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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 7 3595-3600
Copyright © 2004 by The Endocrine Society

A Form of Jansen’s Metaphyseal Chondrodysplasia with Limited Metabolic and Skeletal Abnormalities Is Caused by a Novel Activating Parathyroid Hormone (PTH)/PTH-Related Peptide Receptor Mutation

Murat Bastepe, Annick Raas-Rothschild, Justin Silver, Irit Weissman, Shlomo Wientroub, Harald Jüppner and David Gillis

Endocrine Unit (M.B., H.J.) and Department of Medicine and Pediatric Nephrology Unit (H.J.), Massachussets General Hospital for Children, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114; Departments of Human Genetics (A.R.-R.), Nephrology (J.S.), and Pediatrics (D.G.), Hadassah Hebrew University Hospital, Jerusalem, Israel 91120; Department of Pediatric Nephrology (I.W.), Western Galilee Hospital, Naharyia, Israel 22100; and Department of Pediatric Orthopedics (S.W.), Dana Children’s Hospital, Tel Aviv Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel 64239

Address all correspondence and requests for reprints to: Harald Jüppner, Endocrine Unit, Massachusetts General Hospital, Wellman 5, Boston, Massachusetts 02114. E-mail: jueppner{at}helix.mgh.harvard.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
A novel heterozygous PTH/PTHrP receptor missense mutation (T410R) was identified in a male and his two sons who are all affected by a less severe form of Jansen’s metaphyseal chondrodysplasia (JMC). JMC is a rare disorder that is typically characterized by severe growth plate abnormalities that lead to short-limbed dwarfism. Furthermore, affected individuals usually show significant hypercalcemia, despite normal or undetectable levels of PTH and PTHrP. In contrast, the three affected members of this new family showed only mild skeletal dysplasia, comparatively normal stature, and blood calcium concentrations either within or at the upper end of the normal range. However, PTH levels were suppressed, and urinary calcium excretion was elevated, which led to nephrolithiasis in both children. When expressed in COS-7 cells, the PTH/PTHrP receptor with the T410R mutation led to agonist-independent cAMP formation, which was less pronounced than that observed with the previously identified T410P mutant. Our findings indicate that a mild form of JMC has been identified that is characterized by less pronounced skeletal and laboratory abnormalities.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE PTH/PTHrP RECEPTOR is activated with equivalent efficiency and efficacy by two distinct hormones, PTH and PTHrP (1, 2, 3). In the kidney, this G protein-coupled receptor mediates the PTH-dependent increase in tubular calcium reabsorption, phosphate excretion, and 1-{alpha}-hydroxylase activity. In bone, it mediates directly the stimulation of osteoblast activity and indirectly, through the RANK/RANKL system, osteoclast maturation and activity (4). In the metaphyseal growth plates, the PTH/PTHrP receptor mediates the actions of PTHrP, which slows the differentiation of chondrocytes, thus contributing to normal bone growth and elongation (5). Consistent with this important role in normal bone formation, mice engineered to lack both copies of PTHrP (6) or the PTH/PTHrP receptor (7) and humans with homozygous or compound heterozygous inactivating PTH/PTHrP receptor mutations show a dramatic acceleration of chondrocyte differentiation, leading to premature calcification and closure of growth plates and thus to considerable shortening of most long bones (8). In addition, a recently identified mutation in the PTH/PTHrP receptor gene, R150C, appears to be responsible for some forms of enchondromatosis (Ollier’s disease) (9), and activating PTH/PTHrP receptor mutations leading to severe hypercalcemia, mild hypophosphatemia, and delayed chondrocyte differentiation have been identified as causes of Jansen’s metaphyseal chondrodysplasia (JMC) (8). The JMC phenotype includes short-limbed dwarfism, bowing of long bones, and dysplastic growth plates, which are due to a delay in chondrocyte maturation (10). In addition, all reported JMC patients with activating PTH/PTHrP receptor mutations have similar abnormalities in mineral ion homeostasis, which include hypercalcemia, despite low to undetectable PTH and PTHrP concentration in the circulation (8).

Three different missense mutations have thus far been identified in patients with JMC; these are H223R, T410P, and I458R (11, 12, 13). Systematic analysis of two of these positions revealed that only two amino acid substitutions of residue 223 of the PTH/PTHrP receptor resulted in constitutive, agonist-independent cAMP formation in vitro (14). In contrast, substitution of the threonine residue at position 410, which is strictly conserved in all mammalian PTH/PTHrP receptors, with each of the remaining natural amino acids led to variable degrees of constitutive receptor activation (14). Although the T410P PTH/PTHrP receptor mutant exhibited, in vitro, a high degree of constitutive PTH/PTHrP receptor activation, the level of agonist-independent cAMP accumulation was significantly lower for most, but not all, other mutants. This variation observed in transfected COS-7 cells suggested that milder forms of JMC with less severe skeletal and mineral ion abnormalities could be caused by mutations affecting amino acid residue 410.

