Is IGSF1 involved in human pituitary tumor formation?

Abstract

IGSF1 is a membrane glycoprotein highly expressed in the anterior pituitary. Pathogenic mutations in the IGSF1 gene (on Xq26.2) are associated with X-linked central hypothyroidism and testicular enlargement in males. In this study we tested the hypothesis that IGSF1 is involved in the development of pituitary tumors, especially those that produce growth hormone (GH). IGSF1 was sequenced in 21 patients with gigantism or acromegaly and 92 healthy individuals. Expression studies with a candidate pathogenic IGSF1 variant were carried out in transfected cells and immunohistochemistry for IGSF1 was performed in sections from GH-producing adenomas, familial somatomammotroph hyperplasia and in normal pituitary. In two male patients, and in one female, with somatomammotroph hyperplasia from the same family, we identified the sequence variant p.N604T, which in silico analysis suggested could affect IGSF1 function. Of 60 female controls, two carried the same variant, and seven were heterozygous for other variants. Immunohistochemistry showed increase IGSF1 staining in the GH-producing tumor from the patient with the IGSF1 p.N604T variant compared to a GH-producing adenoma from a patient negative for any IGSF1 variants and to normal control pituitary tissue. The IGSF1 gene appears polymorphic in the general population. A potentially pathogenic variant identified in the germline of three patients with gigantism from the same family (segregating with the disease) was also detected in two healthy female controls. Variations in IGSF1 expression in pituitary tissue in patients with or without IGSF1 germline mutations point to the need for further studies of IGSF1 action in pituitary adenoma formation.

Spatial and temporal expression of immunoglobulin superfamily member 1 in the rat

“…IGSF1 protein expression in pituitary homogenates was previously reported in adult mice (Sun et al 2012) and humans (Chapman & Woodruff 2001). Immunohistochemical staining was previously demonstrated in adult human pituitary tissue (Faucz et al 2015), but co-localization was only assessed in embryonic mouse pituitary. IGSF1 expression was observed in thyrotropes, somatotropes, and lactotropes, but not gonadotropes (Sun et al 2012), which is consistent with our results in the adult rat.…”

Genetics of gigantism and acromegaly

“…60 This variant was associated with increased IGSF1 staining in pituitary tissue when compared with a GH-secreting adenoma from a patient that was negative for the IGSF1 variant, and with a normal control pituitary tissue. Since the affected family was later reported to be affected by the X-LAG syndrome, 7 the findings may imply that IGSF1 , while not playing a direct causative role in GH excess, could act synergistically in pituitary tumorigenesis.…”

Повногеномний Пошук Асоціацій У Пацієнтів Української Популяції З Акромегалією

“…По-третє, лабораторні дослідження в пацієнтів із СТГПАГ, негативних щодо мутацій у відомих генах, дослідження цілого геному за допомогою порівняльної геномної гібридизації (CGH -молекулярний цитогенетичний метод аналізу повторів ДНК) може бути таким же корисним, як цілковите секвенування екзонів (WES). Наприклад, CGH було важливим для ідентифікації дефектів на Х-хромосомі за синдрому X-LAG, тоді як WES не вдалося виявити причинний ген у цьому випадку [14].…”