Cystatin C
Encyclopedia
Cystatin C or cystatin 3 (formerly gamma trace, post-gamma-globulin or neuroendocrine basic polypeptide), a protein
encoded by the CST3 gene
, is mainly used as a biomarker of kidney function. Recently, it has been studied for its role in predicting new-onset or deteriorating cardiovascular disease
. It also seems to play a role in brain disorders involving amyloid
(a specific type of protein deposition), such as Alzheimer's disease
.
In humans, all cells
with a nucleus
(cell core containing the DNA
) produce cystatin C as a chain of 120 amino acid
s. It is found in virtually all tissues and bodily fluids. It is a potent inhibitor
of lysosomal
proteinases (enzyme
s from a special subunit of the cell
that break down proteins) and probably one of the most important extracellular
inhibitors of cysteine protease
s (it prevents the breakdown of proteins outside the cell by a specific type of protein degrading enzymes). Cystatin C belongs to the type 2 cystatin
gene family
.
(GFR), a marker of kidney health, is best measured by injecting compounds such as inulin
, radioisotopes such as 51chromium-EDTA
, 125I-iothalamate, 99mTc-DTPA or radiocontrast agents such as iohexol
, but these techniques are complicated, costly, time-consuming and have potential side-effects.
Creatinine is the most widely used biomarker of kidney function. It is inaccurate at detecting mild renal impairment, and levels can vary with muscle mass and protein intake.
Formulas such as the Cockcroft and Gault formula and the MDRD formula (see Renal function
) try to adjust for these variables.
Cystatin C has a low molecular weight (approximately 13.3 kilodaltons), and it is removed from the bloodstream by glomerular filtration in the kidneys. If kidney function and glomerular filtration rate decline, the blood levels of cystatin C rise. Serum levels of cystatin C are a more precise test of kidney function (as represented by the glomerular filtration rate, GFR) than serum creatinine
levels. This finding is based mainly on cross-sectional studies
(on a single point in time). Longitudinal studies
(that follow cystatin C over time) are scarcer; some studies show promising results.
Cystatin C levels are less dependent on age, sex, race and muscle mass compared to creatinine. Cystatin C measurements alone have not been shown to be superior to formula-adjusted estimations of kidney function. As opposed to previous claims, cystatin C has been found to be influenced by body composition.
It has been suggested that cystatin C might predict the risk of developing chronic kidney disease, thereby signaling a state of 'preclinical' kidney dysfunction.
Studies have also investigated cystatin C as a marker of kidney function in the adjustment of medication dosages.
Cystatin C levels have been reported to be altered in patients with cancer, (even subtle) thyroid dysfunction and glucocorticoid therapy in some but not all situations. Other reports have found that levels are influenced by cigarette smoking and levels of C-reactive protein
. Levels seem to be increased in HIV
infection, which might or might not reflect actual renal dysfunction. The role of cystatin C to monitor GFR during pregnancy remains controversial. Like creatinine, the elimination of cystatin C via routes other than the kidney increase with worsening GFR.
Several studies have found that increased levels of cystatin C are associated with the risk of death, several types of cardiovascular disease (including myocardial infarction
, stroke
, heart failure, peripheral arterial disease and metabolic syndrome
) and healthy aging. Some studies have found cystatin C to be better in this regard than serum creatinine or creatinine-based GFR equations.
Because the association of cystatin C with long term outcomes has appeared stronger than what could be expected for GFR, it has been hypothesized that cystatin C might also be linked to mortality in a way independent of kidney function. In keeping with its housekeeping gene
properties, it has been suggested that cystatin C might be influenced by the basal metabolic rate
.
s in the cystatin 3 gene
are responsible for the Iceland
ic type of hereditary cerebral amyloid angiopathy, a condition predisposing to intracerebral haemorrhage, stroke
and dementia
. The condition is inherited in a dominant fashion
.
Since cystatin 3 also binds amyloid β and reduces its aggregation and deposition, it is a potential target in Alzheimer's disease
. Although not all studies have confirmed this, the overall evidence is in favor of are role for CST3 as a susceptibility gene for Alzheimer's disease. Cystatin C levels have been reported to be higher in subjects with Alzheimer's disease.
