussion
 References
 
Two heterozygous PTH/PTH-related peptide (PTHrP) receptor missense mutations were previously identified in patients with Jansen’s metaphyseal chondrodysplasia (JMC), a rare form of short limb dwarfism associated with hypercalcemia and normal or undetectable levels of PTH and PTHrP. Both mutations, H223R and T410P, resulted in constitutive activation of the cAMP signaling pathway and provided a plausible explanation for the abnormalities in skeletal development and mineral ion homeostasis. In the present study we analyzed genomic DNA from four additional sporadic cases with JMC to search for novel activating mutations in the PTH/PTHrP receptor, to determine the frequency of the two previously identified missense mutations, H223R and T410P, and to determine whether different mutations present with different severity of the disease. The H223R mutation was identified in three novel JMC patients and is, therefore, to date the most frequent cause of JMC. In the fourth patient, a novel heterozygous missense mutation was found that changes isoleucine 458 in the receptor’s seventh membrane-spanning region to arginine (I458R). In COS-7 cells expressing the human PTH/PTHrP receptor with the I458R mutation, basal cAMP accumulation was approximately 8 times higher than that in cells expressing the wild-type receptor despite impaired surface expression of the mutant receptor. Furthermore, the I458R mutant showed higher responsiveness to PTH than the wild-type receptor in its ability to activate both down-stream effectors, adenylyl cyclase and phospholipase C. Like the H223R and the T410P mutants, the I458R mutant had no detectable effect on basal inositol phosphate accumulation. Overall, the patient with the I458R mutation exhibited clinical and biochemical abnormalities similar to those in patients with the previously identified H223R and T410P mutations.


   Introduction
Top
 Abstract
 Introduction
Case Reports
 Materials and Methods
 Results and Discussion
 References
 
JANSEN’S metaphyseal chondrodysplasia (JMC) is a rare autosomal dominant disorder characterized by hypercalcemia and short limb dwarfism secondary to severe abnormalities of the growth plate. Although first described in 1934 (1), it was not until the description of a second patient in 1959 that an association between the abnormalities in endochondral bone formation and those in mineral ion homeostasis was formally considered (2). JMC is associated with severe, but largely asymptomatic, hypercalcemia, hypophosphatemia, decreased tubular reabsorption of phosphate, increased urinary excretion of cAMP, inappropriately normal or even elevated circulating levels of 1,25-dihydroxyvitamin D3, and low or undetectable levels of PTH and PTH-related peptide (PTHrP) (2, 3, 4, 5, 6, 7). Most of the reported cases are sporadic (1, 2, 3, 4, 5, 6, 8), and the disease affects different ethnic groups (9). The description of two unrelated, affected women who gave birth to affected children suggested a dominant mode of inheritance (10, 11); this finding was confirmed at the molecular level (12).

Two different heterozygous PTH/PTHrP receptor mutations that lead to agonist-independent constitutive cAMP accumulation when tested in vitro were previously identified in several unrelated patients with JMC (9, 12, 13) (Fig. 1Go). The first mutation, H223R, changes a conserved amino acid residue located in the second transmembrane domain of the PTH/PTHrP receptor and was identified in several patients (5, 6, 9, 11, 12, 13). The T410P mutation, which is located in the sixth transmembrane domain, has been identified in only one patient to date (2, 3, 4, 7, 12) (Fig. 1Go).



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  		Figure 1. Schematic representation of the human PTH/PTHrP receptor. The circles show the location of the amino acid substitution identified in genomic DNA from different patients with JMC. H, Histidine; R, arginine; T, threonine; P, proline; I, isoleucine.

 
The PTH/PTHrP receptor is abundantly expressed in kidney and bone, where it mediates the PTH-dependent endocrine regulation of calcium and phosphorus, and in the growth plate, where it mediates the PTHrP-dependent regulation of chondrocyte growth and differentiation (14, 15). Mice in which both alleles of the PTHrP gene have been ablated by homologous recombination die before or immediately after birth and show skeletal dysplasia with short limbs due to accelerated chondrocyte maturation (16); even more severe is the phenotype of mice that lack both alleles of the PTH/PTHrP receptor gene (17). The converse findings, i.e. skeletal abnormalities due to decelerated chondrocyte maturation, are observed in transgenic animals, in which expression of either PTHrP or constitutively active PTH/PTHrP receptors is targeted to the growth plate (18, 19). Furthermore, inactivating PTH/PTHrP receptor mutations were recently found in patients with Blomstrand lethal chondrodysplasia, a rare autosomal recessive disorder characterized by skeletal abnormalities similar to those observed in mice that lack the PTH/PTHrP receptor gene (20, 21, 22). Based on these data, the presence of PTH/PTHrP receptor mutations that induce constitutive activity of the cAMP signaling pathway provides the most plausible explanation for both the abnormal regulation of mineral ion homeostasis and that of growth plate development in Jansen’s disease.

