In fact, the concept of using molecular classification for hereditary endocrine disease was proposed a decade ago by Prof. Marx [ 3 ]. The purpose of this manuscript is to describe a molecular classification to serve as basis for classification of hereditary endocrine disease.
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The molecular classification is based upon the biological function of the mutated genes. A discussion of the rationale for the three categories and examples of genes that would fall into each group follows. Specific cell lineage development and differentiation is the first step in constructing a functional endocrine system.
This process involves complex spatiotemporal regulation of cell lineage—specific transcription factors expressed in pluripotential stem cells. A genetic abnormality involving any of these key transcription factors is an important cause of congenital dysgenesis or agenesis. Specific examples of dysgenesis exist for all major endocrine glands including pituitary, thyroid, pancreas, adrenals, and gonads. Additionally, single gene defects may impact multiple glands.
DAX1 is essential for both adrenal and gonad development. Currently, treatment for this category of disease is hormone replacement in the lifetime. In the future, generation of functional endocrine gland from embryonic stem cells may be new avenue [ 7 ]. The two broad classes of hormones include peptide hormones and non-peptide hormones.
Peptide hormones are directly translated from an encoding gene and therefore venerable to direct mutation. Genetic defects in an encoding gene e. Mutation of genes in this category usually leads to solitary hormone deficiency e. Non-peptide hormones are synthesized by a series of synthetic enzymes from natural materials.
Therefore, mutation targeting is indirect. Steroid hormones represent the single most important group of non-peptide hormones.
Growth Hormone Deficiency | Johns Hopkins Medicine
They are all derived from cholesterol and therefore share a complex synthetic pathway. For this reason, mutations targeting these genes often have complex phenotypic outcomes, such as congenital adrenal hyperplasia CAH [ 9 ]. Importantly, mutations targeting early steps of the synthetic pathway effect production of multiple steroids. In addition to synthesis, the appropriate transportation of synthetic materials is indispensable for non-peptide hormones as well. SLC26A4, for example, encodes an iodide chloride transporter that resides in thyroid follicular cells, known as pendrin.
Autoimmune Addison disease
Mutated pendrin is retained in the endoplasmic reticulum instead of being trafficked to plasma membrane, therefore decreasing iodide transport, causing hypothyroidism in Pendred syndrome [ 10 ]. To respond to a hormone, a target cell must contain two essential components of a signaling pathway: a function receptor and effector.
Hormone receptors mainly include two groups, membrane receptor and nuclear receptor. Inactivating mutations in hormone receptors either cause hormone resistance phenotypically or mimic hormone insufficiency, while activated mutations cause hormone hypersensitivity.
You and Your Hormones
Insulin receptor INSR and glucocorticoid receptor GR are ubiquitously expressed membrane and nuclear receptor, respectively. Activating mutations cause familial hyperinsulinemic hypoglycemia [ 11 ] and glucocorticoid hypersensitivity [ 12 ], while inactivating mutations cause insulin resistant syndrome [ 13 ] and glucocorticoid resistance, respectively [ 14 ]. Effectors mainly include signaling molecules and sometimes ion channels as the terminal effector.
Post-receptor signaling molecules are mostly downstream of cell membrane receptor and serve a critical role in the intracellular messaging. GPCRs transduce extracellular signals to hormone-sensitive adenylate cyclase, the activity of which is regulated by at least 2 G proteins, 1 stimulatory G s , and 1 inhibitory G i [ 15 ].
Ion channels are important effectors in mediating mineralocorticoids function. Integrated synthesis and function of ion channels are indispensable in maintaining salt homeostasis.
Diseases targeting hormone function may clinically present as either gain or loss of function. For this reason, we include specific sub-categories related to the molecular functions. The categorization of a specific genetic defect occurring in the hormone pathway helps guide optimal treatment. For example, identification of a defective signaling pathway rather than lack of hormone triggers a completely different treatment route, as supplementation becomes a less viable option. Tumor syndromes are described for all major endocrine glands, and like other cancers have been linked to activating mutations of oncogenes or inactivating mutations of tumor suppressor genes.
Germline RET mutations cause constitutive activation of the RET kinase and downstream signaling pathway, therefore leading to uncontrolled cell proliferation. Targeting RET has opened a new treatment practice in advanced medullary thyroid carcinoma [ 21 ]. While this risk exists in all tissues, the clinical impact is greatest in the parathyroid, pituitary, and pancreas. Tumoriogenesis is a category where genetic testing has a proven benefit that extends well beyond endocrine syndromes.
Knowledge of specific mutation status guides treatment of asymptomatic endocrine glands in patients and their relatives before they anatomically identified. Where cancer has progressed, identification of mutational drivers provides the opportunity for targeted therapy.
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The benefits derived from defining a molecular classification should be integrated with clinical diagnosis. Accurate clinical diagnosis including defining the specific hormone disorder and localizing the disease lesion is a fundamentally important component of clinical care. Genetic diagnosis provides a means of definitive diagnosis, thereby outlining an accurate treatment strategy for the patient and family members potentially at risk.
We are now in a period of transition when genetics is creating the opportunity for a new level of personalized medicine. The endocrine system is a complex collection of hormone-producing glands that control basic body functions such as metabolism, growth and sexual development.
You and Your Hormones
The endocrine glands consist of: pineal; pituitary; thyroid and parathyroids; thymus; adrenals; pancreas; ovaries female ; and testes male. Hormones are the chemical signaling molecules produced by the endocrine glands and secreted directly into the bloodstream. They travel through the blood to distant tissues and organs, where they can bind to specific cell sites called receptors. By binding to receptors, hormones trigger various responses in the tissues containing the receptors.
How does MEN1 affect the endocrine glands and the duodenum?
In addition to the classical endocrine organs, many other cells in the body secrete hormones. Myocytes in the atria of the heart and scattered epithelial cells in the stomach and small intestine are examples of what is sometimes called the "diffuse" endocrine system. If the term hormone is defined broadly to include all secreted chemical messengers, then virtually all cells can be considered part of the endocrine system. Encyclopedia of Endocrine Diseases, Second Edition, comprehensively reviews the extensive spectrum of diseases and disorders that can occur within the endocrine system.
It serves as a useful and comprehensive source of information spanning the many and varied aspects of the endocrine end metabolic system. Students will find a concise description of the physiology and pathophysiology of endocrine and metabolic functions, as well as their diseases. Each article provides a comprehensive overview of the selected topic to inform a broad spectrum of readers, from advanced undergraduate students, to research professionals. Chapters explore the latest advances and hot topics that have emerged in recent years, such as the molecular basis of endocrine and metabolic diseases mutations, epigenetics, signaling , the pathogenesis and therapy of common endocrine diseases e.
Students, clinicians, and researchers in the field of endocrinology seeking specific information on topics outside their immediate area of expertise, as well as help with diagnosing and treating endocrine patients. The Encyclopedia will be of interest to laboratories, pharmaceutical companies, and graduate, departmental and medical school libraries. His clinical specialty is in chemical pathology.
He is an author of about seven hundred peer-reviewed publications as well as several book chapters on basic and clinical reproductive endocrinology and laboratory diagnosis of endocrine diseases. He currently serves as an editorial board member for several academic journals, including as editor-in-chief of Molecular and Cellular Endocrinology Elsevier. Huhtaniemi has also edited several books in the field of reproductive endocrinology and physiology. We are always looking for ways to improve customer experience on Elsevier.
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