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  • Writer's pictureDr Edin Hamzić & Dženita Omerkić Dautovic, MSc

PCSK1 Gene: Implications in Obesity and Metabolic Disorders

This is the first blog post in a two-part series of posts focused on the PCSK1 gene. In this first blog post, we will describe the PCSK1 gene and its role but also focus on its mutations and related PCSK1 deficiency. The second blog post will primarily focus on the pharmacogenomic link between Imcivree (setmelanotide) and the proprotein convertase (PC1/3) deficiency.

What Is the PCSK1 Gene? What Does the PCSK1 Gene Encode?

PCSK1 stands for Proprotein Convertase Subtilisin/Kexin Type 1. The PCSK1 gene encodes an enzyme called proprotein convertase 1 (also known as prohormone convertase or prohormone convertase 3 or neuroendocrine convertase 1).

The proprotein convertase 1 is a member of the subtilisin-like proprotein convertase family of enzymes. Often the abbreviation PC1/3 is used to denote proprotein convertase 1.

In this blog post, we will use the terms proprotein convertase 1 or the concrete abbreviation PC1/3.

Where Is the PCSK1 Gene Located? Who Discovered the PCSK1 Gene?

The PCSK1 gene is located on the long arm of chromosome 5, roughly 43,811 MB long. Two laboratories discovered the PCSK1 gene independently in 1991, Smeekens et al. [citation] and Seidah et al. [citation], during the research on the cleaving prohormones and pre-neuropeptides within the secretory granules [citation].

What Does PC1/3 Enzyme Do? What Is the Function of the PC1/3 Enzyme?

As already mentioned, the PCSK1 gene encodes prohormone convertase 1/3 (PC1/3) enzyme whose role is cleaving immature proproteins (precursors) to generate mature functional proteins that are further essential in prohormone maturation and secretory pathways (for example, leptin-melanocortin pathway) [citation]. Neuropeptides and prohormones require proteolytic activation by prohormone convertase before they are released for subsequent action in various tissues. This activation occurs within the regulated secretory pathway of both neurons and endocrine cells [citation].

Simple Explanation: What Does PC1/3 Enzyme Do? What Is the Function of the PC1/3 Enzyme?

To explain it simply, prohormone convertase 1/3 is an essential enzyme in our body that plays a crucial role in processing and activating other hormones. It acts like a molecular scissor, cutting larger hormone molecules into smaller pieces, which allows them to become active and perform their specific functions.

One may ask why hormones are not cut and processed right away. Well, hormones are produced in one place and must be transported to another to deliver their message. However, when these hormones are first made, they are usually inactive, like a long chain or string of letters.

This is where PC1/3 comes in. It recognizes these long hormone chains and chops them up at specific points. These smaller pieces are now active and ready to perform their functions. It's like cutting the string into individual letters that can be rearranged to form meaningful words.

Once the hormones are activated, they can carry out their essential tasks, such as regulating metabolism, controlling appetite, managing stress responses, and many other functions essential for our body's well-being.

How is the PC1/3 Activated?

There are three stages of activation through which prohormone convertase ⅓ passes until its final form:

  1. Stage 1: PC1/3 synthesis into inactive pro-PC1/3,

  2. Stage 2: PC1/3 converts by autocatalytic cleavage of the NH2-terminal propeptide in the endoplasmic reticulum (ER).

  3. Stage 3: A second internal propeptide cleavage in a post-ER compartment (final step required for activation) [citation].

Why Prohormone Convertase (PC1/3) is Important?

The PC1/3 enzyme is one of the critical elements in

  • Incretin synthesis, secretion, and inactivation; Incretins play a crucial role in regulating blood glucose levels and are essential for maintaining overall metabolic balance.

  • Peptide hormone metabolism; Peptide hormone metabolism is essential because it maintains the proper balance of hormones in the body, preventing excessive or prolonged hormonal effects. It also helps terminate hormone signaling, allowing cells to return to normal after achieving the desired response.

