Molar pregnancy is a gestational trophoblastic disease associated with a trophoblastic proliferation and a protein synthesis alteration. It is characterized by the presence of hydatiform moles, which are fluid-filled cysts derived from the chorionic villi of the placenta. Recent studies have reported a reduced expression of several types of G proteins including Gsalpha in molar pregnancies suggesting alterations in G protein structure in hydatiform moles. To identify mutations that lead to Gsalpha deficiency, we isolated genomic DNA from hydatiform moles and used polymerase chain reaction to amplify all exons of the Gsalpha gene. Amplified Gsalpha gene fragments were analyzed by sequencing using the dideoxy chain termination method. Tissues obtained from three complete hydatiform moles and one partial hydatiform mole were examined. We have identified a heterozygous 8-bp deletion in exon 10 of the Gsalpha gene, in two complete hydatiform moles, that had evidence for a dysfunctional Gsalpha protein. This deletion produced a truncated protein. We have also identified a heterozygous polymorphism in exon 5 in two complete hydatiform moles, and a homozygous substitution (A-->G) in intron 5 of the Gsalpha gene in the other complete hydatiform mole; these two last types of mutations should not have any effects on protein activity.