Proopiomelanocortin (POMC) deficiency causes severe obesity that begins at an early age. In addition to obesity, people with this condition have low levels of a hormone known as adrenocorticotropic hormone (ACTH) and tend to have red hair and pale skin.

Affected infants are usually a normal weight at birth, but they are constantly hungry, which leads to excessive feeding (hyperphagia). The babies continuously gain weight and are severely obese by age 1. Affected individuals experience excessive hunger and remain obese for life. It is unclear if these individuals are prone to weight-related conditions like cardiovascular disease or type 2 diabetes.

Low levels of ACTH lead to a condition called adrenal insufficiency, which occurs when the pair of small glands on top of the kidneys (the adrenal glands) do not produce enough hormones. Adrenal insufficiency often results in periods of severely low blood sugar (glucose), known as hypoglycemia. Adrenal insufficiency may also cause seizures, elevated levels of a toxic substance called bilirubin in the blood (hyperbilirubinemia), and a reduced ability to produce and release a digestive fluid called bile (cholestasis). Without early treatment, adrenal insufficiency can be fatal.

Pale skin that easily burns when exposed to the sun and red hair are common in POMC deficiency, although not everyone with the condition has these characteristics.

POMC deficiency is caused by mutations in the POMC gene, which provides instructions for making the proopiomelanocortin protein. This protein is cut (cleaved) into smaller pieces called peptides that have different functions in the body. One of these peptides, ACTH, stimulates the release of another hormone called cortisol from the adrenal glands. Cortisol is involved in the maintenance of blood glucose levels. Another peptide, alpha-melanocyte stimulating hormone (α-MSH), plays a role in the production of the pigment that gives skin and hair their color. The α-MSH peptide and another peptide called beta-melanocyte stimulating hormone (β-MSH) act in the brain to help maintain the balance between energy from food taken into the body and energy spent by the body. The correct balance is important to control eating and weight.

POMC gene mutations that cause POMC deficiency result in production of an abnormally short version of the POMC protein or no protein at all. As a result, there is a shortage of the peptides made from POMC, including ACTH, α-MSH, and β-MSH. Without ACTH, there is a reduction in cortisol production, leading to adrenal insufficiency. Decreased α-MSH in the skin reduces pigment production, resulting in the red hair and pale skin often seen in people with POMC deficiency. Loss of α-MSH and β-MSH in the brain dysregulates the body's energy balance, leading to overeating and severe obesity.

POMC deficiency is a rare cause of obesity; POMC gene mutations are not frequently associated with more common, complex forms of obesity. Researchers are studying other factors that are likely involved in these forms.

Normal Function

The POMC gene provides instructions for making a protein called proopiomelanocortin (POMC), which is cut (cleaved) into smaller pieces called peptides that have different functions in the body. The peptides attach (bind) to one of several proteins in different regions of the body, and this binding triggers signaling pathways that control many important functions.

One peptide produced from the POMC protein is called adrenocorticotropic hormone (ACTH). ACTH binds to melanocortin 2 receptor (MC2R), stimulating the release of a hormone called cortisol. This hormone helps maintain blood sugar (glucose) levels, protects the body from stress, and stops (suppresses) inflammation.

Three similar peptides called alpha-, beta-, and gamma-melanocyte stimulating hormones (α-, β-, and γ-MSH) are also cut from the POMC protein. The primary role of α-MSH is in the pigment-producing cells of the skin and hair (melanocytes), where it binds to melanocortin 1 receptor (MC1R). This attachment stimulates the production and release of a pigment called melanin, which is the substance that gives skin and hair their color.

The β-MSH peptide plays a role in weight regulation by binding to melanocortin 4 receptor (MC4R). Signaling through this receptor in the brain helps maintain the balance between energy from food taken into the body and energy spent by the body. The correct balance is important to control eating and weight. The α-MSH peptide can also bind to MC4R and help maintain the correct energy balance.

Studies show that γ-MSH binds to melanocortin 3 receptor (MC3R). Signaling stimulated by this interaction appears to be involved in regulating the amount of sodium in the body and controlling blood pressure, although the mechanism is unclear.

Another peptide produced from POMC is β-endorphin. Attachment of β-endorphin to proteins in the brain called opioid receptors stimulates signaling for pain relief.

Health Conditions Related to Genetic Changes

Proopiomelanocortin deficiency

Several mutations in the POMC gene have been found in people with proopiomelanocortin (POMC) deficiency. These gene mutations lead to production of an abnormally short version of the POMC protein or no protein at all. As a result, there is an absence of the peptides made from POMC, including ACTH, α-MSH, β-MSH, β-endorphin, and sometimes γ-MSH. Loss of these peptides prevents signaling through their receptor proteins and disrupts certain functions in the body. Without ACTH, there is a reduction in cortisol production, which leads to low blood glucose (hypoglycemia) and other problems in affected individuals. Decreased α-MSH in the skin reduces pigment production in melanocytes, which results in the red hair and pale skin often seen in people with POMC deficiency. Loss of signaling in the brain stimulated by α-MSH and β-MSH dysregulates the body's energy balance, leading to overeating and severe obesity. Shortage of γ-MSH or β-endorphin does not seem to cause health problems in people with this condition.

Other Names for This Gene

• ACTH
• adrenocorticotropic hormone
• adrenocorticotropin
• alpha-melanocyte-stimulating hormone
• alpha-MSH
• beta-endorphin
• beta-LPH
• beta-melanocyte-stimulating hormone
• beta-MSH
• CLIP
• COLI_HUMAN
• corticotropin-like intermediary peptide
• corticotropin-lipotropin
• gamma-LPH
• gamma-MSH
• lipotropin beta
• lipotropin gamma
• LPH
• melanotropin alpha
• melanotropin beta
• melanotropin gamma
• met-enkephalin
• MSH
• NPP
• opiomelanocortin prepropeptide
• POC
• pro-ACTH-endorphin
• pro-opiomelanocortin
• pro-opiomelanocortin preproprotein
• proopiomelanocortin preproprotein

Genomic Location

POMC deficiency is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with this condition each carry one copy of the mutated gene. They typically do not have POMC deficiency, but they may have an increased risk of obesity.

POMC deficiency is a rare condition; approximately 50 cases have been reported in the medical literature.