Niemann-Pick disease, type C1 (NPC1) is a membrane protein that mediates intracellular cholesterol trafficking in mammals. In humans the protein is encoded by the NPC1 gene (chromosome location 18q11). [5] [6]
Niemann-Pick disease, type C1 (NPC1) is a membrane protein that mediates intracellular cholesterol trafficking in mammals. In humans the protein is encoded by the NPC1 gene (chromosome location 18q11). [5] [6]
NPC1 was identified as the gene that when mutated, results in Niemann-Pick disease, type C. Niemann-Pick disease, type C is a rare neurovisceral lipid storage disorder resulting from autosomal recessively inherited loss-of-function mutations in either NPC1 or NPC2. This disrupts intracellular lipid transport, leading to the accumulation of lipid products in the late endosomes and lysosomes. Approximately 95% of NPC patients are found to have mutations in the NPC1 gene.
NPC1 encodes a putative integral membrane protein containing sequence motifs consistent with a role in intracellular transport of cholesterol and sphingosine to post-lysosomal destinations. [5] [7]
Mutations in the NPC1 gene have been strongly linked with obesity. [8] A genome-wide association study identified NPC1 mutations as a risk factor in childhood obesity and adult morbid obesity, and 1,416 age-matched normal weight controls. [8] Mutations in NPC1 were also correlated with ordinary weight gain in the population. Previous studies in mice have suggested that the NPC1 gene has a role in controlling appetite, as mice with a non-functioning NPC1 gene suffer late-onset weight loss and have poor food intake. NPC1 gene variant could account for around 10 per cent of all childhood obesity and about 14 per cent of adult morbid obesity cases. [8]
Obesity is a widely known disorder that is caused by having too high of a body fat percentage (defined as more than 25% body fat percentage for men, and more than 33% for women) — specifically a large excess of white adipose tissue — responsible for dramatically increasing the risks of developing other medical conditions such as Type 2 diabetes, high blood pressure, osteoarthritis, cancer, and many more. Being obese is different from being overweight (which is simply weighing too much or over the recommended amount) as that does not account for body fat percentage or a body fat to body weight ratio, meaning that the weight can come from other areas in the body such as bone and/or muscle. In just the United States alone, approximately 40% of Americans aged twenty and above are obese, and over 70% of Americans aged twenty and above are overweight (which includes obesity), making obesity a major health issue that must be researched and addressed further.
There are many factors that can affect obesity, including environment, diet, life-style (sedentary vs. active), genetic predisposition—and even within only the genetic component it is rarely ever just one single gene that is the main cause for obesity or increase in obesity risks. There are numerous genes (over a hundred) that can contribute to and are known to be strongly associated with or responsible for obesity. These include genes such as MC4R, LEP, LEPR, and FTO. One of the lesser known gene diseases that is known to be linked to obesity is the NPC1 disease, which is otherwise known as the Niemann-Pick disease type C1. It is important to note that the mutations of this gene are responsible for obesity risk factors, and not the gene itself causing obesity risk factors. The protein product of the NPC1 gene regulates cholesterol and fatty acid transports from lysosomes. It plays a crucial part in metabolism and the overall maintenance of homeostasis related to fats and lipids. One study found that NPC1 mRNA levels were increased in both fat depots, enriched in fat cells, and down-regulated by weight loss. [9] This gene also interacts with diets consisting of high fats to increase weight gain through "differential regulation of central energy metabolism pathways." [10] Specifically, presence of this gene showed significantly increased glycolysis and lipogenesis (which involve turning excess glucose or carbohydrates into fats). In this particular study, Castillo et al. found that when mice with the heterozygous gene (NPC1+/-) were compared to mice with the "normal" homozygous gene (NPC1+/+), heterozygous mice were more susceptible to weight gain when both groups were fed high-fat foods. (BALB/cJ Npc1 mouse models were used, which "possesses a retroposon insertion that prematurely terminates protein translation, thereby producing a nonfunctional truncated NPC1 protein".) Although this isn't a study involving humans, it can be presumed that very similar results will be obtained for people as well and provides valuable information related to this genetic disease and disorder.