  • And insulin processing pathways. Insulin processing pathways are essential because they ensure the production and release of functional insulin, a hormone crucial for regulating blood sugar levels. These pathways involve the synthesis, folding, and cleavage of proinsulin to generate mature insulin, allowing for proper glucose uptake by cells and preventing high blood sugar levels.

PC1/3 and PC2 (proprotein convertase 2 encoded by the PCSK2 gene) are only expressed in neural and endocrine tissues, where they cleave prohormones and pro-neuropeptides within the secretory granules of the regulated secretory pathway [citation]. More than 25 different targets of PC3/1 are detected, and they serve an essential role in metabolic pathways [citation].

Why Is the Prohormone Convertase (PC1/3) Important?

The PCSK1 gene is recognized as one of the first genes causing rare forms of monogenic obesity [citation]. By 2016, only 21 patients with PC1/3 deficiency were reported in the literature according to Härter et al. [citation]. Furthermore, numerous genome-wide association studies (GWAS) show a convincing association between specific polymorphisms in the PCSK1 gene that are exceedingly common in the population and an increased risk of obesity [citation].

What Are the Biological Processes That the PC1/3 Enzyme Is Involved In?

PC1/3 activity is required for the biosynthesis of various hypothalamic, pancreatic, and gut peptide hormones involved in controlling food intake [citation]. PC1/3 is predominantly expressed in neural and endocrine tissues: the pituitary, the brain, and the endocrine pancreas [citation], and is enrolled in cleaving immature proproteins (precursors) to generate mature functional proteins [citation].

What Are the Prohormones That the PC1/3 Cleaves?

PC1/3 is crucial for the processing of several neuropeptides and peptide hormones such as:

  1. Pro-opiomelanocortin (POMC; conditioned by coexpression of both, PC1/3 and PC2) [citation],

  2. Proinsulin,

  3. Proglucagon [citation],

  4. Pro-ghrelin [citation],

  5. Prorenin,

  6. Proenkephalin,

  7. Prodynorphin,

  8. and pro-somatostatin [citation].

What Is the PC1/3 Deficiency? How Common Is PC1/3 Deficiency? What Is Causing the PC1/3 Deficiency?

PC1/3 deficiency is a rare autosomal recessive disorder in which patients present with malabsorptive diarrhea and a series of symptoms of endocrine disorders [citation].

Thus far, only 21 patients have been reported. However, more patients are likely to be misdiagnosed or die soon after birth [citation].

Mutations causing partial PC1/3 deficiency are present in 0.83% of extreme obesity phenotypes [citation].

PC1/3 deficiency is inherited in an autosomal recessive manner [citation]. In patients with PC1/3 deficiency, the proinsulin level and the risk of obesity increase. Proinsulin is one of the major substrates related to PC1/3 [citation].

What Are the Symptoms of PC1/3 Deficiency?

Different symptoms vary between patients [citation], including the following:

  1. Increased BMI,

  2. Polyuria/polydipsia,

  3. Abnormal glucose homeostasis,

  4. Malabsorptive diarrhea,

  5. Decreased linear growth,

  6. Hypogonadotropic hypogonadism,

  7. Hypothyroidism,

  8. and Hypocortisolism.

Increasing numbers of genetic diagnoses of infants with persistent diarrhea have recently led to the finding of many novel PCSK1 mutations [citation]. Children with PCSK1 deficiency develop obesity as they age [citation].

What Are Mutations in the PCSK1 Gene That Cause PC1/3 Deficiency? What Do Mutations in the PCSK1 Gene Cause?

PC1/3 deficiency mutations are either homozygous or compound heterozygous mutations [citation]. Several mutations causing PCSK1 deficiency have been detected, reported, and clinically described in databases, but we will mention and briefly describe some.