In the current study, we examined four additional sporadic patients with JMC who are of different ethnic origins. The goals of the study were 1) to search for novel activating mutations in the PTH/PTHrP receptor gene; 2) to determine the frequency of the two known missense mutations, H223R and T410P; and 3) to assess whether different mutations are associated with similar clinical presentations of the disease.


   Case Reports
Top
 Abstract
 Introduction
 Case Reports
Materials and Methods
 Results and Discussion
 References
 
The genetic studies were approved by the local institutional review board, and informed consent was obtained.

Because of the rarity of the disease, some of the pertinent clinical and biochemical findings in the patients with JMC described in this report will be outlined. All patients were born to healthy nonconsanguineous parents and showed significant growth retardation, but normal intellectual development.

The patient in family 1 has been described previously (23). Significant laboratory findings are shown in Table 1Go.


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  		Table 1. Laboratory findings in four patients with Jansen’s metaphyseal chondrodysplasia

 
The patient in family 2 is an Asian female, who was born at term; no description is available about her phenotypic appearance at birth. She was first evaluated at 1 yr of age because of poor growth. At that time, total and ionized serum calcium and serum alkaline phosphatase levels were markedly elevated, serum phosphate was low, and PTH was well below the normal range (Table 1Go). Daily therapy with intranasal salmon calcitonin, given from age 2–7 yr, had no measurable effect on her biochemical parameters. Treatment with alendronate (10 mg, twice per week), initiated at 7 yr of age because of significant nephrocalcinosis due to increased urinary calcium excretion (calcium/creatinine ratio, 5.56; normal value, <0.7), led to normalization of her serum calcium values and reduced urinary calcium excretion (data not shown). At the time of the report the patient was 9 yr old and showed disproportionate short stature, with a height of 82 cm (28 cm below the third percentile) and a weight of 15 kg (3 kg below the third percentile).

The patient in family 3 is a 10-yr-old Arabic girl from Northern Africa, who was born prematurely at 34 weeks gestation; the pregnancy was complicated by polyhydramnios. At birth, the infant was dystonic and had dysmorphic features, including flattening of the nose and forehead, hypertelorism, low set ears, retrognathia, and apparent macroglossia. During the early postnatal period, inadequate oral formula intake necessitated feeding through a naso-gastric tube. A spontaneous fracture of the left femur occurred on day 4, and radiological evaluation after this event showed numerous abnormalities, including coarse trabecular structure of the entire skeleton (except for the vertebrae, which appeared to be normal), irregular metaphyseal enlargement, and lamination of the cortexes of long bones. Total serum calcium was normal at birth. Laboratory findings at 4 months of age revealed increased total and ionized serum calcium, normal serum phosphorus, markedly elevated alkaline phosphatase activity, and low PTH (Table 1Go). The patient developed progressive kyphoscoliosis that required the wearing of a brace from 3 yr of age. Severe bilateral femoral and tibial bowing required tibial osteotomy at age 6 yr (unilateral) and 10 yr (bilateral). Progressive sclerosis of the base of the skull, previously noted in other patients with this disease (4, 10), presumably led to optical nerve compression that resulted in almost complete blindness. At the time of this report, the patient was 10 yr old, with a height of 92 cm (20 cm below 3rd percentile) and a weight of 18 kg (between 3rd and 10th percentiles).

The patient in family 4 is a 4.5-yr-old Caucasian boy. An ultrasound performed in the middle of gestation revealed polyhydramnios. Labor was induced at term because of maternal hypertension, and cesarian section was required. The infant weighed 3.4 kg at birth and had Apgar scores of 9 and 10 at 1 and 5 min, respectively; he was discharged home after less than 48 h. The first year of life was marked by an episode of reactive airway disease at 8 months of age that required brief hospitalization. The patient demonstrated delayed gross motor development and did not walk until 18 months of age; all other developmental milestones were appropriate. His length was consistently below the third percentile. Skeletal radiographs performed at the age of 2.3 yr revealed findings typical of Jansen’s disease. Total and ionized serum calcium, first measured at 2.5 yr of age, were consistently elevated, and serum phosphorus was low throughout, but PTH was consistently below the normal range; alkaline phosphatase activity was elevated (Table 1Go). At the time of the report, the patient was 4.5 yr old and had disproportionate short stature, with a height of 92.7 cm (6 cm below the fifth percentile) and a weight of 14 kg (fifth percentile). He showed delayed dentition; no obvious skin abnormalities were noted.


