Instituto Valenciano de Microbiología

Masía El Romeral
Ctra. de Bétera a San Antonio Km. 0.3
46117 Bétera (Valencia)
Phone. 96 169 17 02
Fax 96 169 16 37
CIF B-96337217


Somatotropinoma (Somatotropinoma) - Genes and AIP GNAS1

The somatotropinomas are secreting pituitary adenomas growth hormone (GH: Grow Hormone). This process results in the clinical picture of acromegaly or gigantism, depending on the time of development that makes its appearance. Acromegaly is characterized by coarse facial features, protruding jaw , and enlarged extremities.

Most of them are sporadic, but some may occur as associated component of multiple endocrine neoplasia type 1 - see Multiple Endocrine Neoplasia Type 1 - MEN1- gene, Carney complex - see Carney complex - PRKAR1A- gene, pituitary adenoma family isolated (FIPA) or familial isolated somatotropinoma (FIS).

Somatic mutations found in the GNAS1 activating gene in 27-53% of GH - secreting pituitary adenomas. The GNAS1 gene is on the long arm of chromosome 20 (20q13.3) and encodes Gsa subunit of Gs protein signaling. G proteins are transducers that mediate binding of extracellular receptor ligands to intracellular messenger systems. Thus, the activity of adenylate cyclase (lyase which catalyzes the conversion of ATP to cAMP) is under control of Gs stimulation and inhibition of Gi. Thus, the activating mutations in the ? subunits of Gs proteins produce - independent activation of adenylate cyclase system, becoming oncoproteins. Activating mutations in the gene GNAS1 occur in exons 8 and 9. The most frequent are missense mutations that cause substitution of an arginine by a cysteine or a histidine at codon 201 of exon 8 (R201H or R201C), or generating substituting glutamine with an arginine or a leucine at codon 227 of exon 9 (Q227R or Q227L).

Besides GNAS1 gene mutations have been identified in the AIP gene lead to the development of somatotropinomas in people with familial isolated pituitary adenoma (FIPA), a hereditary disease characterized by the development of cancerous tumors in the pituitary gland. The AIP gene, located on the long arm of chromosome 11 (11q13.3), encoding the protein of receptor interaction aryl carbohydrates (AIP). Although AIP function is not clear, it is known to interact with numerous other proteins including the receptor aryl carbohydrates. Through these interactions, AIP probably helps regulate certain cell, such as growth and cell division, differentiation and cell survival processes. In addition, it is believed that this protein acts as a tumor suppressor. Although it is unclear how mutations in the AIP gene are involved in tumor development, it is believed that genetic alterations disrupt the interaction between AIP and one or more proteins. AIP capacity to control cell proliferation can be reduced, allowing pituitary cells grow and divide without control and form a tumor.

Expression analysis carried out to determine the type of inheritance of determined somatotropinomas its autosomal dominant with incomplete penetrance. Early onset of the disease and moderately aggressive behavior of tumors of the pituitary gland, leading to hypopituitarism and infertility, could explain the fact much of the affected individuals can not transmit the disease to their offspring.

Tests in IVAMI: in IVAMI perform detection of mutations associated with the development of somatotropinomas, by complete PCR amplification of the exons of GNAS1 and AIP, respectively, and subsequent sequencing genes. We recommend starting the study by exons 8 and 9 of GNAS1 gene, with the possible reduction of time and cost involved in most cases. If not, there is the possibility of completing the study by amplifying and sequencing the remaining exons of the gene and the AIP GNAS1 gene.

Samples recommended: tissue from tumor biopsy.