Mutations that cause deficiency are primarily located in the catalytic and P domains of the PCSK1 gene. Several nonsense mutations cause a premature stop codon leading to truncated proteins. All mutations cause a complete loss of activity measured in vitro, except for the PCSK1-p.P258T mutation. This mutation retains approximately 50% of the activity compared to the PCSK1-Wild type (normal PCSK1) [citation].

Two common heterozygous variants of PCSK1 are of clinical significance:

  1. N221D (rs6232),

  2. and Q665E-S690T (rs6234-rs6235);

both associated with morbid obesity and/or diabetes [citation; citation; citation; citation].

In addition, the following mutations are also mentioned:

  1. Mutation in a homozygous patient for a loss of function mutation (Ser307Leu, rs137852824) results in reduced maturation and secretion of PC1/3; indications involve obesity due to PC1/3 deficiency [citation].

  2. G593R missense mutation on one allele (Loss-of-function) causing low-grade stress in ER [citation].

  3. PC1/3 deficiency in three siblings results from homozygous N309K mutation [citation].

Some variations cause a significant decrease in enzymatic activity. To date, 30 cases of PCSK1 deficiency have been reported, with patients exhibiting a variable range of symptoms. All these patients were diagnosed with early and severe malabsorptive diarrhea and consistently elevated proinsulin levels [citation].

PCSK1 mutations in patients that are homozygous or compound heterozygous for loss of function mutations show variable and pleiotropic syndrome that involves:

  1. Obesity,

  2. Malabsorptive diarrhea,

  3. Hypogonadotropic hypogonadism,

  4. Altered thyroid and adrenal function,

  5. Impaired regulation of plasma glucose levels in combination with high circulating proinsulin to insulin ratio [citation].

Are There Mutations in the PCSK1 Gene That Cause Increased Levels of PC1/3?

Evidence for increased PC1/3 levels caused by PCSK1 mutations has not been reported. However, there is interesting data from the study by Blanco et al. (2015) where an additional S357G mutation was observed, which can partially mask the damage caused by the N221D modification of PC1/3 activity [citation].

How Can the PC1/3 Deficiency Be Detected? What Genetic Tests Are There to Detect the PC1/3 Deficiency?

The normal conversion of proinsulin to insulin depends on the PC1/3 function in human pancreatic islets. The measurement of the circulating ratio of proinsulin to insulin is therefore a sensitive biochemical test for PC1/3 deficiency [citation].

All tests mentioned in Table 1 can be routinely performed in laboratories; further analysis based on genetic tests is performed if PC1/3 deficiency is suspected. For example, insulin and proinsulin levels can be done in laboratories with a simple blood test.

In addition, there is the POMC/PCSK1/LEPR CDx Panel based on NGS technology for the detection of germline nucleotide substitutions in the following genes:

  1. Pro-opiomelanocortin (POMC)

  2. Proprotein Convertase Subtilisin/Kexin type 1 (PCSK1)

  3. Leptin receptor (LEPR) [citation].

There still needs to be routine detection of PC1/3 deficiency (by genetic tests) because it is not frequent in the population, and tests are expensive. Laboratories like PreventionGenetics offer PCSK1 gene sequencing to mutations and offer a particular cost-covered testing program. POMC/PCSK1/LEPR CDx Panel confirms POMC/PCSK1/LEPR mutations related to deficiency.

Appropriate investigations, such as exome sequencing, can be performed if relevant symptoms are presented:

Table 1: List of all tests that are routinely performed in laboratories in order to detect PC1/3 deficiency

Clinical Symptoms

Clinical Tests [citation]

Increased BMI



Low serum osmolalit

Abnormal glucose homeostasis

Increased proinsulin, low insulin, increased 65,64-des-split proinsulin

Malabsorptive diarrhea

Mild villous atrophy, elevated progastrin and GLP-1 precursors, normal procalcitonin

Decreased linear growth

GH, low IGF-1

Hypogonadotropic hypogonadism

Low FSH, low LH, low T


Low TRH, high TSH, low free T4


Normal ACTH, elevated ACTH precursors

Targeted PCSK1 exons and intron-exon boundaries sequencing are undertaken in several laboratories with a particular interest in PCSK1 deficiency. In addition, the rapidly decreasing cost of the whole exome and whole genome sequencing may lead to route analysis for PCSK1 deficiency [citation].

