LECT2
Leukocyte cell-derived chemotaxin-2 is a protein first described in 1996 as a chemotactic factor for neutrophils, i.e. it stimulated human neutrophils to move directionally in an in vitro assay system. The protein was detected in and purified from cultures of Phytohaemagglutinin-activated human T-cell leukemia SKW-3 cells. Subsequent studies have defined LECT2 as a hepatokine, i.e. a substance made and released into the circulation by liver hepatocyte cells that regulates the function of other cells: it is a hepatocyte-derived, hormone-like, signaling protein.
LECT2 has been detected in the blood and other tissues in a wide range of animal species from zebrafish to man. Furthermore, its levels in these tissues often change as a function of various diseases. These findings indicate that LECT is an evolutionary conserved protein, has one or more important functions, and may be involved in various diseases. However, LECT2's relationships to these diseases requires much further study before they can be regarded as established and clinically useful. One exception to this, however, is its proven role in amyloidosis. LECT2 is one of the more common causes of systemic amyloidosis in North America as well as certain other ethnically-rich locations.
LECT2 and its gene, LECT2, are currently areas of active research that seek to implicate them as contributors to, markers for the presence of, and/or prognostic indicators for the severity of not only amyloidosis but also osteoarthritis, rheumatoid arthritis, and other types of inflammation-related disorders; the metabolic syndrome and diabetes; and various types of liver disease.
Gene
The human LECT2 gene, LECT2, is located on the long, i.e, "q", arm of chromosome 5 at position q31.1. This location is close to several immune modulating genes including interleukins 3, 5, and 9 and granulocyte-macrophage colony stimulating factor. LECT2 is conserved in zebrafish, chicken, rat, mouse, cow. dog, Rhesus monkey, and chimpanzee. Human LECT2 is composed of 4 exons, 3 introns, and ~8,000 base pairs. The gene has numerous single nucleotide variants as well as other variations, some of which have been associated with human disease. Human LECT2 has several different transcriptional initiation sights and codes for a mRNA composed of 1,000 to 1,300 ribonucleotides. mRNA for LECT2 is highly expressed in liver tissue and expressed at far lower levels in a wide range of other tssues.Protein
Human LECT2 is a secreted, 16 kilodalton protein. The secreted protein consists of 133`amino acids. Its structure is similar to that of the M23 family of metalloendopeptidases. Unlike this family of peptidases, however, LECT2 has not been found to possess enzymatic activity and does not appear to share any functions with M23 metalloendopeptidases.LECT2 protein is widely expressed in vascular tissues, smooth muscle cells, adipocytes, cerebral neurons, apical squamous epithelia, parathyroid tissues, the epithelial cells of sweat and sebaceous glands, Hassall bodies, and monocytes. When these cells or tissues are subjected to inflammatory, fibrotic, and other insults, they commonly reduce their expression of LECT2. The liver hepatocyte is considered to be the source of the LECT2 circulating in blood. However, its expression in these cells is extremely low or undetectable even though these cells express very high levels of LECT2 mRNA. This implies that hepatocytes secrete LECT2 almost immediately after they make it. Using very sensitive methods, LECT2 protein can also be detected at low levels in the endothelial cells of hepatic arteries and veins including central veins. Several cell types or tissues, e.g. osteoblasts, chondrocytes, cardiac tissue, gastrointestinal smooth muscle cells, and epithelial cells of some tissues normally do not express LECT2 but do so under a variety of disease conditions.
Disease associations
LECT2 amyloidosis
LECT2 amyloidosis was the third most common cause of amyloidosis in a series of >4,000 individuals studied at the Mayo Clinic in the United States. However, LECT2 amyloidosis has a strong ethnic bias, afflicting particularly Mexicans and to a lesser extent, non-Mexican Hispanics. Hispanics made an important contribution to the Mayo Clinic's rate of LECT2 amyloidosis. LECT2 amyloidosis also has an increased incidence in Punjabis, South Asians, First Nations people of British Columbia, Native Americans, and Egyptians. In Egyptians, LECT2 is second most common cause of renal amyloidosis, accounting for nearly 31% of all cases. LECT2 amyloidosis is likely to be a far less common cause of systemic amyloidosis in populations containing fewer numbers of individuals of the cited ethnic groups. On the other hand, LECT2 amyloidosis represents an important but at present very much under-recognized cause of chronic kidney disease in the cited ethnic groups and, possibly, other ethnic groups yet to be determined.It has been found repeatedly that the mere presence of LECT2 amyloid tissue deposits does not necessarily indicate the presence of LECT2 amyloidosis disease. For example, autopsy studies find that up to 3.1% of Hispanics have these deposits in their kidneys but no history of signs or symptoms that could be attributed to LECT2 amyloidosis. This finding suggests that the LECT2 amyloidosis and its ethnic bias reflect multiple poorly understood factors.
Pathophysiology
While the pathogenesis of LECT2 amyloidosis is unclear, the intact LECT2 protein may have a tendency to fold abnormally thereby forming non-soluble fibrils that are deposited in tissues. It has been suggested that individuals with the disease have an increase in LECT2 production and/or a decrease in LECT2 catabolism which leads to its tissue deposition. However, there appears to be clear genetic variations that lead LECT2 tissue deposition. While studies to date have failed to obtain evidence for LECT2 gene mutations in the disorder, most cases examined in the United States are associated with a particular homozygous single nucleotide polymorphism in the LECT2 gene. This SNP occurs in exon 3 at codon 58 of the gene, contains a guanine rather than adenine nucleotide at this site, and consequently codes for the amino acid valine rather than isoleucine. It is suggested although not yet proven that this Val58Ile variant of LECT2 has a propensity to fold abnormally and therefore deposits in tissues. The Val58Ile LECT2 variant is common in Hispanics and appears to be the cause of their high incidence of LECT2 amyloidosis. Nonetheless, not all homozygous carriers of the variant ever exhibit LECT2 amyloidosis.A second SNP commonly found in Mexicans occurs at codon 172 of the LECT2 gene. This variant is homozygous for a G nucleotide at this codon position and has been associated with an increased incidence of LECT2 amyloidosis. A reason for this association has not yet been proposed.