NPC1 disease is an autosomal-recessive lipid storage disease. It is mostly known for cholesterol infiltration, which in turn can cause liver failure, lung failure, and even neurodegeneration. [11] [12] While the Niemann-Pick disease is caused by homozygous pathogenic mutations in the NPC1 gene, heterozygous mutations can still cause "highly-penetrant obesity." It was also revealed that NPC1 mutations are consistent with a model of balanced selection, where heterozygotes have higher reproductive fitness and homozygotes have lower reproductive fitness. These heterozygous mutations can account for ethnic-dependent percentage of obesity in the general population, while homozygous mutations are recently found to be more frequently appearing in South Asian populations. [12] Results from many previous studies suggest that NPC1 plays a role in adipocyte processes which underlie causes in obesity. More research needs to be done in order to better understand the relationship of the NPC1 gene and obesity risk factors among ethnicities. There are even recent studies being done to investigate other relatedness factors of obesity and NPC1, such as age and sex, that are yet to be absolutely determined.
Cholesterol pathways play an important role at multiple stages during the HIV-1 infection cycle. HIV-1 fusion, entry, assembly, and budding occur at cholesterol-enriched microdomains called lipid rafts. The HIV-1 accessory protein, Nef, has been shown to induce many genes involved in cholesterol biosynthesis and homeostasis. Intracellular cholesterol trafficking pathways mediated by NPC1 are needed for efficient HIV-1 production. [13] [14]
The human Niemann–Pick C1 (NPC1) cholesterol transporter appears to be essential for Ebola virus infection: a series of independent studies have presented evidence that Ebola virus enters human cells after binding to NPC1. [15] [16] When cells from Niemann Pick Type C patients lacking this transporter were exposed to Ebola virus in the laboratory, the cells survived and appeared impervious to the virus, further indicating that Ebola relies on NPC1 to enter cells. [16] The same studies described similar results with Marburg virus, another filovirus, showing that it too needs NPC1 to enter cells. [15] [16] In one of the studies, NPC1 was shown to be critical to filovirus entry because it mediates infection by binding directly to the viral envelope glycoprotein. [16] A later study confirmed the findings that NPC1 is a critical filovirus receptor that mediates infection by binding directly to the viral envelope glycoprotein and that the second lysosomal domain of NPC1 mediates this binding. [17]
In one of the original studies, a small molecule was shown to inhibit Ebola virus infection by preventing the virus glycoprotein from binding to NPC1. [16] [18] In the other study, mice that were heterozygous for NPC1 were shown to be protected from lethal challenge with mouse adapted Ebola virus. [15] Together, these studies suggest NPC1 may be potential therapeutic target for an Ebola anti-viral drug.
In a mouse model carrying the underlying mutation for Niemann-Pick type C1 disease in the NPC1 protein, the expression of Myelin gene Regulatory Factor (MRF) has been shown to be significantly decreased. [19] MRF is a transcription factor of critical importance in the development and maintenance of myelin sheaths. [20] A perturbation of oligodendrocyte maturation and the myelination process might therefore be an underlying mechanism of the neurological deficits. [19]
Niemann–Pick disease (NP), also known as acid sphingomyelinase deficiency, is a group of rare genetic diseases of varying severity. These are inherited metabolic disorders in which sphingomyelin accumulates in lysosomes in cells of many organs. NP types A, A/B, and B are caused by mutations in the SMPD1 gene, which causes a deficiency of an acid sphingomyelinase (ASM). NP type C is now considered a separate disease, as SMPD1 is not involved, and there is no deficiency in ASM.
Apolipoproteins are proteins that bind lipids to form lipoproteins. They transport lipids in blood, cerebrospinal fluid and lymph.
Neuronal ceroid lipofuscinosis is the general name for a family of at least eight genetically separate neurodegenerative lysosomal storage diseases that result from excessive accumulation of lipopigments (lipofuscin) in the body's tissues. These lipopigments are made up of fats and proteins. Their name comes from the word stem "lipo-", which is a variation on lipid, and from the term "pigment", used because the substances take on a greenish-yellow color when viewed under an ultraviolet light microscope. These lipofuscin materials build up in neuronal cells and many organs, including the liver, spleen, myocardium, and kidneys.
Proteolipid protein 1 (PLP1) is a form of myelin proteolipid protein (PLP). Mutations in PLP1 are associated with Pelizaeus–Merzbacher disease. It is a 4 transmembrane domain protein which is proposed to bind other copies of itself on the extracellular side of the membrane. In a myelin sheath, as the layers of myelin wraps come together, PLP will bind itself and tightly hold the cellular membranes together.
Myelin protein zero is a single membrane glycoprotein which in humans is encoded by the MPZ gene. P0 is a major structural component of the myelin sheath in the peripheral nervous system (PNS). Myelin protein zero is expressed by Schwann cells and accounts for over 50% of all proteins in the peripheral nervous system, making it the most common protein expressed in the PNS. Mutations in myelin protein zero can cause myelin deficiency and are associated with neuropathies like Charcot–Marie–Tooth disease and Dejerine–Sottas disease.