How PCSK1, POMC, and LEPR Genes Are Related?

The hypothalamic melanocortin 4 receptor (MC4R) pathway regulates body weight [citation] and products of PCSK1, POMC, and LEPR genes are involved in the given pathway.

Leptin is a hormone that regulates appetite and energy expenditure with the engagement of its receptor, LEPR. Further, LEPR receptors are found on POMC neurons in hypothalamic arcuate neurons. POMC (processed in multiple neuropeptides by enzymes involving PCSK1) activates the MC4R pathway resulting in energy utilization and promoting weight loss [citation].

It has been reported that early-onset severe obesity results from loss of function (LoF) mutations in the MC4R pathway. In addition, mutations are found through epidemiological analysis in pro-opiomelanocortin (POMC), prohormone convertase 1 (PCSK1), and leptin receptor (LEPR) [citation].

Rare homozygous or biallelic variants in POMC, PCSK1, and LEPR can disrupt the signaling of the melanocortin pathway and cause insatiable hunger, hyperphagia, and severe early-onset obesity. The normal function of this hypothalamic pathway is essential for energy balance [citation; citation].

What Is the POMC/PCSK1/LEPR CDx Panel?

The POMC/PCSK1/LEPR CDx Panel is a next-generation sequencing (NGS)-based in vitro diagnostic test that analyzes genomic DNA isolated from blood or saliva for the detection of germline variants in 3 genes (POMC / PCSK1 and LEPR) associated with obesity [citation].

Testing is done for patients older than 6 years and adults to prescribe Imcivree® (setmelanotide) drug, following the purpose and labeling of the drug [citation].

Who Produces the POMC/PCSK1/LEPR CDx Panel?

POMC/PCSK1/LEPR CDx Panel is developed by PreventionGenetics, LLC [citation].

POMC/PCSK1/LEPR CDx Panel is developed and implemented under Clinical Laboratory Improvement Amendments (CLIA) regulations and standards at PreventionGenetics, an ISO 15189 certified and CLIA/CAP (College of American Pathologists) accredited laboratory [citation].

Rhythm Pharmaceuticals has utilized this assay to genetically confirm POMC/PCSK1/LEPR deficiency obesity in clinical studies. Rhythm’s headquarters is in Boston, MA.

For What Mutations Do the POMC/PCSK1/LEPR CDx Panel Test?

The POMC/PCSK1/LEPR CDx Panel is an NGS assay for detecting germline variants in 3 genes (POMC/PCSK1 and LEPR). Variants that are confirmed and interpreted by this test are:

  1. Pathogenic,

  2. Likely pathogenic,

  3. or of uncertain significance (VUS).

This panel covers 99.92% of all coding exons of the genes plus 10 bases of flanking noncoding regions of DNA in which pathogenic variants are detected and reported, whether at PreventionGenetics or somewhere else [citation].

How Does the POMC/PCSK1/LEPR CDx Panel Work?

It is a qualitative in vitro diagnostic device. Whole blood and assisted saliva samples are collected and shipped to the PreventionGenetics laboratory. NGS technologies cover the gene's coding regions plus ~10 bases of noncoding DNA flanking each exon. DNA is captured using an optimized set of DNA hybridization capture probe and then sequenced using Illumina's Reversible Dye Terminator (RDT) platform. Variants interpreted as pathogenic (P), likely pathogenic (LP), or VUS (or VOUS) are reported [citation]. Coverage is defined by >20X NGS reads or Sanger sequencing.

How Much Does POMC/PCSK1/LEPR CDx Panel Cost?

The POMC/PCSK1/LEPR CDx Panel costs about 790$ [citation]. Patients of all ages with severe obesity may be eligible for the Rhythm-sponsored genetic testing program [citation].


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