Olfactory dysfunction in humans with deficient guanine nucleotide-binding protein

The guanine nucleotide-binding stimulatory protein (G_s) couples hormone-receptor interaction to the activation of adenylate cyclase and the generation of cyclic AMP (see ref. 1 for a review). Studies using frog neuroepithelium indicate that the sense of smell is mediated by a G _s-adenylate cyclase system², and this prompted us to test olfaction in the only known model of G_s deficiency in the animal kingdom, G_s-deficient (type 1a) pseudohypoparathyroidism (PHP), which occurs in humans^3-8. Such patients are resistant to the cAMP-mediated actions of several hormones⁹. (Although Henkin ¹⁰ has reported disturbances in the sense of smell in six patients with PHP, currently available biochemical measurements such as the cAMP response to parathyroid hormone (PTH) and determination of G_s activity were not reported and olfactory testing was limited.) In the present study, we found that all G_s-deficient patients had impaired olfaction when compared with PHP patients who had normal G_s activity (type 1b PHP, in which patients are resistant only to the action of PTH in the kidney). This is the first evidence of human olfactory impairment which can be related to G _s deficiency and suggests that G_s-deficient PHP patients may be resistant to cAMP-mediated actions in other non-endocrine systems.