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Christine Gicquel, Anne Dib, Xavier Bertagna, Serge Amselem and Yves Le Bouc

Gicquel C, Dib A, Bertagna X, Amselem S, Le Bouc Y. Oncogenic mutations of α-Gi2 protein are not determinant for human adrenocortical tumourigenesis. Eur J Endocrinol 1995:133:166–72. ISSN 0804–4643

Activating mutations of G proteins, which are membrane signal transducers, have been associated recently with the development of various endocrine neoplasms. Mutations of two highly conserved codons, Arg201 and Gin227, in the α-subunit of the Gs protein, the adenylyl cyclase-stimulating protein, were first described in growth hormone-producing pituitary tumours. They resulted in constitutive activation of the αs-subunit by decreasing intrinsic GTPase activity. A similar mutation, affecting codon Arg179 (exon 5) in the α-subunit of the Gi2 protein, the adenylyl cyclase-inhibiting protein, has been described by a single group in ovarian and adrenocortical tumours. We evaluated the frequency of activating mutations in the α-subunit of the Gi2 protein in 18 human adrenocortical tumours. We screened exons 5 (codon Arg179) and 6 (codon Gln205) for mutations by denaturing gradient gel electrophoresis analysis of leucocyte and tumoural DNA. No abnormal migration pattern was found in either exon. The absence of mutation in exon 5, which includes the Arg179 codon, was confirmed in all tumoural DNA by direct sequencing. In conclusion, we did not find any oncogenic mutations in the GTPase domain of the α-subunit of the Gi2 protein in adrenocortical tumours. Thus, the previously oncogenic gip2 mutations do not appear to be determinant for adrenocortical tumourigenesis.

Christine Gicquel, Laboratoire d'Explorations Fonctionnelles Endocriniennes, Hôpital Trousseau, 26 Avenue Arnold Netter, 75012 Paris, France

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Christelle Pérez, Florence Dastot-Le Moal, Nathalie Collot, Marie Legendre, Isabelle Abadie, Anne-Marie Bertrand, Serge Amselem and Marie-Laure Sobrier


In humans, pituitary hormone deficiency may be part of a syndrome including extra-pituitary defects like ocular abnormalities. Very few genes have been linked to this particular phenotype. In the mouse, Lhx2, which encodes a member of the LIM (Lin-11, Isl-1, and Mec-3) class of homeodomain proteins, was shown to be expressed during early development in the posterior pituitary, eye, and liver, and its expression persists in adulthood in the central nervous system Lhx2 −/− mice display absence of posterior pituitary and intermediate lobes, malformation of the anterior lobe, anophthalmia, and they die from anemia.


We tested the implication of the LHX2 gene in patients presenting pituitary hormone deficiency associated with ectopic or nonvisible posterior pituitary and developmental ocular defects. A cohort of 59 patients, including two familial cases, was studied. Direct sequencing of the LHX2 coding sequence and intron/exon boundaries was performed. LHX2 transcriptional activity on several pituitary promoters (AGSU, PRL, POU1F1, and TSHB) was tested in vitro.


Six heterozygous sequence variations were identified, among which two are novel missense changes (p.Ala203Thr and p.Val333Met). In vitro, LHX2 activates transcription of TSHB, PRL, and POU1F1 promoters in the HEK293 cell line. A synergistic action of POU1F1 and LHX2 was also shown on these promoters. The two missense variations were tested and no significant difference was observed, leading to the conclusion that they are not deleterious.


These results suggest that if LHX2 is involved in pituitary hormone deficiency associated with posterior pituitary and ocular defects, it would be a rare cause of this disease condition.