The role of cystatin C in multiple sclerosis
and other demyelinating disease
s (characterized by a loss of the myelin nerve sheath) remains controversial.
(so-called 'hardening' of the arteries) and aneurysm
al (saccular bulging) lesions of the aorta
.
Genetic and prognostic studies also suggest a role for cystatin C.
Breakdown of parts of the vessel wall in these conditions is thought to result from an imbalance between proteinases (cysteine protease
s and matrix metalloproteinase
s, increased) and their inhibitors (such as cystatin C, decreased).
A few studies have looked at the role of cystatin C or the CST3 gene in age-related macular degeneration. Cystatin C has also been investigated as a prognostic marker in several forms of cancer. Its role in pre-eclampsia
remains to be confirmed.
from which the red blood cell
s and clotting factors have been removed) using immunoassay
s such as nephelometry
or particle-enhanced turbidimetry. It is a more expensive test than serum creatinine (around $2 or $3, compared to $0.02 to $0.15), which can be measured with a Jaffé reaction.
Reference values differ in many populations and with sex and age. Across different studies, the mean reference interval (as defined by the 5th and 95th percentile
) was between 0.52 and 0.98 mg/L. For women, the average reference interval is 0.52 to 0.90 mg/L with a mean of 0.71 mg/L. For men, the average reference interval is 0.56 to 0.98 mg/L with a mean of 0.77 mg/L.
The normal values decrease until the first year of life, remaining relatively stable before they increase again, especially beyond age 50. Creatinine levels increase until puberty and differ according to gender from then on, making their interpretation problematic for pediatric patients.
In a large study from the United States National Health and Nutrition Examination Survey
, the reference interval (as defined by the 1st and 99th percentile
) was between 0.57 and 1.12 mg/L. This interval was 0.55 - 1.18 for women and 0.60 - 1.11 for men. Non-Hispanic blacks and Mexican Americans had lower normal cystatin C levels. Other studies have found that in patients with an impaired renal function, women have lower and blacks have higher cystatin C levels for the same GFR. For example, the cut-off values of cystatin C for chronic kidney disease for a 60-year-old white women would be 1.12 mg/L and 1.27 mg/L in a black man (a 13% increase). For serum creatinine values adjusted with the MDRD equation, these values would be 0.95 mg/dL to 1.46 mg/dL (a 54% increase).
Based on a threshold level of 1.09 mg/L (the 99th percentile in a population of 20 to 39-year-olds without hypertension, diabetes, microalbuminuria
or macroalbuminuria
or higher than stage 3 chronic kidney disease), the prevalence
of increased levels of cystatin C in the United States was 9.6% in subjects of normal weight, increasing in overweight
and obese individuals. In Americans aged 60 and 80 and older, serum cystatin is increased in 41% and more than 50%.
s, while others have lost or perhaps never acquired this inhibitory activity. There are three inhibitory families in the superfamily, including the type 1 cystatins (stefins), type 2 cystatins and the kininogens. The type 2 cystatin proteins are a class of cysteine proteinase inhibitors found in a variety of human fluids and secretions, where they appear to provide protective functions. The cystatin locus on the short arm of chromosome 20 contains the majority of the type 2 cystatin genes and pseudogene
s.
The CST3 gene is located in the cystatin locus and comprises 3 exon
s (coding regions, as opposed to intron
s, non-coding regions within a gene), spanning 4.3 kilo-base pairs. It encodes the most abundant extracellular inhibitor of cysteine proteases. It is found in high concentrations in biological fluids and is expressed in virtually all organs of the body (CST3 is a housekeeping gene
). The highest levels are found in semen
, followed by breastmilk, tears
and saliva
. The hydrophobic leader sequence indicates that the protein is normally secreted. There are three polymorphisms
in the promoter region of the gene, resulting in two common variants. Several single nucleotide polymorphism
s have been associated with altered cystatin C levels.
