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.
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.
Bastepe
Murat
M
Endocrine Unit, Massachusetts General Hospital for Children, MGH/Harvard Medical School, Wellman 5, Boston, MA 02114, USA.
Raas-Rothschild
Annick
A
Silver
Justin
J
Weissman
Irit
I
Wientroub
Shlomo
S
Jüppner
Harald
H
Gillis
David
D
D000328:Adult; D019943:Amino Acid Substitution; D000818:Animals; D001120:Arginine; D001827:Body Height; D001842:Bone and Bones / Q000000981:diagnostic imaging*; D019556:COS Cells; D002118:Calcium / Q000097:blood / Q000652:urine; D002648:Child; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000096:biosynthesis; D006801:Humans; D007669:Kidney Calculi / Q000209:etiology; D008297:Male; D009154:Mutation; D010009:Osteochondrodysplasias / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D010281:Parathyroid Hormone / Q000097:blood; D010375:Pedigree; D011859:Radiography; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000235:genetics*; D013912:Threonine
D010281:Parathyroid Hormone; D044168:Receptor, Parathyroid Hormone, Type 1; D013912:Threonine; D001120:Arginine; D000242:Cyclic AMP; D002118:Calcium