PMID- 10487664
OWN - NLM
STAT- MEDLINE
DCOM- 19991006
LR  - 20131121
IS  - 0021-972X (Print)
IS  - 0021-972X (Linking)
VI  - 84
IP  - 9
DP  - 1999 Sep
TI  - A novel parathyroid hormone (PTH)/PTH-related peptide receptor mutation in
      Jansen's metaphyseal chondrodysplasia.
PG  - 3052-7
AB  - 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 downstream 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.
FAU - Schipani, E
AU  - Schipani E
AD  - Department of Medicine, Massachusetts General Hospital and Harvard Medical
      School, Boston 02114, USA. schipani@helix.mgh.harvard.edu
FAU - Langman, C
AU  - Langman C
FAU - Hunzelman, J
AU  - Hunzelman J
FAU - Le Merrer, M
AU  - Le Merrer M
FAU - Loke, K Y
AU  - Loke KY
FAU - Dillon, M J
AU  - Dillon MJ
FAU - Silve, C
AU  - Silve C
FAU - Juppner, H
AU  - Juppner H
LA  - eng
GR  - DK-50708-01/DK/NIDDK NIH HHS/United States
PT  - Case Reports
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Clin Endocrinol Metab
JT  - The Journal of clinical endocrinology and metabolism
JID - 0375362
RN  - 0 (Inositol Phosphates)
RN  - 0 (Parathyroid Hormone)
RN  - 0 (Receptor, Parathyroid Hormone, Type 1)
RN  - 0 (Receptors, Parathyroid Hormone)
RN  - 04Y7590D77 (Isoleucine)
RN  - 94ZLA3W45F (Arginine)
RN  - E0399OZS9N (Cyclic AMP)
SB  - IM
MH  - Animals
MH  - Arginine/genetics
MH  - COS Cells
MH  - Child
MH  - Child, Preschool
MH  - Cyclic AMP/metabolism
MH  - Female
MH  - Heterozygote
MH  - Humans
MH  - Infant
MH  - Inositol Phosphates/metabolism
MH  - Isoleucine/genetics
MH  - Male
MH  - *Mutation
MH  - Mutation, Missense
MH  - Osteochondrodysplasias/*genetics
MH  - Parathyroid Hormone/pharmacology
MH  - Receptor, Parathyroid Hormone, Type 1
MH  - Receptors, Parathyroid Hormone/*genetics
MH  - Transfection
EDAT- 1999/09/16 00:00
MHDA- 1999/09/16 00:01
CRDT- 1999/09/16 00:00
PHST- 1999/09/16 00:00 [pubmed]
PHST- 1999/09/16 00:01 [medline]
PHST- 1999/09/16 00:00 [entrez]
AID - 10.1210/jcem.84.9.6000 [doi]
PST - ppublish
SO  - J Clin Endocrinol Metab. 1999 Sep;84(9):3052-7. doi: 10.1210/jcem.84.9.6000.