Recently, we had the opportunity to investigate three related JMC patients who had less severe clinical and laboratory manifestations than all previously reported cases. A novel PTH/PTHrP receptor mutation, T410R, was identified, which showed less pronounced constitutive activity in vitro than the previously reported T410P substitution (14) and thus correlated well with this less severe form of JMC.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Clinical report

Patient D1 and patient D2 are two brothers who were referred for evaluation of a bone dysplasia associated with mild hypercalcemia and hypercalciuria, as well as kidney stones in the case of patient D1. We (D.G., S.W., and A.R.-R.) first reviewed the two brothers at the ages of 8 yr and 2 months (patient D1) and 4 yr and 10 months (patient D2). On physical examination, both patients were found to be slightly below the third percentile for height (98 and 111 cm, Fig. 1Go). The weight of patient D1 was 18 kg (50th percentile), and the weight of patient D2 was 21 kg (10th percentile). Both patients had significant genu valgum and obvious widening of the metaphyseal areas of the larger long bones, and the older of the two brothers appeared more severely affected. Skeletal radiological surveys from both children revealed, at the time of diagnosis, generalized osteopenia and symmetric bowing of the long bones, mainly affecting the lower limbs (Fig. 2Go). All long bones appeared short and were characterized by markedly splayed and fragmented metaphyses and mildly broadened diaphyses with evidence for persistent cartilaginous remnants within the growth plates.



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  		FIG. 1. Pedigree and standing heights of the family members examined. Percentiles are indicated within parentheses. Filled and open symbols represent affected and healthy individuals, respectively.

 


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  		FIG. 2. Anterior-posterior radiographs of the knees (A) and hands (B) of one of the affected children (patient D1) showing the splayed and fragmented metaphyses and the mildly broadened diaphyses.

 
Patient D1 was born at term with a birth weight of 3,150 g; his length and head circumference at birth are unknown. He was hypotonic at birth and had bilateral foot deformities that required correction with casts. He was referred to our clinic with the presumptive diagnosis of hypophosphatemic rickets after being treated between age 3 and 5 yr with oral 1{alpha}-hydroxyvitamin D, calcium, and phosphate. At the age of 7.5 yr, patient D1 presented with painful gross hematuria, and renal ultrasound showed findings compatible with nephrolithiasis. The birth weight of patient D2 was 3650 g. Limb deformities were first noted at age 2 yr. Recently, at the age of 7 yr, he developed kidney stones as well.

The parents of the patients are unrelated. Their father (patient D3) is Moroccan Jewish, and their mother is of Kurdish Jewish origin. The heights of family members from three generations are shown in Fig. 1Go. The mother has an unremarkable family history. The father, on the other hand, has limb deformities (Fig. 3Go). He is 162 cm tall (third percentile) but not markedly shorter than his siblings, who apparently lack any skeletal abnormalities. One of the sisters of patient D3 has celiac disease. The paternal grandfather of the two affected boys was also relatively short (Fig. 1Go). Patient D3 and his siblings never had fractures or any kidney stones.



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  		FIG. 3. Limb deformities observed for the father (patient D3). A and B, Right hand, wrist, and forearm. C, Radiograph of the same limb showing the bowing of long bones.

 
Analysis of the PTH/PTHrP receptor gene

Genomic DNA from both affected boys and their affected father and unaffected mother were extracted by standard procedures. Genomic regions encompassing exons M2 and M6/7 were amplified by PCR, and direct sequence analysis of PCR products was carried out at the Massachusetts General Hospital DNA Core Facility. PCR primers for amplification of exon M2 were as follows: 5'-GCCTTGACTCTCCCTTGGTA-3' (forward) and 5'-CCTCTCTCCTGCTGTTCCAC-3' (reverse). PCR primers for amplification of exon M6/7 were as follows: 5'-GTAAGCTGGGGGTCATCGAG-3' (forward) and 5'-GAGGAAGCCTCTGGGGTATC-3' (reverse). Primers that were previously described for mutational analysis of the PTH/PTHrP receptor gene using temperature-gradient gel electrophoresis (15) were used as sequencing primers. The C-to-G mutation in exon M6/7 leading to the T410R substitution was also confirmed by restriction enzymatic digestion of PCR-amplified DNA using MslI, which fails to digest the mutant allele.