Cystatin C is a non-glycosylated
, basic
protein (isoelectric point
at pH
9.3). The crystal structure
of cystatine C is characterized by a short alpha helix
and a long alpha helix running across a large antiparallel, five-stranded beta sheet
. Like other type 2 cystatines, it has two disulfide bond
s. Around 50% of the molecules carry a hydroxylated proline
. Cystatine C forms dimer
s (molecule pairs) by exchanging subdomains; in the paired state, each half is made up of the long alpha helix and one beta strand of one partner, and four beta strands of the other partner.
and in the urine
of patients with renal failure
. Grubb and Löfberg first reported its amino acid sequence. They noticed it was increased in patients with advanced renal failure
. It was first proposed as a measure of glomerular filtration rate by Grubb and coworkers in 1985.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
encoded by the CST3 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
, is mainly used as a biomarker of kidney function. Recently, it has been studied for its role in predicting new-onset or deteriorating cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
. It also seems to play a role in brain disorders involving amyloid
Amyloid
Amyloids are insoluble fibrous protein aggregates sharing specific structural traits. Abnormal accumulation of amyloid in organs may lead to amyloidosis, and may play a role in various neurodegenerative diseases.-Definition:...
(a specific type of protein deposition), such as Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
.
In humans, all cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
with a nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
(cell core containing the DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
) produce cystatin C as a chain of 120 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s. It is found in virtually all tissues and bodily fluids. It is a potent inhibitor
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
of lysosomal
Lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...
proteinases (enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s from a special subunit of the cell
Organelle
In cell biology, an organelle is a specialized subunit within a cell that has a specific function, and is usually separately enclosed within its own lipid bilayer....
that break down proteins) and probably one of the most important extracellular
Extracellular
In cell biology, molecular biology and related fields, the word extracellular means "outside the cell". This space is usually taken to be outside the plasma membranes, and occupied by fluid...
inhibitors of cysteine protease
Cysteine protease
Proteases are enzymes that degrade polypeptides. Cysteine proteases have a common catalytic mechanism that involves a nucleophilic cysteine thiol in a catalytic dyad. The first step is deprotonation of a thiol in the enzyme's active site by an adjacent amino acid with a basic side chain, usually a...
s (it prevents the breakdown of proteins outside the cell by a specific type of protein degrading enzymes). Cystatin C belongs to the type 2 cystatin
Cystatin
The cystatins are a family of cysteine protease inhibitors with homology to chicken cystatin. Cystatins typically comprise about 115 amino acids, are largely acidic, contain four conserved cysteine residues known to form two disulfide bonds, may be glycosylated and/or phosphorylated, with...
gene family
Gene family
A gene family is a set of several similar genes, formed by duplication of a single original gene, and generally with similar biochemical functions...
.
Kidney function
Glomerular filtration rateRenal function
Renal function, in nephrology, is an indication of the state of the kidney and its role in renal physiology. Glomerular filtration rate describes the flow rate of filtered fluid through the kidney...
(GFR), a marker of kidney health, is best measured by injecting compounds such as inulin
Inulin
Inulins are a group of naturally occurring polysaccharides produced by many types of plants. They belong to a class of fibers known as fructans. Inulin is used by some plants as a means of storing energy and is typically found in roots or rhizomes...
, radioisotopes such as 51chromium-EDTA
EDTA
Ethylenediaminetetraacetic acid, widely abbreviated as EDTA , is a polyamino carboxylic acid and a colourless, water-soluble solid. Its conjugate base is named ethylenediaminetetraacetate. It is widely used to dissolve limescale. Its usefulness arises because of its role as a hexadentate ligand...
, 125I-iothalamate, 99mTc-DTPA or radiocontrast agents such as iohexol
Iohexol
Iohexol is a contrast agent, sold under the trade name Omnipaque. It is available in various concentrations, from 140 to 350 milligrams of iodine per milliliter...
, but these techniques are complicated, costly, time-consuming and have potential side-effects.
Creatinine is the most widely used biomarker of kidney function. It is inaccurate at detecting mild renal impairment, and levels can vary with muscle mass and protein intake.
