Skip to main content
Download PDF

Molecular Basis of Human CD36 Gene Mutations

Molecular Medicine volume 13, pages 288–296 (2007)Cite this article

Abstract

CD36 is a transmembrane glycoprotein of the class B scavenger receptor family. The CD36 gene is located on chromosome 7 q11.2 and is encoded by 15 exons. Defective CD36 is a likely candidate gene for impaired fatty acid metabolism, glucose intolerance, atherosclerosis, arterial hypertension, diabetes, cardiomyopathy, Alzheimer disease, and modification of the clinical course of malaria. Contradictory data concerning the effects of antiatherosclerotic drugs on CD36 expression indicate that further investigation of the role of CD36 in the development of atherosclerosis may be important for the prevention and treatment of this disease. This review summarizes current knowledge of CD36 gene structure, splicing, and mutations and the molecular, metabolic, and clinical consequences of these phenomena.

Introduction

CD36 is a type B scavenger receptor located on the surface of many types of cells. More than 20 mutations in the coding sequence of the CD36 gene that lead to type I receptor deficiency have been described, but the molecular basis of type II CD36 deficiency is still unclear. Different systems of nucleotide numbering in the CD36 gene are used by individual authors; thus descriptions of mutation locations are ambiguous. This review summarizes current knowledge of CD36 gene structure, splicing, and mutations and the molecular, metabolic, and clinical consequences of these phenomena.

Structure of the Human CD36 Gene

The CD36 gene is located on chromosome 7 q11.2 (1). The structural organization of the human CD36 gene was described by Armesilla et al. (2,3). The CD36 gene is encoded by 15 exons (Table 1). Exons 1, 2, and 15 are non-coding. Exons 3 and 14 encode N-terminal and C-terminal domains of the CD36 protein, respectively (3). Interestingly, the 5′-untranslated region of CD36 mRNA is encoded by 3 exons. Exon 3 contains the last 89 nucleotides of the 5′-untranslated region and encodes the N-terminal cytoplasmic and transmembrane domains (2). The 3′-untranslated region is contained in exon 14 only or in exons 14 and 15 (3).

Table 1 Exons, Introns, and Mutations in the Human CD36 Gene
Full size table

CD36 Location

CD36 is present on the surface of platelets, endothelial cells, macrophages, dendrite cells, adipocytes, striated muscle cells, and hematopoietic cells (4–9).

CD36 Gene Expression Regulation

CD36 gene expression is tissue dependent. In adipocytes, the nuclear peroxisome proliferation activator receptor γ (PPARγ) is the critical factor for feedback control of the CD36 gene (10–13). In monocytes, receptor expression can be upregulated by adhesion and by action of cytokines (such as M-CSF and GM-CSF), native and modified LDL, cellular cholesterol, interleukin-4, insulin, and glucose (14–17). Expression is inhibited by TGF-β, corticosteroids, HDL, and LPS (lipopolysaccharides) (14,17–19). CD36 expression in the heart and skeletal muscles is increased by triacylglycerides (TG) and fatty acids (FA) in plasma and regulated by energy requirements of the tissue (20).

Alternative Splicing

A marked feature of the CD36 gene is the presence of several (at least five) alternative and independent first exons and their promoters, which lack TATA-boxes and CpG islands (21). Another alternative promoter and first exon have recently been identified downstream of exon 2 (22). Alternative splicing of the first CD36 exon appears to be regulated differently in different tissues, indicating that the promoters are tissue specific. The alternative transcripts are all expressed in more than one human tissue, and their expression patterns are highly variable in skeletal muscle, heart, liver, adipose tissue, placenta, spinal cord, cerebrum, and monocytes (21).

Alternative splicing of 5′-untranslated and 3′-untranslated exons in CD36 pre-mRNA accounts for some of the heterogeneity in the molecular size of CD36 mRNA (23,24). All the splice acceptor and donor sequences conform to the consensus rule for splicing. Of the 11 splice junctions found around coding exons, type 0 occurs between codons, type 1 occurs after the first nucleotide, and type 2 occurs after the second nucleotide of a codon. Such diversity in the type of intron phase limits the number of mRNA forms that might arise by exon deletion while maintaining the same open reading frame (3). Alternatively spliced coding exons can be detected in CD36-expressing cells (24).

The functional diversity of CD36 may result from alternative splicing of CD36 pre-mRNA. Skipping of coding exons 4 and 5 gives rise to a CD36 isoform that lacks 103 amino acid residues, 41–143, and three potential N-glycosylation sites (25).

Andersen et al. have suggested that the molecular mechanisms regulating the CD36 gene expression are unusually complex, reflecting the multifunctional role of CD36 in different tissues and conditions (21).

Protein Structure

CD36 is a transmembrane glycoprotein of the class B scavenger receptor family (26–28). Synonym names of CD36 are platelet glycoprotein, GPIV, glycoprotein IIIb, GPIIIB, leukocyte differentiation antigen CD36, CD36 antigen, SR-BI, PAS IV, PAS-4 protein, platelet collagen receptor, fatty acid translocase, FAT, and thrombospondin (TSP) receptor.

According to the nucleotide sequence, CD36 mRNA (Genbank: NM 000072) codes for 472 amino acids (AA) (SwissProt: P16671; Figure 1). The mature polypeptide is 471 AA long, beginning at the AA residue immediately following the initiator methionine (4). The molecular mass of the functional receptor is 78–88 kDa, depending on the cell type and on post-translational glycosylations (4,6,25). The receptor consists of 1 extracellular, 2 transmembrane, and two cytoplasmic fragments representing the C-terminal and N-terminal parts of the molecule (3). The cytoplasmic and transmembrane regions predicted at both terminal ends of the polypeptide chain are encoded by the single exons 3 and 14. The translation start codon is located 289 (or 356 with alternatively spliced exon 1) nucleotides downstream of the 5′-end of CD36 mRNA (25). The large number of exons encoding the highly glycosylated extracellular domain (exons 4–13 and part of exon 14) may be a consequence of the multiplicity of interactions in which CD36 seems to be involved (3).

Figure 1
figure 1

cDNA nucleotide and amino acid sequences of CD36 with mutations indicated as follows: substitutions (underline), deletions (line over and usually italic), insertions (bold) (based on: https://doi.org/snpper.chip.org).

Full size image

There are no free cysteines in CD36, and the six centrally clustered cysteines are linked by disulfide bonds: Cys242/Cys310, Cys271/Cys332, and Cys312/Cys321, resulting in a 1–3, 2–6, and 4–5 arrangement of the disulfide bridges (3). A diagram of the CD36 structure is presented in Figure 2.

Figure 2
figure 2

Diagram of CD36 structure, based on (23,39,41,49).

Full size image

Posttranslational Modifications

The protein has two short intracellular segments (residues 1–6 and AA 461–472) that may undergo acylation (palmitoylation, Figure 2), and two transmembrane domains (residues 7–28 and AA 439–460) potentially acylated near the intracellular side of the membrane (29). The remaining part of CD36 is extracellular, comprising 7 glycosylation sites and 3 disulfide bridges (6,29,30).

CD36 Functions

The CD36 functions presented in Table 2 include removal of oxidized LDL from plasma (in macrophages and monocytes) (10,31–34), apoptosis induction (together with other membrane proteins such as αVβ3 integrin and thrombospondin 1) (35–37), and enhancement of cytoadherence of abnormally shaped erythrocytes (infected with Plasmodium falciparum or containing hemoglobin S) (4,38). CD36 is a long-chain fatty acid receptor (39,40) with a potential binding site for the fatty acids in its extracellular segment between residues 127 and 279 (39). CD36 is also an adhesion molecule capable of interacting with collagen type I and IV and with thrombospondin (5,41–44). Leung et al. reported that the CD36-TSP interaction is a two-step process; the AA 139–155 region of CD36 binds first to TSP (thrombospondin), triggering a change in TSP structure, which then reveals a second site that binds the AA 93–110 region of CD36 with high affinity (45). On the other hand, Asch et al. (46) reported that three functional sequences exist; one of these mediates TSP binding (AA 87–99) and two other support malarial cytoadhesion (AA 8–21 and AA 97–110). The data reported by Asch et al. also suggest that CD36 ligand specificity is directed by the extracellular release or activation of threonine phosphatase in response to a platelet agonist and that CD36 dephosphorylation may affect signaling. Phosphorylation was observed to inhibit TSP binding to the peptide by 60% (46). Ren et al reported that transfection of the macrophage adhesion molecule CD36 into human Bowes melanoma cells specifically conferred greatly increased capacity, comparable to that exhibited by macrophages, to ingest apoptotic neutrophils, lymphocytes, and fibroblasts (35).

Table 2 Functions of the CD36 receptor
Full size table

CD36 Gene Mutations

Different systems of nucleotide numbering in the CD36 gene are used by individual authors. Therefore, to standardize the nomenclature, we consistently use the numbering system in which the position of the first protein-encoding mRNA nucleotide is +1 (Figure 1). This position corresponds to nucleotide +211 according to the nomenclature used by Kashiwagi et al. (47).

The following mutations in the CD36 gene (presented in Table 1) have been described so far: nucleotide substitutions (47–54), small deletions (53,55–57), small insertions (56,58), small indels (53,57), gross deletion (59), duplication (56), complex rearrangements (53), and repeat variation, a dinucleotide repeat (TG)n in intron 3 (50,60), where the repeat number n = 12 is involved in the nonproduction of the variant CD36 transcript that lacks exons 4 and 5 (50).

Molecular Consequences of CD36 Gene Mutations

CD36 deficiency is divided into two subgroups according to the phenotypes. In type I deficiency, neither platelets nor monocytes express CD36, whereas in type II deficiency (very rare in whites, 0.3% of the population, more frequent in Asians and Afro-Americans, 3%–4% of the population), CD36 is expressed in monocytes but not in platelets (7,44).

Type I Deficiency

The type I CD36 deficiency is most commonly detected in subjects who are homozygous or compound heterozygous for the following three mutations: C268T, 949insA, and 329-330delAC (18,61). A survey of the CD36 mutations in type I CD36 deficiency has revealed that C268T is the most common mutation, and is responsible for more than 50% of the mutated allele frequency in Asians (57). This mutation is the most frequent factor responsible for the absence of CD36 receptor expression in platelets and monocytes/macrophages (47,48). Substitution leads directly to CD36 deficiency via posttranslational modification defects (probably due to defective glycosylation of the 81 kDa protein). In an expression assay using the C268 or T268 form of CD36 cDNA-transfected cells, the substitution markedly impaired maturation of the 81-kDa precursor to the 88-kDa mature form of CD36 (47,48). The mutated precursor form of CD36 was subsequently degraded in the cytoplasm.

Another mutation responsible for type I deficiency—deletion of 12 bp, ATTGTGCCTATT, at nl. 1228–1239 (exon 13)—is present with or without skipping of exon 9 (nl. 749–818). The mechanism of exon 9 skipping is unknown because there are no mutations at the junction sites of exon 9. The 12-bp deletion leads to an inframe 4-AA deletion, whereas exon 9 skipping leads to a frameshift and appearance of a premature stop codon. In an expression assay, both 1228–1239del and exon 9 skipping directly caused impairment of the surface expression of CD36 (57).

Individuals with type I CD36 deficiency may be at risk of developing an anti-CD36 isoantibody after receiving a transfusion or during pregnancy (44).

Type II Deficiency

The genomic or molecular background of type II CD36 deficiency is not clearly understood and is probably heterogenous, leading to confounding interpretations of cause-and-effect relationships in human CD36 deficiency (18,51,61). Type II CD36 deficiency has been observed in individuals who lack a CD36 mutation but have a heterozygous mutation (most often C268T). The genotype-phenotype correlations indicated that the platelet CD36 protein expression level was regulated by other heritable platelet-restricted factors in addition to the CD36 coding region genotype (51). Kashiwagi et al. observed (47,55,57) that monocyte CD36 cDNA samples from two subjects with type II deficiency were heterozygous for the C268 and T268 forms, whereas their platelet CD36 cDNA consisted of only the T268 form.

As reported by Lipsky et al., in the Japanese population 6 different alleles (A1 to A6) of the CD36 gene were detected according to the size of a (TG)n repeat within intron 3 (60). To explain the tangled phenotype-genotype correlation in type II CD36 deficiency, Kashiwagi et al. hypothesized the “platelet-specific silent allele” and predicted its linkage to the A5 allele, which encodes (TG)12 (42,60). However, no DNA sequence corresponding to such a platelet-specific silent allele has yet been identified. Yanai et al. investigated the polymorphic site in the 5′-proximal flanking region and the 3′-untranslated region (61). According to these authors, an altered DNA sequence in or near the 3′-untranslated region may change the structure of mRNA and its stability in CD36 deficiency. Yanai et al. suggested that if the proposed platelet-specific silent allele exists, it may be remote to the CD36 gene, because the previously reported linkage with the A5 allele was not confirmed.

Metabolic Consequences of CD36 Gene Mutations

CD36 may play an important role in the pathogenesis of some metabolic diseases. The receptor is responsible for the removal of approximately 50% of oxidatively modified LDL (ox-LDL) from plasma (10,31). Binding takes place in the 155–183 amino acid region of the protein (34). Long-chain fatty acids (FA) are the main ligand for the receptor (26). Reduced expression of CD36 protects the vessels, according to some authors (62,63), and some have pointed out that CD36 gene mutations are associated with increased serum concentrations of total cholesterol and LDL (18,64). Other investigators have reported significant decreases in binding and uptake of ox-LDL in peritoneal macrophages of null mutation mice (65). Kashiwagi et al. demonstrated a marked reduction in the uptake of ox-LDL by CD36-deficient macrophages, a finding that suggests that differences in atherosclerosis may occur in type I or type II CD36-deficient individuals and CD36-positive individuals. In type II-deficient subjects, alleles having hypothetical platelet-specific mRNA transcription defects may be involved (42). Type I and type II deficiencies are believed to differ in their effects on the course of atherogenesis. Ox-LDL plays a role in macrophage transformation to foam cells, but the absence of expression of the macrophage CD36 can cause retention of ox-LDL in plasma (8,31,66).

Other authors have observed abnormalities of glucose and lipid metabolism in type I CD36 deficiency. For example, increased plasma triglycerides, decreased HDL-cholesterol, impaired glucose tolerance, and delayed response of insulin secretion (57,67). Kadlecova et al. proposed that defective CD36 is probably a candidate gene for disordered fatty-acid metabolism, glucose intolerance, and insulin resistance in spontaneously hypertensive rats (SHR), but other genes may also play a role in the pathogenesis of the metabolic syndrome in Prague hereditary hypertriglyceridemic rats (68). As shown by Glazier, chromosomal deletion at the CD36 locus in SHR was mediated by unequal recombination between the CD36 gene and the second pseudogene CD36-ps2, and was induced by extensive homology between these sequences. This recombination resulted in the creation of a single chimeric gene in SHR. The trait of insulin resistance and defective fatty acid metabolism is probably caused by CD36 deficiency (69). Recently, CD36 has been reported to play an important role in atherogenicity. To understand the role of CD36, it is important to clarify the condition of CD36-deficient subjects. Some authors suggest that upregulation of class B scavenger receptors could have therapeutic potential for the treatment of atherosclerosis (70,71). CD36 expression in tissues with very active fatty acid metabolism (skeletal muscle, heart, mammary epithelium, and adipose tissue), and its involvement in foam cell formation (macrophages), suggest that lipoprotein binding to CD36 might contribute to the regulation of lipid metabolism and to the pathogenesis of atherosclerosis (72).

Long-chain fatty acids (LCFA) are the major energy substrate for the heart, and their oxidation is important to ensure maximum cardiac performance. CD36 acts as a major myocardial-specific LCFA transporter in humans (73,74). FA translocase/CD36 is probably involved in regulating FA oxidation along with the well-known regulator carnitine palmitoyltransferase I (74). Some authors suggest that polymorphisms at the CD36 gene modulate lipid metabolism and cardiovascular risk in whites (75,76). Homozygous or compound heterozygous mutations of the CD36 gene in humans result in severe defects of the uptake of long-chain fatty acids (LCFAs) in the heart (56,77). Type I CD36 deficiency is closely related to the absence of LCFA accumulation and metabolism in the myocardium (19,78). CD36 deficiency leads also to decreased myocardial accumulation of 123I-BMIPP (iodine-123-(R,S)-15-(p-iodophenyl)-3-methylpentadecanoic acid) (79). Tanaka et al. hypothesized that this deficiency is a possible etiology of hereditary hypertrophic cardiomyopathy (HCM) (80). Some patients with HCM demonstrate abnormal myocardial LCFA metabolism. Data reported by Okamoto et al. suggest that abnormal myocardial LCFA metabolism seen in HCM patients may be related to abnormality of the CD36 molecule, and that abnormalities of this molecule may be the cause of some HCM types. On the other hand, patients in the Okamoto et al. study with apical HCM showed normal CD36 molecule expression and no severe impairment of myocardial BMIPP accumulation. Thus, abnormalities of the CD36 molecules may be related to the pathogenesis of some HCM types (81). Moreover, some CD36 mutations found in persons in Thailand are associated with reduced risk of cerebral malaria (50,60). In Africans, such mutations may be maintained by unidentified selection pressures and probably protect against some infections other than malaria (53).

Perspectives

Since the CD36 receptor was first isolated in 1973 (82), its function has been associated with an increased risk of or protection against many pathological conditions, including metabolic diseases. There are indications that abnormalities of the CD36 gene are implicated in the pathogenesis of hypercholesterolemia, peripheral vessel atherosclerosis, arterial hypertension, diabetes, cardiomyopathy, Alzheimer disease, and malaria (9,10,16,25,83–86). An animal model revealed that lack of CD36 expression restrained atherosclerosis (87). Increased expression of CD36 was shown in atheroslerotic plaques and in damaged vascular tissue (88). Contradictory data (89–91) concerning the effects of antiatherosclerotic drugs on CD36 expression indicate the necessity for further investigation of the role of CD36 in the development of atherosclerosis. The results may be important for the prevention and treatment of this disease. The association between cardiovascular risk and CD36 deficiency should be analyzed in extensive prospective studies in various populations.

The spectrum of CD36 mutations differs in various populations. The influence on CD36 expression of polymorphisms in noncoding regions of the CD36 gene is currently under investigation. Further research is needed to characterize the roles of numerous alternative CD36 transcripts and tissue-specific promoters. The results of these studies may elucidate the still unclear molecular background of type II CD36 deficiency.

References

  1. Fernandez-Ruiz E, Armesilla AL, Sanchez-Madrid F, Vega MA. (1993) Gene encoding the collagen type I and thrombospondin receptor CD36 is located on chromosome 7q11.2. Genomics 17:759–61.

    Article  CAS  Google Scholar 

  2. Armesilla AL, Calvo D, Vega MA. (1996) Structural and functional characterization of the human CD36 gene promoter: identification of a proximal PEBP2/CBF site. J. Biol. Chem. 271:7781–7.

    Article  CAS  Google Scholar 

  3. Armesilla AL, Vega MA. (1994) Structural organization of the gene for human CD36 glycoprotein. J. Biol. Chem. 269:18985–91.

    CAS  PubMed  Google Scholar 

  4. Oquendo P, Hundt E, Lawler J, Seed B. (1989) CD36 directly mediates cytoadherence of Plasmodium falciparum parasitized erythrocytes. Cell 58:95–101.

    Article  CAS  Google Scholar 

  5. McGregor JL, Catimel B, Parmentier S, Clezardin P, Dechavanne M, Leung LL. (1989) Rapid purification and partial characterization of human platelet glycoprotein IIIb. Interaction with thrombospondin and its role in platelet aggregation. J. Biol. Chem. 264:501–6.

    CAS  PubMed  Google Scholar 

  6. Greenwalt DE, Lipsky RH, Ockenhouse CF, Ikeda H, Tandon NN, Jamieson GA. (1992) Membrane glycoprotein CD36: a review of its roles in adherence, signal transduction, and transfusion medicine. Blood 80:1105–15.

    CAS  PubMed  Google Scholar 

  7. Take H, Kashiwagi H, Tomiyama Y, et al. (1993) Expression of GPIV and N(aka) antigen on monocytes in N(aka)-negative subjects whose platelets lack GPIV. Br. J. Haematol. 84:387–91.

    Article  CAS  Google Scholar 

  8. Nicholson AC, Han J, Febbraio M, Silversterin RL, Hajjar DP. (2001) Role of CD36, the macrophage class B scavenger receptor, in atherosclerosis. Ann. N. Y. Acad. Sci. 947:224–8.

    Article  CAS  Google Scholar 

  9. Rusinol AE, Yang L, Thewke D, Panini SR, Kramer MF, Sinensky MS. (2000) Isolation of a somatic cell mutant resistant to the induction of apoptosis by oxidized low density lipoprotein. J. Biol. Chem. 275:7296–303.

    Article  CAS  Google Scholar 

  10. Matsumoto K, Hirano K, Nozaki S, et al. (2000) Expression of macrophage (Mphi) scavenger receptor, CD36, in cultured human aortic smooth muscle cells in association with expression of peroxisome proliferator activated receptor-gamma, which regulates gain of Mphi-like phenotype in vitro, and its implication in atherogenesis. Arterioscler. Thromb. Vasc. Biol. 20:1027–32.

    Article  CAS  Google Scholar 

  11. Nicholson AC, Hajjar DP. (2004) CD36, oxidized LDL and PPAR gamma: pathological interactions in macrophages and atherosclerosis. Vascul. Pharmacol. 2004; 41:139–46.

    Article  CAS  Google Scholar 

  12. Nicholson AC. (2004) Expression of CD36 in macrophages and atherosclerosis: the role of lipid regulation of PPARgamma signaling. Trends Cardiovasc. Med. 14:8–12.

    Article  CAS  Google Scholar 

  13. Sato O, Kuriki C, Fukui Y, Motojima K. (2002) Dual promoter structure of mouse and human fatty acid translocase/CD36 genes and unique transcriptional activation by peroxisome proliferator-activated receptor alpha and gamma ligands. J. Biol. Chem. 277:15703–11.

    Article  CAS  Google Scholar 

  14. Feng J, Han J, Pearce SF, Silverstein RL, Gotto AM Jr, Hajjar DP, Nicholson AC. (2000) Induction of CD36 expression by oxidized LDL and IL-4 by a common signaling pathway dependent on protein kinase C and PPAR-gamma. J. Lipid. Res. 41:688–96.

    CAS  PubMed  Google Scholar 

  15. Griffin E, Re A, Hamel N, Fu C, Bush H, McCaffrey T, Asch AS. (2001) A link between diabetes and atherosclerosis: Glucose regulates expression of CD36 at the level of translation. Nat. Med. 7:840–6.

    Article  CAS  Google Scholar 

  16. Liang CP, Han S, Okamoto H, Carnemolla R, Tabas I, Accili D, Tall AR. (2004) Increased CD36 protein as a response to defective insulin signaling in macrophages. J. Clin. Invest. 113:764–73.

    Article  CAS  Google Scholar 

  17. Yesner LM, Huh HY, Pearce SF, Silverstein RL. (1996) Regulation of monocyte CD36 and thrombospondin-1 expression by soluble mediators. Arterioscler. Thromb. Vasc. Biol. 16:1019–25.

    Article  CAS  Google Scholar 

  18. Yanai H, Chiba H, Morimoto M, et al. (2000) Human CD36 deficiency is associated with elevation in low-density lipoprotein-cholesterol. Am. J. Med. Genet. 93:299–304.

    Article  CAS  Google Scholar 

  19. Watanabe K, Ohta Y, Toba K, et al. (1998) Myocardial CD36 expression and fatty acid accumulation in patients with type I and II CD36 deficiency. Ann. Nucl. Med. 12:261–6.

    Article  CAS  Google Scholar 

  20. Bastie CC, Hajri T, Drover VA, Grimaldi PA, Abumrad NA. (2004) CD36 in myocytes channels fatty acids to a lipase-accessible triglyceride pool that is related to cell lipid and insulin responsiveness. Diabetes 53:2209–16.

    Article  CAS  Google Scholar 

  21. Andersen M, Lenhard B, Whatling C, Eriksson P, Abumrad NA. (2006) Alternative promoter usage of the membrane glycoprotein CD36. BMC Mol. Biol. 7:8.

    Article  Google Scholar 

  22. Sato O, Takanashi N, Motojima K. (2007) Third promoter and differential regulation of mouse and human fatty acid translocase/CD36 genes. Mol. Cell. Biochem. 299:37–43.

    Article  CAS  Google Scholar 

  23. Noguchi K, Naito M, Tezuka K, et al. (1993) cDNA expression cloning of the 85-kDa protein overexpressed in adriamycin-resistant cells. Biochem. Biophys. Res. Commun. 192:88–95.

    Article  CAS  Google Scholar 

  24. Taylor KT, Tang Y, Sobieski DA, Lipsky RH. (1993) Characterization of two alternatively spliced 5′-untranslated exons of the human CD36 gene in different cell types. Gene 133:205–12.

    Article  CAS  Google Scholar 

  25. Tang Y, Taylor KT, Sobieski DA, Medved ES, Lipsky RH. (1994) Identification of a human CD36 isoform produced by exon skipping. Conservation of exon organization and pre-mRNA splicing patterns with a CD36 gene family member, CLA-1. J. Biol. Chem. 269:6011–5.

    CAS  PubMed  Google Scholar 

  26. Abumrad NA, el-Maghrabi MR, Amri EZ, Lopez E, Grimaldi PA. (1993) Cloning of a rat adipocyte membrane protein implicated in binding or transport of long-chain fatty acids that is induced during preadipocyte differentiation: homology with human CD36. J. Biol. Chem. 268:17665–8.

    CAS  PubMed  Google Scholar 

  27. Acton S, Rigotti A, Landschulz KT, Xu S, Hobbs HH, Krieger M. (1996) Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science 271:518–20.

    Article  CAS  Google Scholar 

  28. Febbraio M, Hajjar DP, Silverstein RL. (2001) CD36: a class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolism. J. Clin. Invest. 108:785–91.

    Article  CAS  Google Scholar 

  29. Rasmussen JT, Berglund L, Rasmussen MS, Petersen TE. (1998) Assignment of disulfide bridges in bovine CD36. Eur. J. Biochem. 257:488–94.

    CAS  Google Scholar 

  30. Gruarin P, Thorne RF, Dorahy DJ, Burns GF, Sitia R, Alessio M. (2000) CD36 is a ditopic glycoprotein with the N-terminal domain implicated in intracellular transport. Biochem. Biophys. Res. Commun. 275:446–54.

    Article  CAS  Google Scholar 

  31. Endemann G, Stanton LW, Madden KS, Bryant CM, White RT, Protter AA. (1993) CD36 is a receptor for oxidized low density lipoprotein. J. Biol. Chem. 268:11811–6.

    CAS  PubMed  Google Scholar 

  32. Nicholson AC, Hajjar DP. (1998) Herpesvirus in atherosclerosis and thrombosis: etiologic agents or ubiquitous bystanders? Arterioscler. Thromb. Vasc. Biol. 18:339–8.

    Article  CAS  Google Scholar 

  33. Nozaki S, Kashiwagi H, Yamashita S, et al. (1995) Reduced uptake of oxidized low density lipoproteins in monocyte-derived macrophages from CD36-deficient subjects. J. Clin. Invest. 1995; 96:1859–65.

    Article  CAS  Google Scholar 

  34. Puente-Navazo MD, Daviet L, Ninio E, McGregor JL. (1996) Identification on human CD36 of a domain (155–183) implicated in binding oxidized low-density lipoproteins (Ox-LDL). Arterioscler. Thromb. Vasc. Biol. 16:1033–9.

    Article  CAS  Google Scholar 

  35. Ren Y, Silverstein RL, Allen J, Savill J. (1995) CD36 gene transfer confers capacity for phagocytosis of cells undergoing apoptosis. J. Exp. Med. 181:1857–62.

    Article  CAS  Google Scholar 

  36. Savill J, Hogg N, Ren Y, Haslett C. (1992) Thrombospondin cooperates with CD36 and the vitronectin receptor in macrophage recognition of neutrophils undergoing apoptosis. J. Clin. Invest. 90:1513–22.

    Article  CAS  Google Scholar 

  37. Silverstein RL, Asch AS, Nachman RL. (1989) Glycoprotein IV mediates thrombospondin-dependent platelet-monocyte and platelet-U937 cell adhesion. J. Clin. Invest. 84:546–52.

    Article  CAS  Google Scholar 

  38. Alessio M, Greco NJ, Primo L, et al. (1993) Platelet activation and inhibition of malarial cytoadherence by the anti-CD36 IgM monoclonal antibody NL07. Blood 82:3637–47.

    CAS  PubMed  Google Scholar 

  39. Baillie AG, Coburn CT, Abumrad NA. (1996) Reversible binding of long-chain fatty acids to purified FAT, the adipose CD36 homolog. J. Membr. Biol. 153:75–81.

    Article  CAS  Google Scholar 

  40. Hwang EH, Taki J, Yasue S, et al. (1998) Absent myocardial iodine-123-BMIPP uptake and platelet/monocyte CD36 deficiency. J. Nucl Med. 39:1681–4.

    CAS  PubMed  Google Scholar 

  41. Frieda S, Pearce A, Wu J, Silverstein RL. (1995) Recombinant GST/CD36 fusion proteins define a thrombospondin binding domain. Evidence for a single calcium-dependent binding site on CD36. J. Biol. Chem. 270:2981–6.

    Article  CAS  Google Scholar 

  42. Kashiwagi H, Tomiyama Y, Kosugi S, et al. (1995) Family studies of type II CD36 deficient subjects: linkage of a CD36 allele to a platelet-specific mRNA expression defect(s) causing type II CD36 deficiency. Thromb. Haemost. 74:758–63.

    Article  CAS  Google Scholar 

  43. Tandon NN, Kralisz U, Jamieson GA. (1989) Identification of glycoprotein IV (CD36) as a primary receptor for platelet-collagen adhesion. J. Biol. Chem. 264:7576–83.

    CAS  PubMed  Google Scholar 

  44. Yamamoto N, Akamatsu N, Sakuraba H, Yamazaki H, Tanoue K. (1994) Platelet glycoprotein IV (CD36) deficiency is associated with the absence (type I) or the presence (type II) of glycoprotein IV on monocytes. Blood 83:392–7.

    CAS  PubMed  Google Scholar 

  45. Leung LL, Li WX, McGregor JL, Albrecht G, Howard RJ. (1992) CD36 peptides enhance or inhibit CD36-thrombospondin binding. A two-step process of ligand-receptor interaction. J. Biol. Chem. 267:18244–50.

    CAS  PubMed  Google Scholar 

  46. Asch AS, Liu I, Briccetti FM, et al. (1993) Analysis of CD36 binding domains: ligand specificity controlled by dephosphorylation of an ectodomain. Science 262:1436–40.

    Article  CAS  Google Scholar 

  47. Kashiwagi H, Tomiyama Y, Honda S, et al. (1995) Molecular basis of CD36 deficiency. Evidence that a 478C→ T substitution (proline90→ serine) in CD36 cDNA accounts for CD36 deficiency. J. Clin. Invest. 95:1040–6.

    Article  CAS  Google Scholar 

  48. Kashiwagi H, Honda S, Tomiyama Y, et al. (1993) A novel polymorphism in glycoprotein IV (replacement of proline-90 by serine) predominates in subjects with platelet GPIV deficiency. Thromb. Haemost. 1993; 69:481–4.

    CAS  PubMed  Google Scholar 

  49. Gelhaus A, Scheding A, Browne E, Burchard GD, Horstmann RD. (2001) Variability of the CD36 gene in West Africa. Hum. Mutat. 18:444–50.

    Article  CAS  Google Scholar 

  50. Omi K, Ohashi J, Patarapotikul J, Hananantachai H, Naka I, Looareesuwan S, Tokunaga K. (2003) CD36 polymorphism is associated with protection from cerebral malaria. Am. J. Hum. Genet. 72:364–74.

    CAS  Google Scholar 

  51. Imai M, Tanaka T, Kintaka T, Ikemoto T, Shimizu A, Kitaura Y. (2002) Genomic heterogeneity of type II CD36 deficiency. Clin. Chim. Acta 321:97–106.

    Article  CAS  Google Scholar 

  52. Hanawa H, Watanabe K, Nakamura T, et al. (2002) Identification of cryptic splice site, exon skipping, and novel point mutations in type I CD36 deficiency. J. Med. Genet. 39:286–91.

    Article  CAS  Google Scholar 

  53. Aitman TJ, Cooper LD, Norsworthy PJ, et al. (2000) Malaria susceptibility and CD36 mutation. Nature 405:1015–6.

    Article  CAS  Google Scholar 

  54. Lepretre F, Vasseur F, Vaxillaire M, et al. (2004) A CD36 nonsense mutation associated with insulin resistance and familial type 2 diabetes. Hum. Mutat. 24:104–10.

