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  • Writer's pictureDr Edin Hamzić

🧬 All Things You Need to Know About the POMC Gene

Updated: Jan 5

📒 A Short Introduction! TL;DR

As the post's title says, this post aims to cover all the key things you need to learn about the POMC gene in a 5 minutes read. The post can be divided into the following three sections:

  • Shortly about the gene and what it encodes? What is the function of the proteins it encodes?

  • What are the most common health conditions related to genetic mutations in the gene?

  • How can one do genetic testing for the POMC gene?

🗺️ Where Is Located? 🧬 What It Encodes?

  • The POMC gene is located on chromosome 2 and it is roughly 7721 bases long [citation].

  • Nakanishi et al. discovered the POMC gene in 1978 [citation]. It has been initially discovered in cows, but humans, of course, have the POMC gene as well.

  • The POMC gene encodes proopiomelanocortin, a pre-protein (precursor polypeptide) with ten different cleavage sites. This means that once it is expressed it produces a single protein that is cut into a smaller pieces (peptides) which have their own function. I will write about that in the following chapters.

  • So, multiple different protein products (peptides) are produced (as illustrated in the figure below) from the original proopiomelanocortin pre-protein.

✂️ What Peptides Are Produced by the POMC Gene?

The final products of the cleavage are following (the color coding follows the figure below):

  1. the N-terminal peptide of proopiomelanocortin (N-POMC)

    1. γ3-melanotropin (γ3-MSH)

      1. γ-melanotropin (γ-MSH)

  2. joining peptide (JP)

  3. corticotropin (adrenocorticotropic hormone, or ACTH)

    1. corticotropin-like intermediate peptide (CLIP)

    2. α-melanotropin (α-melanocyte-stimulating hormone, or α-MSH)

  4. β-lipotropin (β-LPH)

    1. γ-Lipotropin (γ-LPH)

      1. β-melanotropin (β-MSH)

    2. β-Endorphin

The POMC gene structure going from exons over mRNA to protein products including primary product (pro-opiomelanocortin) over to secondary and tertiary products such as N-POMC, JP, ACTH,  beta LPH, gamma3 MSH, gamma MSH, alpha MSH, CLIP, gamma LPH, beta EP and beta MSH
Structure of the POMC gene and corresponding proteins it encodes

🕴🏽 What Are Functions of the POMC Peptides?

This is short summary of the main functions of proopiomelanocortin peptides:

  • γ-MSH is involved regulation of salt and water balance, regulation of blood pressure, modulating of energy metabolism, regulation on immune system and potential anti-inflammatory effects.

  • ACTH is invovled in production of steroids, regulating immune system, regulating adrenal gland size and function and stress response.

    • α-MSH is involved in skin pigmentation, appetite regulation, anti-inflammatory effects, modulation of immune system, sexual arousal.

    • CLIP

  • β-lipotropin (β-LPH) primary function is to stimulate the release of fatty acids from adipose tissue, a process known as lipolysis. This makes fatty acids available for energy production.

    1. The function of γ-lipotropin (γ-LPH) is not well-defined. In general, lipotropins are involved in lipid metabolism, but the exact role of γ-lipotropin requires more research for clarification.

      1. β-melanotropin (β-MSH)  is involved in increasing the production and release of melanin in skin cells, contributing to skin pigmentation. It's a fragment of ACTH and has similar melanocyte-stimulating properties.

    2. β-Endorphin is primarily known for its role in pain management and providing feelings of well-being or euphoria. β-Endorphin acts as a natural painkiller and is released in response to stress, exercise, or pain.

Also, important aspect to cover is related to other hormones and molecules that affect or act regulatory on proopiomelanocortin. Proopiomelanocortin is regulated in the arcuate nucleus by several hormones, nutrients, neuropeptides, and neurotransmitters which affect energy balance. The proopiomelanocortin is regulated by:

  • Leptin

  • Insulin

  • Dietary nutrients such as glucose and leucine [citation].