Formulas such as the Cockcroft and Gault formula and the MDRD formula (see Renal function
Renal function
Renal function, in nephrology, is an indication of the state of the kidney and its role in renal physiology. Glomerular filtration rate describes the flow rate of filtered fluid through the kidney...
) try to adjust for these variables.
Cystatin C has a low molecular weight (approximately 13.3 kilodaltons), and it is removed from the bloodstream by glomerular filtration in the kidneys. If kidney function and glomerular filtration rate decline, the blood levels of cystatin C rise. Serum levels of cystatin C are a more precise test of kidney function (as represented by the glomerular filtration rate, GFR) than serum creatinine
Creatinine
Creatinine is a break-down product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body...
levels. This finding is based mainly on cross-sectional studies
Cross-sectional study
Cross-sectional studies form a class of research methods that involve observation of all of a population, or a representative subset, at one specific point in time...
(on a single point in time). Longitudinal studies
Longitudinal study
A longitudinal study is a correlational research study that involves repeated observations of the same variables over long periods of time — often many decades. It is a type of observational study. Longitudinal studies are often used in psychology to study developmental trends across the...
(that follow cystatin C over time) are scarcer; some studies show promising results.
Cystatin C levels are less dependent on age, sex, race and muscle mass compared to creatinine. Cystatin C measurements alone have not been shown to be superior to formula-adjusted estimations of kidney function. As opposed to previous claims, cystatin C has been found to be influenced by body composition.
It has been suggested that cystatin C might predict the risk of developing chronic kidney disease, thereby signaling a state of 'preclinical' kidney dysfunction.
Studies have also investigated cystatin C as a marker of kidney function in the adjustment of medication dosages.
Cystatin C levels have been reported to be altered in patients with cancer, (even subtle) thyroid dysfunction and glucocorticoid therapy in some but not all situations. Other reports have found that levels are influenced by cigarette smoking and levels of C-reactive protein
C-reactive protein
C-reactive protein is a protein found in the blood, the levels of which rise in response to inflammation...
. Levels seem to be increased in HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
infection, which might or might not reflect actual renal dysfunction. The role of cystatin C to monitor GFR during pregnancy remains controversial. Like creatinine, the elimination of cystatin C via routes other than the kidney increase with worsening GFR.
Death and cardiovascular disease
Kidney dysfunction increases the risk of death and cardiovascular disease.Several studies have found that increased levels of cystatin C are associated with the risk of death, several types of cardiovascular disease (including myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
, stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
, heart failure, peripheral arterial disease and metabolic syndrome
Metabolic syndrome
Metabolic syndrome is a combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease and diabetes. It affects one in five people in the United States and prevalence increases with age...
) and healthy aging. Some studies have found cystatin C to be better in this regard than serum creatinine or creatinine-based GFR equations.
Because the association of cystatin C with long term outcomes has appeared stronger than what could be expected for GFR, it has been hypothesized that cystatin C might also be linked to mortality in a way independent of kidney function. In keeping with its housekeeping gene
Housekeeping gene
A housekeeping gene is typically a constitutive gene that is required for the maintenance of basic cellular function, and are found in all cells of an organism. Although some housekeeping genes are expressed at relatively constant levels , other housekeeping genes may vary depending on...
properties, it has been suggested that cystatin C might be influenced by the basal metabolic rate
Basal metabolic rate
Basal Metabolic Rate , and the closely related resting metabolic rate , is the amount of daily energy expended by humans and other animals at rest. Rest is defined as existing in a neutrally temperate environment while in the post-absorptive state...
.
Neurologic disorders
MutationMutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s in the cystatin 3 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
are responsible for the Iceland
Iceland
Iceland , described as the Republic of Iceland, is a Nordic and European island country in the North Atlantic Ocean, on the Mid-Atlantic Ridge. Iceland also refers to the main island of the country, which contains almost all the population and almost all the land area. The country has a population...
ic type of hereditary cerebral amyloid angiopathy, a condition predisposing to intracerebral haemorrhage, stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
and dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
. The condition is inherited in a dominant fashion
Dominance relationship
Dominance in genetics is a relationship between two variant forms of a single gene, in which one allele masks the effect of the other in influencing some trait. In the simplest case, if a gene exists in two allelic forms , three combinations of alleles are possible: AA, AB, and BB...