The epididymal secretory protein E1, also known as NPC2, is one of two main lysosomal transport proteins that assist in the regulation of cellular cholesterol by exportation of LDL-derived cholesterol from lysosomes. Lysosomes have digestive enzymes that allow it to break down LDL particles to LDL-derived cholesterol once the LDL particle is engulfed into the cell via receptor mediated endocytosis.
Niemann-Pick C1-Like 1 (NPC1L1) is a protein found on the gastrointestinal tract epithelial cells as well as in hepatocytes. Specifically, it appears to bind to a critical mediator of cholesterol absorption.
Gap junction beta-1 protein (GJB1), also known as connexin 32 (Cx32), is a transmembrane protein that in humans is encoded by the GJB1 gene. Gap junction beta-1 protein is a member of the gap junction connexin family of proteins that regulates and controls the transfer of communication signals across cell membranes, primarily in the liver and peripheral nervous system. However, the protein is expressed in multiple organs, including in oligodendrocytes in the central nervous system.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme encoded by the PCSK9 gene in humans on chromosome 1. It is the 9th member of the proprotein convertase family of proteins that activate other proteins. Similar genes (orthologs) are found across many species. As with many proteins, PCSK9 is inactive when first synthesized, because a section of peptide chains blocks their activity; proprotein convertases remove that section to activate the enzyme. The PCSK9 gene also contains one of 27 loci associated with increased risk of coronary artery disease.
Peripheral myelin protein 22 (PMP22), also called Growth arrest-specific protein 3 (GAS-3), is a protein which in humans is encoded by the PMP22 gene. Mutations in PMP22 cause changes in the expression of peripheral myelin protein 22 which can result in several neuropathies.
Sphingomyelin phosphodiesterase 1 (SMPD1), also known as acid sphingomyelinase (ASM), is an enzyme that in humans is encoded by the SMPD1 gene.
ATP-binding cassette sub-family G member 8 is a protein that in humans is encoded by the ABCG8 gene.
CTNS may also refer to the Center for Theology and the Natural Sciences.
Niemann–Pick type C (NPC) is a lysosomal storage disease associated with mutations in NPC1 and NPC2 genes. Niemann–Pick type C affects an estimated 1:150,000 people. Approximately 50% of cases present before 10 years of age, but manifestations may first be recognized as late as the sixth decade.
Marburg virus (MARV) is a hemorrhagic fever virus of the Filoviridae family of viruses and a member of the species Marburg marburgvirus, genus Marburgvirus. It causes Marburg virus disease in primates, a form of viral hemorrhagic fever. The virus is considered to be extremely dangerous. The World Health Organization (WHO) rates it as a Risk Group 4 Pathogen. In the United States, the National Institute of Allergy and Infectious Diseases ranks it as a Category A Priority Pathogen and the Centers for Disease Control and Prevention lists it as a Category A Bioterrorism Agent. It is also listed as a biological agent for export control by the Australia Group.
Myelin regulatory factor, also known as myelin gene regulatory factor (MRF), is a protein that in humans is encoded by the MYRF gene.
Acid sphingomyelinase is one of the enzymes that make up the sphingomyelinase (SMase) family, responsible for catalyzing the breakdown of sphingomyelin to ceramide and phosphorylcholine. They are organized into alkaline, neutral, and acidic SMase depending on the pH in which their enzymatic activity is optimal. Acid sphingomyelinases' (aSMases) enzymatic activity can be influenced by drugs, lipids, cations, pH, redox and other proteins in the environment. Specifically aSMases have been shown to have increased enzymatic activity in lysobisphosphatidic acid (LBPA) or phosphatidylinositol (PI) enriched environments, and inhibited activity when phosphorylated derivatives of PI are present.
Zaire ebolavirus, more commonly known as Ebola virus, is one of six known species within the genus Ebolavirus. Four of the six known ebolaviruses, including EBOV, cause a severe and often fatal hemorrhagic fever in humans and other mammals, known as Ebola virus disease (EVD). Ebola virus has caused the majority of human deaths from EVD, and was the cause of the 2013–2016 epidemic in western Africa, which resulted in at least 28,646 suspected cases and 11,323 confirmed deaths.
A sterol-sensing domain (SSD) is a protein domain which consists of 180 amino acids forming five transmembrane segments capable of binding sterol groups. This type of domain is present in proteins involved in cholesterol metabolism and signalling.
Ansuvimab, sold under the brand name Ebanga, is a monoclonal antibody medication for the treatment of Zaire ebolavirus (Ebolavirus) infection.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.