Concurrent hormone resistance (pseudohypoparathyroidism type Ia) and hormone independence (testotoxicosis) caused by a unique mutation in the G alpha s gene.
Defects in the G (guanine nucleotide-binding)-protein subunit (G alpha s) which stimulates adenylyl cyclase may result in either loss or gain of endocrine function. Reduced G alpha s activity is found in the hormone resistance syndrome, pseudohypoparathyroidism type Ia (PHP-Ia), while constitutive activation of G alpha s is associated with endocrine organ overactivity, including the gonadotropin-independent sexual precocity seen in patients with McCune-Albright syndrome. We identified two unrelated boys presenting with concurrent PHP-Ia and gonadotropin-independent sexual precocity (testotoxicosis). Mutational screening by denaturing gradient gel electrophoresis and sequencing of PCR-amplified exons of the G alpha s gene revealed a point mutation which generates an alanine-to-serine substitution in codon 366 of one G alpha s allele (A366S), an alanine present at the homologous position in all G-proteins. We have previously shown in transfected testis cells that the A366S mutation activates G alpha s by decreasing affinity for GDP, thereby increasing the rate of nucleotide exchange in a receptor-independent fashion. In contrast to differential stability of the activated mutant G alpha s protein in Leydig cells, with stability at 32 degrees C but not at 37 degrees C, skin fibroblasts with the mutation had the same reduced G alpha s levels at both temperatures. Our findings explain the limitation of clinical manifestations of G alpha s overactivity to testis, without involvement of other body appendages which are generally at lower than core body temperature. This unique mutation at a critically conserved residue of G alpha s is the first mutant G-protein which affects guanine nucleotide affinity and is associated with human disease, producing widely divergent and tissue-specific effects.
Nakamoto
J M
JM
Department of Pediatrics, University of California at Los Angeles 90095, USA.
Zimmerman
D
D
Jones
E A
EA
Loke
K Y
KY
Siddiq
K
K
Donlan
M A
MA
Brickman
A S
AS
Van Dop
C
C
D015152:Blotting, Northern; D015153:Blotting, Western; D003062:Codon; D004591:Electrophoresis, Polyacrylamide Gel; D005091:Exons; D019204:GTP-Binding Proteins / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011547:Pseudohypoparathyroidism / Q000235:genetics*; D011629:Puberty, Precocious / Q000235:genetics*; D015183:Restriction Mapping
D003062:Codon; D019204:GTP-Binding Proteins