.
Since cystatin 3 also binds amyloid β and reduces its aggregation and deposition, it is a potential target in Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
. Although not all studies have confirmed this, the overall evidence is in favor of are role for CST3 as a susceptibility gene for Alzheimer's disease. Cystatin C levels have been reported to be higher in subjects with Alzheimer's disease.
The role of cystatin C in multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
and other demyelinating disease
Demyelinating disease
A demyelinating disease is any disease of the nervous system in which the myelin sheath of neurons is damaged. This impairs the conduction of signals in the affected nerves, causing impairment in sensation, movement, cognition, or other functions depending on which nerves are involved.The term...
s (characterized by a loss of the myelin nerve sheath) remains controversial.
Other roles
Cystatin C levels are decreased in atheroscleroticAtherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
(so-called 'hardening' of the arteries) and aneurysm
Aneurysm
An aneurysm or aneurism is a localized, blood-filled balloon-like bulge in the wall of a blood vessel. Aneurysms can commonly occur in arteries at the base of the brain and an aortic aneurysm occurs in the main artery carrying blood from the left ventricle of the heart...
al (saccular bulging) lesions of the aorta
Aorta
The aorta is the largest artery in the body, originating from the left ventricle of the heart and extending down to the abdomen, where it branches off into two smaller arteries...
.
Genetic and prognostic studies also suggest a role for cystatin C.
Breakdown of parts of the vessel wall in these conditions is thought to result from an imbalance between proteinases (cysteine protease
Cysteine protease
Proteases are enzymes that degrade polypeptides. Cysteine proteases have a common catalytic mechanism that involves a nucleophilic cysteine thiol in a catalytic dyad. The first step is deprotonation of a thiol in the enzyme's active site by an adjacent amino acid with a basic side chain, usually a...
s and matrix metalloproteinase
Matrix metalloproteinase
Matrix metalloproteinases are zinc-dependent endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs belong to a larger family of proteases known as the metzincin superfamily....
s, increased) and their inhibitors (such as cystatin C, decreased).
A few studies have looked at the role of cystatin C or the CST3 gene in age-related macular degeneration. Cystatin C has also been investigated as a prognostic marker in several forms of cancer. Its role in pre-eclampsia
Pre-eclampsia
Pre-eclampsia or preeclampsia is a medical condition in which hypertension arises in pregnancy in association with significant amounts of protein in the urine....
remains to be confirmed.
Laboratory measurement
Cystatin C can be measured in a random sample of serum (the fluid in bloodBlood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
from which the red blood cell
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
s and clotting factors have been removed) using immunoassay
Immunoassay
An immunoassay is a biochemical test that measures the presence or concentration of a substance in solutions that frequently contain a complex mixture of substances. Analytes in biological liquids such as serum or urine are frequently assayed using immunoassay methods...
s such as nephelometry
Nephelometry
Nephelometry is a technique used in immunology to determine levels of IgM, IgG, and IgA.It is performed by measuring the turbidity in a water sample by passing light through the sample being measured...
or particle-enhanced turbidimetry. It is a more expensive test than serum creatinine (around $2 or $3, compared to $0.02 to $0.15), which can be measured with a Jaffé reaction.
Reference values differ in many populations and with sex and age. Across different studies, the mean reference interval (as defined by the 5th and 95th percentile
Percentile
In statistics, a percentile is the value of a variable below which a certain percent of observations fall. For example, the 20th percentile is the value below which 20 percent of the observations may be found...
) was between 0.52 and 0.98 mg/L. For women, the average reference interval is 0.52 to 0.90 mg/L with a mean of 0.71 mg/L. For men, the average reference interval is 0.56 to 0.98 mg/L with a mean of 0.77 mg/L.