👨🏼‍⚕️ The POMC Gene & Diseases

Mutations in the POMC gene have been associated with the following diseases:

  1. Obesity

  2. Corticotropic tumor

  3. Cushing disease

  4. Pigmentation disorders [citation]

In this blog post, we will focus mainly on the link between obesity and the POMC gene.

🐼 The POMC Deficiency & Obesity

  • As mentioned above the main focus in the post will be on obesity caused by the POMC deficiency.

  • The POMC deficiency is a rare autosomal recessive disorder that causes severe obesity [citation].

  • Premature termination of POMC protein causes the overall lack of α-MSH and β-MSH in the brain.

  • Genetic mutations that cause a lack of melanocortin receptor (MC-R) ligands ACTH, alpha, beta, and gamma MSH in essence cause the POMC deficiency

  • These peptides are melanocortin receptor ligands and are involved in the melanocortin pathway. The melanocortin pathway regulates the “fed feeling” in the brain. Therefore, lack of α-MSH and β-MSH peptides in the brain disrupts the body’s energy balance leading to constant hunger, overeating, and obesity [citation].

🧪 How to Detect the POMC Deficiency Caused Obesity?

  • The POMC/PCSK1/LEPR CDx Panel is a next-generation sequencing (NGS)-based in-vitro diagnostic test used to detect the POMC deficiency.

  • This panel typically provides 99.92% coverage of all coding exons of the genes plus ten bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere [citation].

  • The panel analyzes genomic DNA isolated from blood or saliva, and it detects different types of genetic mutations (nucleotide substitutions, short insertions and deletions, and copy number variants (CNVs)) within the:

    • Pro-opiomelanocortin (POMC) gene

    • Proprotein Convertase Subtilisin/Kexin type 1 (PCSK1) gene

    • Leptin Receptor (LEPR) gene

  • The panel is indicated to be used in case person has an obesity of unknown origin [citation].

  • Mutations causing deficiency in this case can be successfully treated by Imcivree (setmelanotide) are tested using sequencing technologies [citation]. I created a CSV file containing a list of pathogenic and likely pathogenic genetic variants in the POMC gene.

Download CSV • 17KB

💊 What Is Imcivree?

  • Imcivree (generic name: setmelanotide) is a medicine used for obesity treatment, and it is based on hunger control in the case of POMC, PCSK1, and LEPR gene deficiencies [citation].

  • In addition, Imcivree is an antagonist of the melanocortin four receptor, meaning that it restores the impaired MC4 receptor pathway activity caused by genetic deficiencies upstream of the MC4 receptor [citation].

💊 When Is Imcivree Indicated to Be Used?

  • Indications for the usage of Imcivree are detected variants causing deficiency in POMC, PCSK1, and LEPR genes.

  • Imcivree is an antagonist of the MC4 receptor. MC4 receptors in the brain are involved in hunger regulation, satiety, and energy expenditure. The POMC, PCSK1, and LEPR genes produce ligands of MC4, and their deficiency disrupts the MC4 receptor pathway. The antagonist of the MC4 receptor restores the activity of the pathway by reactivating the MC4 receptor [citation].

🔗 How POMC, PCSK1, and LEPR Genes Are Related?

  • POMC, PCSK1, and LEPR genes are part of the central melanocortin pathway [citation].

  • The LEPR gene provides instructions for making leptin receptors, which act as a body weight regulator. Therefore, mutations in the LEPR gene lead to a lack of leptin receptors, thus rendering leptin binding impossible. Due to this fact, the entire leptin-melanocortin signaling pathway is disrupted, leading to the energy balance disruption [citation].

  • PCSK1 encodes prohormone-convertase ⅓. The PCSK1 gene is one of the first genes in a pathway involved in early-onset obesity. The PCSK1 deficiency leads to severe difficulties in the absorption of nutrients during the first years of life, leading to overeating and associated obesity [citation].

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