Background: Immunoglobulin superfamily, member 1 (IGSF1) was originally proposed to function as an inhibin co-receptor in pituitary gonadotroph cells. More recently, however, loss of function mutations in the human IGSF1 gene were linked to a novel syndrome of central hypothyroidism, testicular enlargement, and variable prolactin-deficiency. Igsf1-deficient mice are also centrally hypothyroid, with reduced pituitary thyrotropin-releasing hormone receptor (Thrhr1) expression. Although these observations provide some insight into the potential causes of central hypothyroidism in IGSF1-deficient patients, IGSF1s normal function in pituitary and hypothalamus remains unresolved.
Objective and Hypotheses: The objectives of our ongoing studies are to understand: i) how pathogenic mutations in IGSF1 impair protein expression, and ii) physiological roles of IGSF1 in the HPT axis.
Method: To address these research objectives, we are using a combination of in vitro biochemical and cell biological approaches in heterologous and homologous cell lines, and in vivo analyses of Igsf1-deficient mice.
Results: Preliminary data indicate the missense mutations in IGSF1 not only impair membrane trafficking of the IGSF1 protein (as previously reported), but also decrease the proteins stability. Recent in vitro and in vivo results may finally uncover IGSF1 function(s) in the brain and/or pituitary gland.
Conclusion: Genetic analyses in humans and mice have established a previously unappreciated role for IGSF1 in the hypothalamicpituitary control of thyroid function. Novel data promise not only to define IGSF1s normal functions in cells but to provide mechanistic insight into how the loss of these functions result in a novel endocrinopathy.
20 - 22 Sep 2014
European Society for Paediatric Endocrinology