All endocrine systems consist of interacting networks of lig-ands, receptors, postreceptor signaling molecules, enzymes, and protein products. Each of these proteins is encoded by a gene, and these genes, in turn, are regulated by networks of transcription factors. Mutations in any of the involved genes can lead to alterations in the function of a given system and, thus, to disease. Selected endocrine disorders that illustrate particular molecular mechanisms of disease will be discussed here; other disorders are discussed in more detail later in the chapter.
A variety of mutations have been reported in the genes encoding hormones themselves. Deletions of such genes will result in complete absence of hormone, whereas less drastic mutations will result in a nonfunctional protein product. Mutations have also been reported that alter processing and packaging of the hormone. One example is the AVP gene (OMIM 192340), which encodes both the hormone arginine vasopressin (AVP) and its packaging protein neurophysin II. Mutations within the neurophysin II domain impair packaging and secretion of AVP, leading to central diabetes insipidus (2).
Mutations in cell surface receptors are another important genetic cause of endocrine disorders. The severity and manifestations of an illness can vary depending on whether mutations result in no receptor function (null mutations) or only in decreased functioning. Receptor mutations can lead to decreased ligand binding or impaired signaling. For example, null mutations of the insulin receptor lead to leprechaunism (also called Donohue syndrome, OMIM 246200); these patients have nearly absent insulin function and die in infancy (3-6). Less severe mutations in the insulin receptor cause Rabson-Mendenhall syndrome (OMIM 262190), which is associated with survival into late childhood and early adolescence (7).
Two groups of hormones, the steroid hormones and the thyroid hormones, interact with nuclear receptors. In order to function properly, the receptor must be able to bind both its ligand and its appropriate DNA-binding site, as well as to interact with other cofactors. For example, androgen insensitivity syndrome is caused by mutations in the androgen receptor (OMIM 313700); the majority of such mutations are in the ligand-binding domain, but up to 20 % occur in the DNA-binding domain (8,9).
Mutations in the proteins of post-receptor signaling systems can also cause endocrine disease. The classic example is the McCune-Albright syndrome (OMIM 174800). This syndrome is caused by postzygotic somatic mutations in the a-subunit of the adenylate cyclase stimulatory G-protein (Gsa, encoded by GNAS1, OMIM 139320). Gsa is a key regulator of the hormone-responsive adenylate cyclase system and is involved in intracellular signaling by many endocrine receptors, including those for adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), parathyroid hormone (PTH), leutinizing hormone (LH), and follicle-stimulating hormone (FSH). Activating mutations lead to constitutive activity of these receptors. The classic triad of McCune-Albright syndrome consists of polyostotic fibrous dysplasia, precocious puberty, and café au lait spots, but hyperfunction of multiple endocrine systems can occur including hyperthyroidism, hypercortisolism, growth hormone excess, and hyperprolactinemia. The timing of the somatic mutation causes variation in the type and extent of manifestations. The majority of patients have a point mutation in exon 8 of the GNAS1 gene (Arg201His or Arg201Cys), although individuals with other mutations have been reported. Molecular analysis is best done on affected tissue, as unaffected tissue might not show the mutation (10-12).
Many endocrine disorders result from defects in the enzymes that synthesize the respective hormones. Deficiencies in any of the several enzymes involved in adrenal steroid hormone biosynthesis can result in congenital adrenal hyperplasia, whereas defects in thyroid hormone biosynthesis can result in congenital hypothyroidism.
Finally, descriptions of how defects in various transcription factors can cause clinical disease are provided in the following sections on the growth hormone pathway and maturity-onset diabetes of youth (MODY).
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