APOA4 resides on chromosome 11 in close linkage to APOA1 and APOC3. APOA4 contains 3 exons separated by two introns, and is polymorphic, although most of the reported sequence polymorphisms occur in exon 3. The best validated and studied non-synonymous SNPs are a glutamine → histidine substitution at codon 360 and a threonine → serine substitution at codon 347; a sequence polymorphism has also been identified in the 3'UTR of the third exon. Intra-species comparative gene sequence analysis suggests that the APOA4 gene arose from APOA1 by gene duplication approximately 270 MYA.
The primary translation product of the APOA4 gene is a 396-residue preprotein, which undergoes proteolytic processing to yield apo A-IV, a 376-residue mature O-linked glycoprotein. In most mammals, including humans, apo A-IV synthesis is confined to the intestine; however in mice and rats hepatic synthesis also occurs. Apo A-IV is secreted into circulation on the surface of newly synthesized chylomicron particles. Intestinal fat absorption dramatically increases the synthesis and secretion of apo A-IV. Although its primary function in human lipid metabolism has not been established, apo A-IV has been found to:
^Elshourbagy NA, Walker DW, Paik YK, Boguski MS, Freeman M, Gordon JI, Taylor JM (June 1987). "Structure and expression of the human apolipoprotein A-IV gene". J. Biol. Chem.262 (17): 7973–81. PMID3036793.
^Deeg, M A; Bierman E L; Cheung M C (March 2001). "GPI-specific phospholipase D associates with an apoA-I- and apoA-IV-containing complex". J. Lipid Res. (United States) 42 (3): 442–51. ISSN0022-2275. PMID11254757.
Kamboh MI, Williams ER, Law JC et al. (1993). "Molecular basis of a unique African variant (A-IV 5) of human apolipoprotein A-IV and its significance in lipid metabolism.". Genet. Epidemiol.9 (6): 379–88. doi:10.1002/gepi.1370090602. PMID1487136.
Lohse P, Kindt MR, Rader DJ, Brewer HB (1991). "Three genetic variants of human plasma apolipoprotein A-IV. apoA-IV-1(Thr347----Ser), apoA-IV-0(Lys167----Glu,Gln360----His), and apoA-IV-3(Glu165----Lys).". J. Biol. Chem.266 (21): 13513–8. PMID1677358.
Tenkanen H, Koskinen P, Metso J et al. (1992). "A novel polymorphism of apolipoprotein A-IV is the result of an asparagine to serine substitution at residue 127.". Biochim. Biophys. Acta1138 (1): 27–33. doi:10.1016/0925-4439(92)90147-f. PMID1737067.
Lohse P, Kindt MR, Rader DJ, Brewer HB (1990). "Human plasma apolipoproteins A-IV-0 and A-IV-3. Molecular basis for two rare variants of apolipoprotein A-IV-1.". J. Biol. Chem.265 (21): 12734–9. PMID1973689.
Tenkanen H, Lukka M, Jauhiainen M et al. (1991). "The mutation causing the common apolipoprotein A-IV polymorphism is a glutamine to histidine substitution of amino acid 360.". Arterioscler. Thromb.11 (4): 851–6. doi:10.1161/01.atv.11.4.851. PMID2065039.
Wei S, Rocchi M, Archidiacono N et al. (1990). "Physical mapping of the human chromosome 11q23 region containing the ataxia-telangiectasia locus.". Cancer Genet. Cytogenet.46 (1): 1–8. doi:10.1016/0165-4608(90)90002-R. PMID2331673.
Lohse P, Kindt MR, Rader DJ, Brewer HB (1990). "Genetic polymorphism of human plasma apolipoprotein A-IV is due to nucleotide substitutions in the apolipoprotein A-IV gene.". J. Biol. Chem.265 (17): 10061–4. PMID2351649.
Elshourbagy NA, Walker DW, Boguski MS et al. (1986). "The nucleotide and derived amino acid sequence of human apolipoprotein A-IV mRNA and the close linkage of its gene to the genes of apolipoproteins A-I and C-III.". J. Biol. Chem.261 (5): 1998–2002. PMID3080432.
Bisgaier CL, Sachdev OP, Lee ES et al. (1987). "Effect of lecithin:cholesterol acyltransferase on distribution of apolipoprotein A-IV among lipoproteins of human plasma.". J. Lipid Res.28 (6): 693–703. PMID3611972.
Karathanasis SK, Yunis I, Zannis VI (1986). "Structure, evolution, and tissue-specific synthesis of human apolipoprotein AIV.". Biochemistry25 (13): 3962–70. doi:10.1021/bi00361a034. PMID3755616.
Gordon JI, Bisgaier CL, Sims HF et al. (1984). "Biosynthesis of human preapolipoprotein A-IV.". J. Biol. Chem.259 (1): 468–74. PMID6706947.
Menzel HJ, Dieplinger H, Sandholzer C et al. (1995). "Apolipoprotein A-IV polymorphism in the Hungarian population: gene frequencies, effect on lipid levels, and sequence of two new variants.". Hum. Mutat.5 (1): 58–65. doi:10.1002/humu.1380050108. PMID7728150.