Abnormal Gs function in mitral valve prolapse dysautonomia is not associated with abnormal alpha S cDNA sequence.
We have previously shown that a subset of patients with mitral valve prolapse and hyperadrenergic symptoms has enhanced isoprenaline-stimulated beta-adrenergic receptor high-affinity state formation (supercoupling) and increased adenylyl cyclase activity due to abnormal signal transduction by the stimulatory guanine nucleotide regulatory protein (Gs). In this study we looked for an alteration of the nucleotide coding sequence of the gene for alpha s, the subunit of Gs that is directly responsible for formation of the high affinity state and adenylyl cyclase activation, by cloning and sequencing the alpha s cDNA from neutrophils of 4 symptomatic patients and 1 control. No difference was observed between patients and control in the alpha s cDNA sequence. The splice variant concentrations in the fully expressed protein were also grossly unchanged in five patients and four controls. These data show that a primary alteration of the alpha s gene coding sequence is not responsible for defective Gs-associated signal transduction in dysautonomic MVP patients, and suggest that the molecular lesion could be an abnormal posttranslational modification of alpha s, a defect in the beta or gamma subunits of Gs, or an unusual interaction between the subunits in the Gs of these patients.
Balasubramanyam
A
A
Department of Internal Medicine, Baylor College of Medicine, Houston, Texas 77030.
Davies
A O
AO
Codina
J
J
Birnbaumer
L
L
D000262:Adenylyl Cyclases / Q000378:metabolism; D000328:Adult; D001342:Autonomic Nervous System Diseases / Q000503:physiopathology*; D001483:Base Sequence; D003001:Cloning, Molecular; D004247:DNA / Q000096:biosynthesis / Q000235:genetics*; D004789:Enzyme Activation; D005260:Female; D019204:GTP-Binding Proteins / Q000502:physiology*; D006801:Humans; D008875:Middle Aged; D008945:Mitral Valve Prolapse / Q000503:physiopathology*; D016133:Polymerase Chain Reaction; D011943:Receptors, Adrenergic, beta / Q000378:metabolism
D011943:Receptors, Adrenergic, beta; D004247:DNA; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases