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HGNC Approved Gene Symbol: CLU

Cytogenetic location: 8p21.1 Genomic coordinates (GRCh38): 8:27,596,916-27,614,699 (from NCBI)

▼ Cloning and Expression
Murphy et al. (1988) described a novel serum protein, SP-40,40, using a series of monoclonal antibodies directed to the immune deposit-containing glomerular basement membranes of a patient with membranous glomerulonephritis. The protein was shown to be a normal constituent of human blood. It consists of two 40-kD chains, alpha and beta, covalently joined by disulfide bonds. They established that SP-40,40 is a member of the human complement system by directly demonstrating its presence within the S-protein-containing soluble variant of the C5b-9 complex, SC5b-9. SP-40,40 is also called complement lysis inhibitor or clusterin. It acts as a control mechanism of the complement cascade; specifically, it prevents the binding of a C5b-C7 complex to the membrane of the target cell and in this way inhibits complement-mediated cytolysis.

Kirszbaum et al. (1989) cloned a cDNA for the SP-40,40 protein. They showed that the 2 chains are coded in a single open reading frame on the same mRNA molecule, indicating that a precursor protein matures postsynthetically by the proteolysis of at least 1 peptide bond. They found that the sequence of the SP-40,40 precursor has 77% identity with rat sulfated glycoprotein-2 (SGP2), which is the major secreted product of Sertoli cells. They demonstrated the presence of SP-40,40 within human seminal plasma at levels comparable to those in serum, indicating that SP-40,40 and SGP2 are serum and seminal forms of the same protein. A sequence of 23 amino acids within the beta-chain of SP-40,40 showed significant homology to corresponding segments in C7, C8, and C9. The findings of Kirszbaum et al. (1989) document a link between the immune and reproductive systems.

O'Bryan et al. (1990) reported the purification and characterization of human seminal clusterin. There is reason to think that testosterone-repressed prostate message-2 is coded by the same gene (Purrello et al., 1991). Comparison of the multiple functions suggests involvement of this protein in the cascade of events leading to programmed cell death.

Apolipoprotein J is another name for the human analog of the rat protein SGF2. Its primary structure was deduced by de Silva et al. (1990) using the combined strategies of protein sequencing and cDNA cloning and sequencing. It is a 70-kD protein associated with high-density lipoproteins (HDL) in human plasma. There is a single copy of the APOJ gene in the human and mouse genomes. The protein is synthesized as a 427-amino acid polypeptide that is posttranslationally cleaved at an internal bond between arg205 and ser206. Two subunits, designated alpha (34 to 36 kD), corresponding to residues 1-205, and beta (36 to 39 kD), corresponding to residues 206-427, are associated through disulfide bonds. Studies indicated that the alpha and beta subunits are derived from a common precursor by proteolytic cleavage and that the subunits, while distinct, have limited regions of homology. De Silva et al. (1990) found APOJ mRNA (1.9 kb) in all but one tissue examined. Its concentration was relatively high in brain, ovary, testis, and liver, lower in heart, spleen, lung, and breast, and absent in T lymphocytes. Apolipoprotein J is distinct from other known apolipoproteins in molecular weight, subunit structure, and isoelectric point.

▼ Mapping
By Southern analysis of somatic cell hybrids, Purrello et al. (1991) concluded that a single gene is responsible for the multiple functions of sulfated glycoprotein-2 and that the SGP2 gene is located on human chromosome 8. Slawin et al. (1990) also mapped SGP2 to chromosome 8 by Southern analysis of hamster-human hybrid cell lines. Likewise, Tobe et al. (1991) mapped the CLI gene to human chromosome 8 by spot blot hybridization of flow-sorted chromosomes using a cDNA probe.

Dietzsch et al. (1992) regionalized the gene to 8p21-p12 by isotopic in situ hybridization. By fluorescence in situ hybridization, Fink et al. (1993) showed that CLI is located on 8p21, proximal to the lipoprotein lipase gene (238600). They cited information suggesting that the CLI gene may be a candidate gene determining susceptibility to atherosclerosis.

Using RFLVs (restriction fragment length variations) for interspecies linkage analysis, Birkenmeier et al. (1993) demonstrated that mouse Cli gene is located on chromosome 14.

▼ Gene Structure
By isolating and characterizing 3 partially overlapping cosmid clones, Fink et al. (1993) established the complete physical map of the clusterin gene which spans about 20 kb.

Wong et al. (1994) reported that the CLU gene is organized into 9 exons, ranging in size from 47 bp (exon 1) to 412 bp (exon 5), and spanning a region of 16,580 bp. Southern analysis and fluorescence in situ hybridization indicated that the clusterin gene is present in single copy.

▼ Gene Function
See review of Jenne and Tschopp (1992). Clusterin mRNA is distributed heterogeneously in the central nervous system with highest levels in ependymal cells, as well as in some neurons of the hypothalamus, brainstem, hebenula, and ventral horn of the spinal cord. It has been hypothesized to be involved with ongoing synapse turnover (Danik et al., 1993). Wong et al. (1993) hypothesized that clusterin may be a suicide gene active in programmed cell death. Dragunow et al. (1995) studied expression of clusterin immunoreactivity after induction of status epilepticus. Massive clusterin-like immunoreactivity was observed in CA1 pyramidal cells and dentate hilar neurons, both neuronal populations destined to die after status epilepticus.

Duguid et al. (1989) found that SGP2 mRNA is synthesized at high levels in degenerating hippocampus from individuals with Alzheimer disease or Pick disease. Bertrand et al. (1995) used Western blot analysis to examine levels of apolipoprotein E and apolipoprotein J (clusterin) in the brains of Alzheimer disease subjects. The allele dose of apolipoprotein E4 was correlated with the reduction of apoE levels and an increase in apolipoprotein J (clusterin) levels, suggesting compensatory induction of apoJ by those subjects showing low levels of apoE.

In a series of animal experiments, Navab et al. (1997) demonstrated that the ratio of APOJ to PON (168820) was increased in fatty streak-susceptible mice fed an atherogenic diet, in APOE knockout mice on a chow diet, in LDL receptor knockout mice on a cholesterol-enriched diet, and in fatty streak-susceptible mice injected with mildly oxidized LDL fed a chow diet. Human studies showed that the APOJ/PON ratio was significantly higher than that of controls in 14 normolipemic patients with coronary artery disease in whom the cholesterol/HDL ratio did not differ significantly from that of controls.

Ostermeier et al. (2004) showed that human male gametes pass over more to the oocyte than just the haploid male genome--paternal mRNAs are also delivered to the egg at fertilization. Ostermeier et al. (2004) used RT-PCR to identify which transcripts are present in human spermatozoa but not in unfertilized human oocytes and identified 6 candidates. The implication is that the spermatozoa deliver these transcripts to the ooplasm at fertilization. Using the zona-free hamster egg/human sperm penetration assay to investigate this possibility, Ostermeier et al. (2004) consistently detected only protamine-2 (182890) and clusterin transcripts in spermatozoa, zygotes, and in the positive control, and not in hamster oocytes or in the negative control. These results demonstrated that spermatozoa deliver RNAs to the oocyte at fertilization. Ostermeier et al. (2004) suggested that sperm RNAs could be important in early zygotic and embryonic development and that they may hold the key to more successful somatic-cell nuclear transfer or to the identification of male-derived factors that underlie idiopathic infertility.

CLU is overexpressed in human prostate and breast cancers and in squamous cell carcinomas, and suppression of CLU renders these cells sensitive to chemotherapeutic drug-mediated apoptosis. Zhang et al. (2005) found that intracellular CLU inhibited apoptosis by interfering with BAX (600040) activation in mitochondria. CLU specifically interacted with BAX that was conformationally altered by chemotherapeutic drugs, and the interaction inhibited BAX-mediated apoptosis. Zhang et al. (2005) concluded that elevated CLU levels in human cancers may promote oncogenic transformation and tumor progression by interfering with BAX proapoptotic activities.

Zenkel et al. (2006) provided evidence for a selective downregulation of expression of clusterin in anterior segment tissues and significantly reduced aqueous levels of clusterin in eyes of patients with pseudoexfoliation syndrome (XFS; 177650). The expression of clusterin was significantly downregulated by TGFB1 (190180) in vitro, providing a possible explanation for this downregulation. Zenkel et al. (2006) suggested that the accumulation of the characteristic pathologic matrix product in XFS eyes may partly arise from stress-induced protein misfolding and aggregation promoted by a deficiency of clusterin.

▼ Molecular Genetics
By means of isoelectric focusing and immunoblotting techniques, Kamboh et al. (1991) demonstrated a common 2-allele polymorphism in populations with African ancestry. APOJ was found to be monomorphic in US whites, Amerindians, Eskimos, and New Guineans. In US blacks the frequencies of the APOJ1 and APOJ2 alleles were 0.76 and 0.24, respectively; in Nigerian blacks, these values were 0.72 and 0.28, respectively. They found no significant impact of the APOJ polymorphism on total cholesterol, LDL-cholesterol, HDL-cholesterol, HDL3-cholesterol, HDL2-cholesterol, VLDL-cholesterol, and triglycerides.