The normal values decrease until the first year of life, remaining relatively stable before they increase again, especially beyond age 50. Creatinine levels increase until puberty and differ according to gender from then on, making their interpretation problematic for pediatric patients.
In a large study from the United States National Health and Nutrition Examination Survey
National Health and Nutrition Examination Survey
The National Health and Nutrition Examination Survey is a survey research program conducted by the National Center for Health Statistics to asses the health and nutritional status of adults and children in the United States, and to track changes over time. The survey combines interviews and...
, the reference interval (as defined by the 1st and 99th percentile
Percentile
In statistics, a percentile is the value of a variable below which a certain percent of observations fall. For example, the 20th percentile is the value below which 20 percent of the observations may be found...
) was between 0.57 and 1.12 mg/L. This interval was 0.55 - 1.18 for women and 0.60 - 1.11 for men. Non-Hispanic blacks and Mexican Americans had lower normal cystatin C levels. Other studies have found that in patients with an impaired renal function, women have lower and blacks have higher cystatin C levels for the same GFR. For example, the cut-off values of cystatin C for chronic kidney disease for a 60-year-old white women would be 1.12 mg/L and 1.27 mg/L in a black man (a 13% increase). For serum creatinine values adjusted with the MDRD equation, these values would be 0.95 mg/dL to 1.46 mg/dL (a 54% increase).
Based on a threshold level of 1.09 mg/L (the 99th percentile in a population of 20 to 39-year-olds without hypertension, diabetes, microalbuminuria
Microalbuminuria
Microalbuminuria occurs when the kidney leaks small amounts of albumin into the urine, in other words, when there is an abnormally high permeability for albumin in the renal glomerulus.-Diagnosis:...
or macroalbuminuria
Albuminuria
Albuminuria is a pathological condition wherein albumin is present in the urine. It is a type of proteinuria.Measurement=The amount of protein being lost in the urine can be quantified by collecting the urine for 24 hours, measuring a sample of the pooled urine, and extrapolating to the volume...
or higher than stage 3 chronic kidney disease), the prevalence
Prevalence
In epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population...
of increased levels of cystatin C in the United States was 9.6% in subjects of normal weight, increasing in overweight
Overweight
Overweight is generally defined as having more body fat than is optimally healthy. Being overweight is a common condition, especially where food supplies are plentiful and lifestyles are sedentary...
and obese individuals. In Americans aged 60 and 80 and older, serum cystatin is increased in 41% and more than 50%.
Molecular biology
The cystatin superfamily encompasses proteins that contain multiple cystatin-like sequences. Some of the members are active cysteine protease inhibitorCysteine protease
Proteases are enzymes that degrade polypeptides. Cysteine proteases have a common catalytic mechanism that involves a nucleophilic cysteine thiol in a catalytic dyad. The first step is deprotonation of a thiol in the enzyme's active site by an adjacent amino acid with a basic side chain, usually a...
s, while others have lost or perhaps never acquired this inhibitory activity. There are three inhibitory families in the superfamily, including the type 1 cystatins (stefins), type 2 cystatins and the kininogens. The type 2 cystatin proteins are a class of cysteine proteinase inhibitors found in a variety of human fluids and secretions, where they appear to provide protective functions. The cystatin locus on the short arm of chromosome 20 contains the majority of the type 2 cystatin genes and pseudogene
Pseudogene
Pseudogenes are dysfunctional relatives of known genes that have lost their protein-coding ability or are otherwise no longer expressed in the cell...
s.
The CST3 gene is located in the cystatin locus and comprises 3 exon
Exon
An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
s (coding regions, as opposed to intron
Intron
An intron is any nucleotide sequence within a gene that is removed by RNA splicing to generate the final mature RNA product of a gene. The term intron refers to both the DNA sequence within a gene, and the corresponding sequence in RNA transcripts. Sequences that are joined together in the final...
s, non-coding regions within a gene), spanning 4.3 kilo-base pairs. It encodes the most abundant extracellular inhibitor of cysteine proteases. It is found in high concentrations in biological fluids and is expressed in virtually all organs of the body (CST3 is a housekeeping gene
Housekeeping gene
A housekeeping gene is typically a constitutive gene that is required for the maintenance of basic cellular function, and are found in all cells of an organism. Although some housekeeping genes are expressed at relatively constant levels , other housekeeping genes may vary depending on...