In vitro expression of wild-type and mutant PTH/PTHrP receptors and determination of basal cAMP accumulation

Plasmid DNAs encoding wild-type and mutant PTH/PTHrP receptors have been described previously (14). For in vitro expression, COS-7 cells were seeded in 24-well plates at a density of 8 x 104 cells per well. The following day, transfection was performed with varying amounts of plasmid DNA through the use of Effectene reagent (Qiagen, Valencia, CA) according to manufacturer’s instructions. Basal level of cAMP accumulation was determined 72 h after transfection by incubation of the cells at 37 C for 15 min in HEPES-buffered DMEM (pH 7.4) containing 2 mM isobutyl methylxanthine and 1% BSA. Cells were subsequently lysed with 50 mM HCl, and the amount of cAMP in each well was determined by RIA, as previously described (14).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Laboratory studies

The patients and their father showed normal serum calcium and phosphate concentration but elevated urinary calcium excretion and elevated serum 1,25 dihydroxy vitamin D3 (Table 1Go). Serum PTH was below the normal range in both boys, and it was in the lower end of the normal range in the father. Tubular reabsorption of phosphate was below the normal limit in patient D2, and it was low-normal in patients D1 and D3. Bone mineral density measurements were obtained by dual-energy x-ray absorptiometry for both children, and the results were compared with those of age-matched healthy controls (unpublished data provided by the manufacturer of the equipment). The Z scores at the spine (L2–L4) were –2.40 and –2.66 for patients D2 and D1, respectively, whereas the Z scores for whole-body bone mineral content were –0.47 and –1.59, respectively. The combination of the clinical, biochemical, and radiological findings were consistent with a mild form of JMC, and therefore, we searched for PTH/PTHrP receptor gene mutations.


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  		TABLE 1. Biochemical features of the investigated individuals affected by JMC

 
Genetic studies

Mutational analysis of the PTH/PTHrP receptor gene identified identical heterozygous nucleotide substitutions in the affected father and his two affected sons but not in the healthy mother (Fig. 4AGo). The nucleotide change abolishes an MslI restriction site, which was used to confirm the mutation originally detected by direct sequence analysis (Fig. 4BGo). The identified substitution is predicted to change the PTH/PTHrP receptor residue 410 from threonine (T) to arginine (R) (T410R). One hundred chromosomes of healthy unrelated individuals have been previously analyzed, and nucleotide changes at this codon were ruled out as polymorphisms (12).



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  		FIG. 4. Identification of the PTH/PTHrP receptor gene mutation. A, Nucleotide sequence traces obtained from direct sequence analysis of the PCR-amplified exon M6/7 and the adjacent intronic sequences. The identified C-to-G exchange changes the encoded amino acid from threonine (T) to arginine (R). B, PCR products were digested with MslI to verify the identified nucleotide exchange. Note that the full-length PCR product comprises 1127 bp and is cleaved upon MslI digestion into three fragments of 656, 166, and 305 bp. When the identified C-to-G exchange is present, one of the two sites is removed (*), and a 471-bp fragment, instead of the 166- and 305-bp fragments, is generated. As a result, the affected individuals ({blacksquare}), but not the healthy female ({circ}), show an additional DNA fragment.

 
In vitro analysis of the PTH/PTHrP receptor with the T410R mutation

The T410P substitution has been previously identified in a patient with JMC (12). It has also been shown that all amino acids at position 410, with the exception of the normally occurring threonine, lead to agonist-independent cAMP accumulation in vitro, but the degree of constitutive activity showed significant variation (14). The basal cAMP level in cells transiently expressing the T410P mutant was approximately 6-fold higher than the level in cells transiently expressing the wild-type receptor, whereas the basal cAMP accumulation associated with the T410R mutant was only approximately 4-fold higher, even though the latter mutant was expressed at higher levels than the T410P mutant (14). Analysis of COS-7 cells transiently transfected with varying amounts of each plasmid also showed that the T410R mutant was functionally active in the absence of an agonist and that the degree of constitutive activity for the T410R mutant was not as high as that for the T410P mutant (Fig. 5Go).



