Pseudohypoparathyroidism, type Ia (PHP-Ia), is a dominantly inherited endocrine disorder characterized by resistance to hormones that act by stimulating adenylyl cyclase. It is caused by inheritance of an autosomal mutation that inactivates the ␣ subunit (␣ s ) of G s , the stimulatory regulator of adenylyl cyclase. In three members of a family, the PHP-Ia phenotype is associated with a mutation (R231H) that substitutes histidine for an arginine at position 231 in ␣ s . We assessed signaling function of ␣ s -WT versus ␣ s -R231H transiently transfected in HEK293 cells. Hormone receptor-dependent stimulation of cAMP accumulation in cells expressing ␣ s -R231H is reduced by ϳ75% in comparison to cAMP accumulation in cells expressing ␣ s -WT. A second mutation, ␣ s -R201C, inhibits the GTPase turnoff reaction of ␣ s , thus producing receptor-independent stimulation of cAMP accumulation. The double mutant, ␣ s -R231H/ R201C, stimulates cAMP accumulation almost as well (ϳ80%) as does ␣ s -R201C itself, indicating that the R231H mutation selectively impairs receptor-dependent signaling. In three-dimensional structures of G protein heterotrimers, Arg-231 is located in a region, switch 2, that is thought to interact with the ␤␥ subunit rather than with the hormone receptor. Thus, the R231H phenotype suggests that switch 2 (perhaps in concert with ␤␥) mediates G protein activation by receptors at a site distant from the receptor-G protein contact surface.Heterotrimeric G proteins relay information from receptors for extracellular stimuli to effector enzymes and ion channels that mediate cell responses. Receptors interact with the G protein ␣/␤␥ complex, causing release of GDP bound in the guanine nucleotide binding pocket of the G protein ␣ subunit and its replacement by GTP. GTP-induced conformational changes cause G␣GTP to dissociate from the ␤␥ dimer, allowing both subunits to interact with effectors. Effector stimulation is then terminated by the intrinsic GTPase activity of G␣, followed by reassociation of G␣GDP and ␤␥. With respect to this cycle, recently published crystal structures have revealed details of GTP-induced conformational change in G␣ (1-3), a plausible structure for the catalytic intermediate in the GTPase reaction (4, 5), and three-dimensional structures for the G␣␤␥ heterotrimer (6, 7). Because we do not have the structure of a receptor-G␣␤␥ complex, however, we cannot yet describe in molecular detail the pivotal event in receptor-G protein signaling, receptor-triggered release of GDP from G␣.At present we can try to understand this event by interpreting effects of instructive mutations. A potential source of such mutations is an inherited disease of G protein signaling, pseudohypoparathyroidism, type Ia (PHP-Ia) (8). PHP-Ia patients inherit a defect in one of the two autosomal alleles of the gene for ␣ s , the ␣ subunit of G s , the stimulatory regulator of adenylyl cyclase. Although G s mediates effects of many hormones, the ϳ50% decrease in G s activity produced by loss of an autosomal allele cau...

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An evaluation of intellectual, personal and social functioning was made in 16 young patients with craniopharyngioma. No changes were found in the overall IQ verbal and performances scores before and after operation, however, discrepancies between verbal and performance scores suggest that one of the manifestations of craniopharyngioma in children are disturbance in cognitive functions. The decrease in the quality of life of the patients and their families manifested through the deterioration of familial and social relationships and the decrease in scholastic achievements lead to the conclusion that children with craniopharyngioma and their families require close psychological supervision and counselling both before and after surgery.

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