A. Zung et al., URINARY CYCLIC ADENOSINE-3',5'-MONOPHOSPHATE RESPONSE IN MCCUNE-ALBRIGHT SYNDROME - CLINICAL-EVIDENCE FOR ALTERED RENAL ADENYLATE-CYCLASE ACTIVITY, The Journal of clinical endocrinology and metabolism, 80(12), 1995, pp. 3576-3581
The recent finding of an activating mutation in the G(s) alpha protein
, the protein that couples receptors to stimulation of adenylate cycla
se, from endocrine and nonendocrine tissues of patients with McCune-Al
bright syndrome (MAS) suggests that alterations in adenylate cyclase a
ctivity may account for the clinical abnormalities in these patients.
Many patients with MAS have hypophosphatemia. This may result from the
presence of the activating G(s) alpha mutation in proximal renal tubu
les or the elaboration of a phosphaturic factor from fibrous dysplasia
. We, therefore, sought to characterize renal cAMP generation and phos
phate handling in MAS patients. Intravenous infusion of PTH is a class
ic clinical test used to evaluate hormonal responsiveness of renal pro
ximal tubule adenylate cyclase and examine PTH-dependent phosphate cle
arance. We per formed PTH infusion in 6 MAS patients, 10 normal subjec
ts, and 6 patients with pseudohypoparathyroidism (PHP). The basal urin
ary cAMP (UcAMP) level in the MAS group [5.5 +/- 2.6 nmol/dL glomerula
r filtration (GF)] was elevated (P < 0.05) compared to those in both n
ormal subjects (3.2 +/- 1.2 nmol/dL GF) and patients with PHP (1.9 +/-
0.6 nmol/dL GF). However, PTH-stimulated peak UcAMP (15.0 +/- 7.0 nmo
l/dL GF) and the peak/basal UcAMP ratio (3.1 +/- 1.7) in MAS were sign
ificantly lower than the respective values in normal subjects (30.8 +/
- 16.9 nmol/dL GF and 9.3 +/- 2.9; P < 0.05 for both) and were statist
ically similar to the blunted levels in PHP (respectively, 3.1 +/- 1.5
nmol/dL GF and 2.0 +/- 1.7). By contrast, the PTH-induced phosphaturi
c response in MAS patients was similar to that in the normal subjects.
Our study provides clinical evidence that MAS patients have altered r
enal adenylate cyclase activity, manifested by an elevated basal UcAMP
, but a blunted UcAMP response to PTH stimulation. These observations
are presumably due to a mutation in the G(s) alpha protein in the rena
l tubules. Despite the blunted UcAMP excretion, the phosphaturic respo
nse to PTH in MAS patients is intact.