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  		FIG. 5. Basal level of cAMP in cells transfected with plasmid DNA encoding the wild-type PTH/PTHrP receptor ({blacksquare}), the T410P mutant ({triangleup}), or the T410R mutant ({blacktriangledown}). Cells transfected with varying amounts of plasmid DNA encoding individual receptors were assayed 72 h after transfection as described in Subjects and Methods. Cells were incubated without agonist at 37 C in HEPES-buffered DMEM containing 2 mM isobutyl methylxanthine and 1% BSA. After lysing the cells with 50 mM HCl, cAMP concentration was determined in each well. The data are given in picomoles/well and represent the mean ± SEM of three independent experiments.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In contrast to most other reported cases, which appear to result from de novo mutations (11, 12, 13), we now report on a small family with an inherited form of JMC. A novel missense mutation was identified as the underlying genetic defect in the affected members of this family. Based on in vitro characterizations, the constitutive activity of the identified T410R receptor mutant is not as pronounced as that observed for the receptor mutations previously described in other JMC patients (11, 12, 13). Consistent with this difference in constitutive receptor activity, the clinical and biochemical features of the disease in this family are less severe than those for all other patients reported to have this disorder. For instance, despite having limb deformities, the affected father is not significantly shorter than his siblings, and he is considerably taller than all other previously reported patients (11, 12, 13). Furthermore, the bone dysplasia does not appear to be as pronounced as seen in the other cases. Moreover, serum calcium and phosphate levels in the three patients are within the normal range, although the increased urinary calcium excretion and the suppressed serum PTH levels suggest that all three patients could be intermittently hypercalcemic. Hence, the familial cases reported in this study provide evidence for genotype-phenotype correlation for JMC, which was predicted on the basis of in vitro studies with transfected cells (14). A similar correlation between genotype and clinical presentation has been previously reported for precocious puberty involving mutations that induce constitutive activity of the LH/chorionic gonadotropin (CG) receptor (16). Like in the PTH/PTHrP receptor, different substitutions at a single amino acid residue at the sixth membrane-spanning domain of the LH/CG receptor (D578) lead to different degrees of agonist-independent cAMP accumulation and are associated with different pathological outcomes that range from Leydig-cell hyperplasia to Leydig-cell tumor. The constitutively active LH/CG receptor mutant that demonstrated the highest basal cAMP accumulation in vitro (D578H) also showed a robust agonist-independent phospholipase C activation, which may explain, at least partly, the severity of the clinical presentation in patients carrying this mutation. In contrast, agonist-independent phospholipase C activity could not be detected for any of the PTH/PTHrP receptor mutants that couple to adenylyl cyclase stimulation in a constitutive manner, although more sensitive assays in the future may prove otherwise.

Previously, only two females affected by JMC were reported to have given birth to children (12, 20), but there were no reports regarding the fertility of male patients with a heterozygous PTH/PTHrP receptor gene mutation that led to constitutive receptor activity. The observation that the affected adult male in our study is fertile suggests that it should be possible to generate a mouse carrying one of the known constitutively activating PTH/PTHrP receptor mutations and to maintain these lines through males and females. The resulting model of JMC could provide new insights into the role of the PTH/PTHrP receptor in bone metabolism and mineral ion homeostasis and its possible functions in other tissues and organs.

The dual-energy x-ray absorptiometry finding of diminished vertebral bone density is similar to findings in adult patients with primary hyperparathyroidism (18). However, transgenic mice expressing the H223R mutant under the control of the type I collagen promoter showed increased trabecular volume in long bones (19), and therefore, constitutive PTH/PTHrP receptor activation would be predicted to result also in increased bone mineral density at the spine. However, such data have not yet been reported for genetically manipulated mice, and the decrease in vertebral BMD in both affected children thus remains unexplained.

Urinary calcium excretion was significantly elevated in the two sons, and consistent with that finding, both pediatric patients developed renal stones; however, at least in the case of patient D1, treatment with oral phosphate, calcium, and 1{alpha}-hydroxy vitamin D for the initially presumed diagnosis of hypophosphatemic rickets may have contributed to stone formation by increasing the filtered renal load of calcium. In view of the significant urinary calcium excretion despite relatively mild skeletal findings in this particular family, one might raise the question whether certain patients with hypercalciuria and nephrolithiasis should be screened for PTH/PTHrP receptor mutations, even in the absence of readily detectable growth plate abnormalities. Besides screening residue 410 for missense mutations, the molecular screening of these patients could be focused on the membrane-spanning domains and the intracellular loops because most mutations that lead to constitutive activation of a variety of different G protein-coupled receptors have been found in those regions (17).


   Footnotes
 
This work was supported in part by grants from the National Institutes of Health (DK-50708 to H.J. and DK062973 to M.B.).

M.B. and A.R.-R. contributed equally to this work.

Abbreviations: CG, Chorionic gonadotropin; JMC, Jansen’s metaphyseal chondrodysplasia.

Received January 8, 2004.

Accepted March 31, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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