   Materials and Methods
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 Abstract
 Introduction
 Case Reports
 Materials and Methods
Results and Discussion
 References
 
Materials

[Nle8,21,Tyr34]Rat PTH-(1–34)amide [PTH-(1–34)] was synthesized as previously described (24). Na125I (SA, 2000 Ci/mmol), for peptide and monosuccinyl cAMP tyrosylmethylester iodination, and 125I-labeled goat anti-rabbit IgG were purchased from DuPont-New England Nuclear (Boston, MA). DMEM was obtained from Mediatech (Washington DC), ethylenediamine tetraacetate/trypsin and penicillin/streptomycin were obtained from Life Technologies, Inc. (Grand Island, NY), and FBS was obtained from Sigma Chemical Co. (St. Louis, MO). COS-7 cells were provided by B. Seed, Laboratory of Molecular Biology, Massachusetts General Hospital (Boston, MA). Oligonucleotide primers were synthesized using an PE Applied Biosystems 380B DNA Synthesizer (Foster City, CA). DNA sequencing was performed by the dideoxy chain termination method using the Sequenase version 2 sequencing kit (U.S. Biochemical Corp., Cleveland, OH). Restriction enzymes, T4 polynucleotide kinase, and T4 DNA ligase were obtained from New England Biolabs, Inc. (Beverly, MA). Calf alkaline phosphatase was purchased from Boehringer Mannheim (Mannheim, Germany). All other reagents were of the highest purity available.

Laboratory studies

Serum calcium, phosphorus, and alkaline phosphatase were measured by standard technique with an automated analyzer. Serum intact PTH was measured by immunoradiometric assay [Nichols Institute Diagnostics (San Juan Capistrano, CA) or INCSTAR Corp. (Stillwater, MN)]. Bone-specific alkaline phosphatase for patient 4 was measured by a specific enzyme-linked immunosorbent assay, as described previously (25).

Identification of PTH/PTHrP receptor mutations

Coding exons of the gene encoding the PTH/PTHrP receptor were amplified from blood leukocyte genomic DNA by PCR; the DNA products were analyzed by direct nucleotide sequence analysis (26). The nucleotide changes that cause the H223R mutation in exon M2 and the T410P mutation in exon M6/7, respectively, were confirmed by restriction enzymatic digestion and/or Southern blot analysis of genomic DNA as previously described (12, 13). The novel isoleucine to arginine mutation in exon M7 (residue 458 of the human PTH/PTHrP receptor) was also confirmed by restriction enzymatic digestion. For this purpose, the PCR product of 380 bp comprising exons M6/7 and M7 and adjacent intronic nucleotides was generated as previously described (26); if thymidine at position 1401 was mutated to guanidine, restriction enzymatic digestion with AlwNI resulted in two DNA fragments of 278 and 102 bp, respectively.

In vitro evaluation of wild-type and mutant PTH/PTHrP receptors

Mutations were introduced by site-directed mutagenesis into the complementary DNA encoding the wild-type human PTH/PTHrP receptor (27, 28), and plasmid DNA from at least two independent bacterial colonies was used for transfection of COS-7 cells as previously described (27).

Assessment of receptor expression using an antibody that specifically recognizes the human PTH/PTHrP receptor (Babco, Richmond, CA) and PTH-induced accumulation of intracellular cAMP and inositol phosphate (IP) were performed as described previously (27).


   Results and Discussion
Top
 Abstract
 Introduction
 Case Reports
 Materials and Methods
 Results and Discussion
References
 
We previously reported the identification of two heterozygous missense mutations, H223R and T410P, in the gene encoding the PTH/PTHrP receptor in patients with JMC (Fig. 1Go); both mutations lead in vitro to ligand-independent constitutive cAMP accumulation (12, 13). The H223R mutation, which was also identified by another group (9), introduces a SphI restriction site in exon M2, whereas the T410P mutation introduces an AciI restriction site in exon M6/7 of the human PTH/PTHrP receptor gene (12). To confirm or exclude these known mutations, PCR products comprising exon M2 or exon M6/7 were amplified from genomic DNA of four additional patients (Table 1Go) with biochemical and radiological evidence of JMC and were screened by SphI or AciI digestion, respectively. After digestion with SphI, exon M2 PCR products from the affected patients in families 1, 2, and 3 yielded, in addition to the undigested PCR product, DNA fragments that were 58 and 148 bp in length (data not shown). This indicated that these patients were heterozygous for the H223R mutation; the adenine to guanine transition that causes this mutation was confirmed by Southern blot analysis of SphI-digested genomic DNA (data not shown). The H223R mutation was not detected in the patients’ unaffected first degree relatives. To date, the H223R mutation has been identified in eight patients (this report and Refs. 9, 12) and is thus the most frequent PTH/PTHrP receptor mutation in JMC.