    Article  Google Scholar 

  55. Kashiwagi H, Tomiyama Y, Kosugi S, et al. (1994) Identification of molecular defects in a subject with type I CD36 deficiency. Blood 83:3545–52.

    CAS  PubMed  Google Scholar 

  56. Tanaka T, Nakata T, Oka T, et al. (2001) Defect in human myocardial long-chain fatty acid uptake is caused by FAT/CD36 mutations. J. Lipid. Res. 42:751–9.

    CAS  PubMed  Google Scholar 

  57. Kashiwagi H, Tomiyama Y, Nozaki S, et al. (2001) Analyses of genetic abnormalities in type I CD36 deficiency in Japan: identification and cell biological characterization of two novel mutations that cause CD36 deficiency in man. Hum. Genet. 108:459–66.

    Article  CAS  Google Scholar 

  58. Kashiwagi H, Tomiyama Y, Nozaki S, et al. (1996) A single nucleotide insertion in codon 317 of the CD36 gene leads to CD36 deficiency. Arterioscler. Thromb. Vasc. Biol. 16:1026–32.

    Article  CAS  Google Scholar 

  59. Curtis BR, Ali S, Glazier AM, Ebert DD, Aitman TJ, Aster RH. (2002) Isoimmunization against CD36 (glycoprotein IV): description of four cases of neonatal isoimmune thrombocytopenia and brief review of the literature. Transfusion 42:1173–9.

    Article  CAS  Google Scholar 

  60. Lipsky RH, Ikeda H, Medved ES. (1994) Adinucleotide repeat in the third intron of CD36. Hum. Mol. Genet. 3:217

    Article  CAS  Google Scholar 

  61. Yanai H, Chiba H, Fujiwara H, et al. (2000) Phenotype-genotype correlation in CD36 deficiency types I and II. Thromb. Haemost. 84:436–41.

    Article  CAS  Google Scholar 

  62. Kincer JF, Uittenbogaard A, Dressman J, Guerin TM, Febbraio M, Guo L, Smart EJ. (2002) Hypercholesterolemia promotes a CD36-dependent and endothelial nitric-oxide synthase-mediated vascular dysfunction. J. Biol. Chem. 277:23525–33.

    Article  CAS  Google Scholar 

  63. Steinberg HO, Baron AD. (2002) Vascular function, insulin resistance and fatty acids. Diabetologia 45:623–34.

    Article  CAS  Google Scholar 

  64. Hayek T, Aviram M, Heinrich R, Sakhnini E, Keidar S. (2000) Losartan inhibits cellular uptake of oxidized LDL by monocyte-macrophages from hypercholesterolemic patients. Biochem. Biophys. Res. Commun. 273:417–20.

    Article  CAS  Google Scholar 

  65. Febbraio M, Abumrad NA, Hajjar DP, Sharma K, Cheng W, Pearce SF, Silverstein RL. (1999) Anull mutation in murine CD36 reveals an important role in fatty acid and lipoprotein metabolism. J. Biol. Chem. 274:19055–62.

    Article  CAS  Google Scholar 

  66. Rać ME. (2005) CD36 receptor mutations and atherosclerosis. Prog. Med. Res. 3:9 (on-line)

    Google Scholar 

  67. Miyaoka K, Kuwasako T, Hirano K, Nozaki S, Yamashita S, Matsuzawa Y. (2001) CD36 deficiency associated with insulin resistance. Lancet 357:686–7.

    Article  CAS  Google Scholar 

  68. Kadlecova M, Cejka J, Zicha J, Kunes J. (2004) Does CD36 gene play a key role in disturbed glucose and fatty acid metabolism in Prague hypertensive hypertriglyceridemic rats? Physiol. Res. 53:265–71.

    CAS  PubMed  Google Scholar 

  69. Glazier AM, Scott J, Aitman TJ. (2002) Molecular basis of the Cd36 chromosomal deletion underlying SHR defects in insulin action and fatty acid metabolism. Mamm. Genome 13:108–113.

    Article  CAS  Google Scholar 

  70. Hsu LA, Ko YL, Wu S, et al. (2003) Association between a novel 11-base pair deletion mutation in the promoter region of the scavenger receptor class B type I gene and plasma HDL cholesterol levels in Taiwanese Chinese. Arterioscler. Thromb. Vasc. Biol. 23:1869–74.

    Article  CAS  Google Scholar 

  71. Huszar D, Varban ML, Rinninger F, et al. (2000) Increased LDL cholesterol and atherosclerosis in LDL receptor-deficient mice with attenuated expression of scavenger receptor B1. Arterioscler. Thromb. Vasc. Biol. 20:1068–73.

    Article  CAS  Google Scholar 

  72. Calvo D, Gomez-Coronado D, Suarez Y, Lasuncion MA, Vega MA. (1998) Human CD36 is a high affinity receptor for the native lipoproteins HDL, LDL, and VLDL. J. Lipid. Res. 39:777–88.

    CAS  PubMed  Google Scholar 

  73. Nozaki S, Tanaka T, Yamashita S, et al. (1999) CD36 mediates long-chain fatty acid transport in human myocardium: complete myocardial accumulation defect of radiolabeled long-chain fatty acid analog in subjects with CD36 deficiency. Mol. Cell. Biochem. 192:129–135.

    Article  CAS  Google Scholar 

  74. Bonen A, Campbell SE, Benton CR, et al. (2004) Regulation of fatty acid transport by fatty acid translocase/CD36. Proc. Nutr. Soc. 63:245–9.