). The highest levels are found in semen
Semen
Semen is an organic fluid, also known as seminal fluid, that may contain spermatozoa. It is secreted by the gonads and other sexual organs of male or hermaphroditic animals and can fertilize female ova...
, followed by breastmilk, tears
Tears
Tears are secretions that clean and lubricate the eyes. Lacrimation or lachrymation is the production or shedding of tears....
and saliva
Saliva
Saliva , referred to in various contexts as spit, spittle, drivel, drool, or slobber, is the watery substance produced in the mouths of humans and most other animals. Saliva is a component of oral fluid. In mammals, saliva is produced in and secreted from the three pairs of major salivary glands,...
. The hydrophobic leader sequence indicates that the protein is normally secreted. There are three polymorphisms
Polymorphism (biology)
Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...
in the promoter region of the gene, resulting in two common variants. Several single nucleotide polymorphism
Single nucleotide polymorphism
A single-nucleotide polymorphism is a DNA sequence variation occurring when a single nucleotide — A, T, C or G — in the genome differs between members of a biological species or paired chromosomes in an individual...
s have been associated with altered cystatin C levels.
Cystatin C is a non-glycosylated
Glycosylation
Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
, basic
Base (chemistry)
For the term in genetics, see base A base in chemistry is a substance that can accept hydrogen ions or more generally, donate electron pairs. A soluble base is referred to as an alkali if it contains and releases hydroxide ions quantitatively...
protein (isoelectric point
Isoelectric point
The isoelectric point , sometimes abbreviated to IEP, is the pH at which a particular molecule or surface carries no net electrical charge....
at pH
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
9.3). The crystal structure
Protein structure
Proteins are an important class of biological macromolecules present in all organisms. Proteins are polymers of amino acids. Classified by their physical size, proteins are nanoparticles . Each protein polymer – also known as a polypeptide – consists of a sequence formed from 20 possible L-α-amino...
of cystatine C is characterized by a short alpha helix
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
and a long alpha helix running across a large antiparallel, five-stranded beta sheet
Beta sheet
The β sheet is the second form of regular secondary structure in proteins, only somewhat less common than the alpha helix. Beta sheets consist of beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet...
. Like other type 2 cystatines, it has two disulfide bond
Disulfide bond
In chemistry, a disulfide bond is a covalent bond, usually derived by the coupling of two thiol groups. The linkage is also called an SS-bond or disulfide bridge. The overall connectivity is therefore R-S-S-R. The terminology is widely used in biochemistry...
s. Around 50% of the molecules carry a hydroxylated proline
Hydroxyproline
-4-Hydroxyproline, or L-hydroxyproline , is a common non-proteinogenic amino acid, abbreviated as HYP, e.g., in Protein Data Bank.-Structure and discovery:...
. Cystatine C forms dimer
Protein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
s (molecule pairs) by exchanging subdomains; in the paired state, each half is made up of the long alpha helix and one beta strand of one partner, and four beta strands of the other partner.
History
Cystatin C was first described as 'gamma-trace' in 1961 as a trace protein together with other ones (such as beta-trace) in the cerebrospinal fluidCerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
and in the urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
of patients with renal failure
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
. Grubb and Löfberg first reported its amino acid sequence. They noticed it was increased in patients with advanced renal failure
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
. It was first proposed as a measure of glomerular filtration rate by Grubb and coworkers in 1985.
External links
- The MEROPSMeropsMerops may refer to:* Merops , a genus of bee-eaters.* MEROPS, an on-line database for peptidases.It may also refer to several figures from Greek mythology:* King of Ethiopia, husband of Clymene, who lay with Helios and bore Phaethon...
online database for peptidases and their inhibitors: I25.004