The presence of either the H223R or the T410P mutation in the genomic DNA of patient 4 (Table 1Go) was excluded by restriction enzymatic digestion and/or direct nucleotide sequence analysis (data not shown). To search for a novel PTH/PTHrP receptor mutation in this patient, other coding exons were amplified by PCR from genomic DNA, and the resulting products were analyzed by direct nucleotide sequencing (12). A heterozygous thymidine to guanidine transversion was identified in exon M7 (Fig. 2AGo), which corresponds to position 1401 of the complementary DNA encoding the human PTH/PTHrP receptor. This mutation introduces a restriction site for AlwNI (Fig. 2BGo) and changes a conserved isoleucine at position 458 to arginine (Fig. 1Go). The mutation was not detected in either of the healthy parents (Fig. 2BGo).



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  		Figure 2. Identification of the I458R mutation in the PTH/PTHrP receptor gene in patient 4. A, Portions of the direct nucleotide sequence analysis of PCR-amplified exon M7 of the PTH/PTHrP receptor gene. Note the heterozygous T to G transversion. B, AlwNI digestion of PCR-amplified genomic DNA and electrophoresis of the resulting DNA fragment through a 3% metaphor agarose gel with ethidium bromide staining. {square} and {circ}, Unaffected parents; , patient 4. Relevant size markers are indicated. Lanes 1 and 2, Unaffected parents; lane 3, patient 4.

 
COS-7 cells were transiently transfected with increasing concentrations (0.8–400 ng/well) of the plasmid encoding the I458R mutant or the wild-type PTH/PTHrP receptor. Depending on the dose of plasmid DNA used for transfection, cells expressing the I458R mutant accumulated, in the absence of agonist, 2- to 8-fold more cAMP than cells expressing the wild-type receptor (160.4 ± 10.2 vs. 19.8 ± 1.1 pmol/well·15 min in cells transfected with 400 ng/well plasmid DNA; mean ± SE; Fig. 3AGo). This degree of constitutive activity was comparable to that previously observed with cells expressing receptors with the H223R or the T410P mutation, respectively (12).



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  		Figure 3. Functional evaluation of the wild-type human PTH/PTHrP receptor and the I458R mutant in COS-7 cells. A, Basal cAMP accumulation in cells transiently transfected with increasing doses (0.8–400 ng/well) of plasmid DNA encoding wild-type ({square}) or mutant ({circ}) PTH/PTHrP receptor. B, Cell surface expression of wild-type and mutant receptors in cells transiently transfected with increasing doses (0.8–400 ng/well) of plasmid DNA encoding wild-type ({square}) or mutant ({circ}) PTH/PTHrP receptor. Expression levels of either receptor were determined as described in Materials and Methods. C, PTH-stimulated cAMP accumulation in cells transfected with saturating amounts (400 ng/well) of plasmid DNA encoding either wild-type ({square}) or mutant receptor ({circ}). Data are shown as percentages of maximal cAMP accumulation with cells expressing the wild-type receptor. D, IP accumulation in cells transfected with saturating amounts of plasmid DNA encoding either wild-type ({square}) or mutant ({circ}) receptor in the absence or presence of PTH-(1–34) (1000 nmol/L). Data are shown as the fold increase over basal IP accumulation of cells expressing the wild-type receptor. Data are the mean (±SE) of at least three independent experiments, each performed in duplicate. For some data points, the SE is smaller than the size of the symbols.

 
Similar to previously reported experiments with the H223R or the T410P mutant (12), the number of I458R mutant receptors on the cell surface, as detected by antibody binding, was significantly reduced compared to the number of wild-type receptors (Fig. 3BGo). However, despite impaired expression levels, cells transfected with saturating amounts of the plasmid encoding either the I458R mutant or the wild-type receptor (400 ng/well) showed comparable maximal cAMP accumulation in response to PTH (100 nmol/L; 506.4 ± 32.7 vs. 547.5 ± 44.4 pmol/well·15 min; mean ± SE; Fig. 3CGo). Furthermore, when levels of maximal PTH-dependent cAMP accumulation were correlated with levels of receptor expression, PTH displayed increased efficacy with the I458R mutant compared to the wild-type receptor (Fig. 4Go). PTH efficacy was also higher with the T410P mutant, but not with the H223R mutant (Fig. 4Go) (12). Similar findings, i.e. constitutive activity in vitro combined with increased efficacy of the agonist, have been described for other G protein-coupled receptors with naturally occurring mutations (29, 30, 31).