For discussion of a possible association between variation in the CLU gene and Alzheimer disease, see 104300.

▼ Animal Model
Following neonatal hypoxic-ischemic brain injury in mice (a model of cerebral palsy), there is evidence of apoptotic changes such as activation of neuronal caspase-3 (600636), as well as an accumulation of clusterin in dying neurons. Han et al. (2001) generated mice deficient in clusterin by targeted disruption. Clusterin -/- mice had 50% less brain injury following neonatal hypoxia-ischemia. The absence of clusterin had no effect on caspase-3 activation, and clusterin accumulation and caspase-3 activation did not colocalize to the same cells. Studies with cultured cortical neurons demonstrated that exogenous purified astrocyte-secreted clusterin exacerbated oxygen/glucose-deprivation-induced necrotic death. Han et al. (2001) concluded that clusterin may be a therapeutic target to modulate noncaspase-dependent neuronal death following acute brain injury.

ApoJ is induced in myocarditis and numerous other inflammatory injuries. To test its ability to modify myosin-induced autoimmune myocarditis, McLaughlin et al. (2000) generated apoJ-deficient mice. Deficient and wildtype mice exhibited similar initial onset of myocarditis. Furthermore, autoantibodies against the primary antigen cardiac myosin were induced to the same extent. Although the same proportion of challenged mice exhibited some degree of inflammatory infiltrate, inflammation was more severe in these mice. Inflammatory lesions were more diffuse and extensive in deficient mice, particularly in females. In marked contrast to wildtype mice, the development of a strong generalized secondary response against cardiac antigens in the deficient mice was predictive of severe myocarditis. Wildtype mice with a strong antibody response to secondary antigens appeared to be protected from severe inflammation. After resolution of inflammation, apoJ-deficient, but not wildtype, mice exhibited cardiac function impairment and severe myocardial scarring. These results suggested that apoJ normally limits progression of autoimmune myocarditis and protects the heart from postinflammatory tissue destruction.

Chen et al. (2003) sought to discover candidate biomarkers without the restrictive choice of markers placed on microarrays, and without the biologic complications of genetic and environmental heterogeneity. They compared by cDNA subtraction 2 genetically matched sets of mice, 1 developing multiple intestinal neoplasia due to the Min mutation in the Apc gene and the other the mutation-free parent strain, C57BL/6J. One prominent candidate biomarker, clusterin, was then subjected to a series of validation steps. Elevated clusterin expression was characterized within certain regions of murine and human tumors regardless of tumor stage, location, or mode of initiation. Cells showing high clusterin levels generally lacked differentiation markers and adenomatous polyposis coli antigen. Tumor cells undergoing apoptosis expressed low levels of clusterin. Its specific expression patterns and correlation with cellular events during tumorigenesis made it a useful diagnostic tool in the mouse and a potential contributor to the set of biomarkers for early detection of human colon cancer.

DeMattos et al. (2004) generated transgenic mice with a mutation in the amyloid precursor protein (APP) (V717F; 104760.0003) that were also null for apoE (107741), apoJ, or null for both apo genes. The double apo knockout mice showed early-onset beta-amyloid deposition beginning at 6 months of age and a marked increase in amyloid deposition compared to the other mice. The amyloid plaques were compact and diffuse, were thioflavine S-positive (indicating true fibrillar amyloid), and were distributed throughout the hippocampus and some parts of the cortex, contributing to neuritic plaques. The findings suggested that apoE and apoJ are not required for amyloid fibril formation. The double apo knockout mice also had increased levels of intracellular soluble beta-amyloid compared to the other mice. Insoluble beta-42 was similar to the apoE-null mice, suggesting that ApoE has a selective effect on beta-42. As APP is produced and secreted by neurons in the CNS and apoE and clusterin are produced and secreted primarily by astrocytes in the CNS, the interaction between the apolipoproteins and beta-amyloid occurs in the interstitial fluid of the brain, an extracellular compartment that is continuous with the CSF. DeMattos et al. (2004) found that apoE-null and apoE/apoJ-null mice had increased levels of beta-amyloid in the CSF and interstitial space, suggesting that apoE, and perhaps apoJ, play a role in regulating extracellular CNS beta-amyloid clearance independent of beta-amyloid synthesis. The data suggested that, in the mouse, apoE and apoJ cooperatively suppress beta-amyloid deposition.

Tags: 8p21.1