    Article  CAS  Google Scholar 

  75. Ma X, Bacci S, Mlynarski W, et al. (2004) A common haplotype at the CD36 locus is associated with high free fatty acid levels and increased cardiovascular risk in Caucasians. Hum. Mol. Genet. 13:2197–2205.

    Article  CAS  Google Scholar 

  76. Ibrahimi A, Abumrad NA. (2002) Role of CD36 in membrane transport of long-chain fatty acids. Curr. Opin. Clin. Nutr. Metab. Care 5:139–45.

    Article  CAS  Google Scholar 

  77. Kintaka T, Tanaka T, Imai M, Adachi I, Narabayashi I, Kitaura Y. (2002) CD36 genotype and long-chain fatty acid uptake in the heart. Circ. J. 66:819–25.

    Article  CAS  Google Scholar 

  78. Nozaki S, Tanaka T, Yamashita S, et al. (1999) CD36 mediates long-chain fatty acid transport in human myocardium: complete myocardial accumulation defect of radiolabeled long-chain fatty acid analog in subjects with CD36 deficiency. Mol. Cell. Biochem. 192:129–35.

    Article  CAS  Google Scholar 

  79. Teraguchi M, Ohkohchi H, Ikemoto Y, Higashino H., Kobayashi Y. (2003) CD36 deficiency and absent myocardial iodine-123-(R,S)-15-(p-iodophenyl)-3-methylpentadecanoic acid uptake in a girl with cardiomyopathy. Eur. J. Pediatr. 162:264–6.

    PubMed  Google Scholar 

  80. Tanaka T, Sohmiya K, Kawamura K. (1997) Is CD36 deficiency an etiology of hereditary hypertrophic cardiomyopathy? J. Mol. Cell. Cardiol. 29:121–7.

    Article  CAS  Google Scholar 

  81. Okamoto F, Tanaka T, Sohmiya K, Kawamura K. (1998) CD36 abnormality and impaired myocardial long-chain fatty acid uptake in patients with hypertrophic cardiomyopathy. Jpn. Circ. J. 62:499–504.

    Article  CAS  Google Scholar 

  82. Kobylka D, Carraway KL. (1973) Proteolytic digestion of proteins of the milk fat globule membrane. Biochim. Biophys. Acta. 307:133–40.

    Article  CAS  Google Scholar 

  83. Ge Y, Elghetany MT. (2005) CD36: a multiligand molecule. Lab. Hematol. 11:31–7.

    Article  CAS  Google Scholar 

  84. Hajri T, Han XX, Bonen A, Abumrad NA. (2002) Defective fatty acid uptake modulates insulin responsiveness and metabolic responses to diet in CD36-null mice. J. Clin. Invest. 109:1381–9.

    Article  CAS  Google Scholar 

  85. Tedgui A, Mallat Z. (2002) Platelets in atherosclerosis: a new role for beta-amyloid peptide beyond Alzheimer’s disease. Circ. Res. 90:1145–6.

    Article  CAS  Google Scholar 

  86. Uittenbogaard A, Shaul PW, Yuhanna IS, Blair A, Smart EJ. (2000) High density lipoprotein prevents oxidized low density lipoprotein-induced inhibition of endothelial nitric-oxide synthase localization and activation in caveolae. J. Biol. Chem. 275:11278–83.

    Article  CAS  Google Scholar 

  87. Febbraio M, Podrez EA, Smith JD, et al. (2000) Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice. J. Clin. Invest. 105:1049–56.

    Article  CAS  Google Scholar 

  88. Nakata A, Nakagawa Y, Nishida M, et al. (1999) CD36, a novel receptor for oxidized low-density lipoproteins, is highly expressed on lipid-laden macrophages in human atherosclerotic aorta. Arterioscler. Thromb. Vasc. Biol. 19:1333–9.

    Article  CAS  Google Scholar 

  89. Nakamura T, Saito Y, Ohyama Y, Uchiyama T, Sumino H, Kurabayashi M. (2004) Effect of cerivastatin on endothelial dysfunction and aortic CD36 expression in diabetic hyperlipidemic rats. Hypertens. Res. 27:589–98.

    Article  CAS  Google Scholar 

  90. Ruiz-Velasco N, Dominguez A, Vega MA. (2004) Statins upregulate CD36 expression in human monocytes, an effect strengthened when combined with PPAR-gamma ligands Putative contribution of Rho GTPases in statin-induced CD36 expression. Biochem. Pharmacol. 67:303–13.

    Article  CAS  Google Scholar 

  91. Puccetti L, Sawamura T, Pasqui AL, Pastorelli M, Auteri A, Bruni F. (2005) Atorvastatin reduces platelet-oxidized-LDL receptor expression in hypercholesterolaemic patients. Eur J. Clin. Invest. 35:47–51.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, Powstańców Wielkopolskich 72, 70-111, Szczecin, Poland

    Monika Ewa Rać & Krzysztof Safranow

  2. Department of Diagnostic Imaging and Interventional Radiology, Pomeranian Medical University, Szczecin, Poland

    Wojciech Poncyljusz

Authors
  1. Monika Ewa Rać
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Krzysztof Safranow
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wojciech Poncyljusz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Monika Ewa Rać.

Rights and permissions

Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and permissions

About this article

Cite this article

Rać, M.E., Safranow, K. & Poncyljusz, W. Molecular Basis of Human CD36 Gene Mutations. Mol Med 13, 288–296 (2007). https://doi.org/10.2119/2006-00088.Rac

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2119/2006-00088.Rac

Keywords

Molecular Medicine

ISSN: 1528-3658