Immunoglobulin superfamily, member 1
is a plasma membrane glyco
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
encoded by the ''IGSF1''
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
,
which maps to the
X chromosome
The X chromosome is one of the two sex-determining chromosomes (allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO sex ...
in humans and other mammalian species.
Function
IGSF1's function in normal cells is unresolved. The protein is a member of the
immunoglobulin (Ig) superfamily. It was predicted to contain 12 Ig loops, a transmembrane domain, and a short cytoplasmic tail. However, during translation of the
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
, it is cleaved into
amino- and
carboxy-terminal domains (NTD and CTD, respectively).
Only the CTD is trafficked to the
plasma membrane. The NTD is trapped within the
endoplasmic reticulum (ER). Pathogenic mutations in the ''IGSF1'' gene block the transport of the CTD to the plasma membrane.
Clinical relevance
Mutations in ''IGSF1'' cause a condition called IGSF1 deficiency syndrome
or central hypothyroidism/testicular enlargement (CHTE
). The condition, which affects an estimated 1:100,000 people,
is more common in males than females. Most affected males are discovered through neonatal screening for
hypothyroidism. The extent of hypothyroidism is variable, but most male cases require treatment with thyroid hormone replacement. Males with IGSF1 deficiency exhibit enlarged testicles (also known as
macroorchidism
Macroorchidism is a disorder found in males, specifically in children, where a subject has abnormally large testes. The condition is commonly inherited in connection with fragile X syndrome (FXS), which is also the second most common genetic ca ...
) and a delay in the development of secondary sexual characteristics. Post-pubertally, there is no evidence of impaired fertility in these men.
The ''IGSF1'' gene is also active in the brain and in the developing liver. It can also become reactivated in liver cancer (hepatocellular carcinoma).
Animal model
Mice lacking a functional ''Igsf1'' gene similarly exhibit hypothyroidism of central origin.
The ''IGSF1'' gene is particularly active in the
pituitary gland
In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The ...
. The pituitary synthesizes and secretes
thyroid-stimulating hormone (TSH). TSH, in turn, stimulates production of the
thyroid hormones, thyroxine and triiodothyronine, by the
thyroid gland. TSH secretion is controlled by
thyrotropin-releasing hormone (TRH), which is released by neurons in the hypothalamus of the brain. In ''Igsf1'' deficient mice, the receptor for TRH is downregulated in the pituitary.
This decrease could explain, at least in part, the central hypothyroidism observed in both humans and mice with IGSF1 deficiency. How the loss of IGSF1 causes a decrease in TRH receptors is presently unknown.
References
Further reading
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