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  		Figure 4. Correlation between PTH-stimulated cAMP accumulation and cell surface expression for the wild-type human PTH/PTHrP receptor and the three mutant receptors. COS-7 cells were transiently transfected with increasing doses (0.8–400 ng/well) of plasmid DNA encoding the wild-type PTH/PTHrP receptor ({square}) or with saturating amounts (400 ng/well) of the receptors with the I458R ({circ}), H223R ({triangleup}), or T410P ({triangledown}) mutation. Cell surface expression and maximal PTH-stimulated cAMP accumulation were assessed as described in Materials and Methods. On the y-axis, PTH-stimulated cAMP accumulation is shown as a percentage of the maximal stimulation of the wild-type receptor; on the x-axis, antibody binding is shown as a percentage of the maximal expression levels of the wild-type receptor. All data are the mean (±SE) of at least three independent experiments, each performed in duplicate. For all data points, the SE is smaller than the size of the symbols.

 
No correlation between localization of the receptor mutation and the in vitro phenotype of the mutant receptor has been observed to date for most members of the G protein-coupled receptor family (32). With regard to the constitutively active PTH/PTHrP receptor mutants, our data indicate that, differently from the mutation identified in the second transmembrane domain, mutations in the sixth and seventh transmembrane domains are associated with an increased efficacy of the agonist. Interestingly, residues in these regions have been implicated in ligand-dependent activation of the PTH/PTHrP receptor (33).

The PTH/PTHrP receptor is able to stimulate, at least in vitro, two independent signaling pathways, adenylate cyclase and phospholipase C (34). Basal and PTH-dependent IP accumulations were, therefore, measured in cells transiently transfected with the wild-type receptor or the I458R mutant. Basal IP accumulation was indistinguishable in cells expressing the wild-type receptor or the I458R mutant, respectively (1065 ± 288 vs. 1267 ± 202 cpm/well·30 min; mean ± SE). Thus, none of the JMC mutants (H223R, T410P, or I458R) showed any evidence for constitutive activation of the IP signaling pathway (Fig. 3DGo) (12). However, similar to the T410P mutant (12), the I458R mutant displayed PTH-dependent maximal IP accumulation almost equivalent to that observed with the wild-type receptor (Fig. 3DGo) despite reduced cell surface expression. In contrast, previous studies with the H223R mutant had not shown any evidence for PTH-dependent activation of this second messenger pathway (12).

As described above, activation of the PTH/PTHrP receptor can evoke multiple signaling events, but the links between signaling events and downstream tissue responses to PTH or PTHrP have not been clearly defined. In vitro evidence implicates IP signaling pathway activation by the PTH/PTHrP receptor in the regulation of sodium-phosphate cotransport and 25-hydroxyvitamin 1{alpha}-hydroxylation (35, 36). Interestingly, despite the differential ability of the mutant PTH/PTHrP receptors to activate phospholipase C, no obvious differences were evident in the clinical and biochemical phenotypes of patients with JMC who carry any of the three mutations identified to date.

In summary, PTH/PTHrP receptors with the I458R, the H223R, or the T410P mutation showed ligand-independent constitutive cAMP accumulation. The I458R and T410P mutants were able to activate, after challenge with PTH, the adenylate cyclase signaling pathway with higher efficacy than the wild-type receptor; furthermore, both receptor mutants mediated agonist-dependent IP accumulation. On the contrary, the H223R mutant was less responsive to PTH with regard to the cAMP pathway and did not trigger any detectable agonist-dependent IP accumulation. However, this second messenger pathway is, at least in vitro, less efficiently activated by the PTH/PTHrP receptor than the cAMP signaling pathway (35). Taken together, our data suggest that higher levels of agonist-dependent cAMP accumulation are associated with an improved ability of the mutant PTH/PTHrP receptor to stimulate the IP signaling pathway after agonist challenge.


   Acknowledgments
 
We thank Drs. H. M. Kronenberg and P. H. Carter for helpful discussions and critical review of the manuscript, and Ronda Shaykin, R.N., M.S., for help with collecting the samples.


   Footnotes
 
1 This work was supported by a grant from the NIH (DK-50708–01; to H.J.). Back

Received April 9, 1999.

Revised June 15, 1999.

Accepted June 18, 1999.


   References
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 Abstract
 Introduction
 Case Reports
 Materials and Methods
 Results and Discussion
 References
 

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