Apolipoprotein L1

Apolipoprotein L1 is a protein that in humans is encoded by the APOL1 gene.[3][4][5][6] Two transcript variants encoding two different isoforms have been found for this gene.[6]

APOL1
Identifiers
Aliases	APOL1, APO-L, APOL, APOL-I, FSGS4, apolipoprotein L1
External IDs	OMIM: 607254, 603743 GeneCards: APOL1
Gene location (Human) Chr. Chromosome 22 (human)[1] Band 22q12.3 Start 36,253,010 bp[1] End 36,267,530 bp[1]
RNA expression pattern More reference expression data
Gene ontology Molecular function • GO:0001948 protein binding • chloride channel activity • lipid binding Cellular component • extracellular region • intrinsic component of membrane • blood microparticle • very-low-density lipoprotein particle • high-density lipoprotein particle • extracellular • endoplasmic reticulum lumen Biological process • lipoprotein metabolic process • steroid metabolic process • lipid transport • innate immune system • cholesterol metabolic process • cytolysis • receptor-mediated endocytosis • killing of cells of other organism • lipid metabolism • post-translational modification • cellular protein metabolic process • chloride transmembrane transport • transport Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	8542	n/a
Ensembl	ENSG00000100342	n/a
UniProt	O14791	n/a
RefSeq (mRNA)	NM_001136540 NM_001136541 NM_003661 NM_145343 NM_145344 NM_001362927	n/a
RefSeq (protein)	NP_001130012 NP_001130013 NP_003652 NP_663318 NP_001349856	n/a
Location (UCSC)	Chr 22: 36.25 – 36.27 Mb	n/a
PubMed search	[2]	n/a
Wikidata
View/Edit Human

Species distribution

This gene is found only in humans, African green monkeys, and gorillas.[7][8]

Structure

The gene that encodes the APOL1 protein is 14,522 base pairs long and found on the human chromosome 22, on the long arm at position 13.1 from base pair 36,253,070 to base pair 36,267,530.[4][9]

The protein is a 398 amino acid protein. It consists of 5 functional domains:

• S domain-secretory signal
• MAD (membrane-addressing domain)-ph sensor and regulator of cell death
• BH3 domain - associated with programmed cell death
• PFD (pore forming domain)
• SRA (serum resistance-associated binding domain)- confers resistance to Trypanosoma brucei

Mutations

Two coding variants, G1 and G2, have been recently identified with relevance to human phenotypes. The G1 is a pair of two non-synonymous single nucleotide polymorphisms (SNPs) in almost complete linkage disequilibrium. G2 is an in-frame deletion of the two amino acid residues, N388 and Y389.[10]

Function

Apolipoprotein L1 (apoL1) is a minor apoprotein component of HDL (High-density lipoprotein) or 'good cholesterol' which is synthesized in the liver and also in many other tissues, including pancreas, kidney, and brain. APOL1 is found in vascular endothelium, liver, heart, lung, placenta,[7] podocytes, proximal tubules, and arterial cells.[11] The protein has a secreted form that allows it to circulate in the blood. It forms a complex, known as a trypanosome lytic factor (TLF),[12] with high-density lipoprotein 3 (HDL3) particles that also contain apolipoprotein A1 (APOA1) and the hemoglobin-binding, haptoglobin-related protein (HPR). The APOL1 protein acts as the main lytic component in this complex.[12] Once uptaken by the trypanosome, the complex is trafficked to acidic endosomes, where the APOL1 protein may insert into the endosomal membrane. If the endosome is then recycled to the plasma membrane, where it encounters neutral pH conditions, APOL1 may form cation-selective channels.[13]

APOL1 is a member of a family of apolipoproteins which consists of 6 other proteins and it is a member of bcl2 genes which are involved in autophagic cell death. In fact an overabundance of APOL1 within a cell results in autophagy.[14]

APOL1 may play a role in the inflammatory response. Pro-inflammatory cytokines interferon-γ(IFN), tumor necrosis factor-α (TNF-α) and p53 can increase the expression of APOL1.[14]

APOL1 has a role in innate immunity by protecting against Trypanosoma brucei infection, which is a parasite transmitted by the tsetse fly. Trypanosomes endocytose the secreted form of APOL1; APOL1 forms pores on the lysosomal membranes of the trypanosomes which causes in influx of chloride, swelling of the lysosome and lysis of the trypanosome.[5][15]

Clinical significance

African trypanosomiasis (sleeping sickness)

Although its intracellular function has not been elucidated, apoL1 circulating in plasma has the ability to kill the trypanosome Trypanosoma brucei that causes sleeping sickness. Recently, two coding sequence variants in APOL1 have been shown to associate with kidney disease in a recessive fashion while at the same time conferring resistance against Trypanosoma brucei rhodesiense.[16] This resistance is due, in part, to decreased binding of the G1 and G2 APOL1 variants to the T. b. rhodesiense virulence factor, serum resistance-associated protein (SRA) as a result of the C-terminal polymorphisms.[17] People who have at least one copy of either the G1 or G2 variant are resistant to infection by trypanosomes, but people who have two copies of either variant are at an increased risk of developing a non-diabetic kidney disease.

Kidney disease

The distribution of the variants most associated with kidney disease risk was analyzed in African populations and found to be more prevalent in western compared to northeastern African populations and absent in Ethiopia,[18] consistent with the reported protection from forms of kidney disease known to be associated with the APOL1 variants.[19] In the Yoruba people of Nigeria (West Africa), the prevalence of G1 and G2 risk alleles are 40% and 8% respectively.[16][20] African nations with high frequencies of APOL1 risk alleles also have large populations of Trypanosomes suggesting that the risk alleles underwent positive selection as a defense mechanism. The existence of these variants are only found on African chromosomes and exist in people with recent African ancestry (<10,000 years).

Many African Americans are descendants of people of West African nations and consequently, also have a high prevalence of APOL1 risk alleles as well as APOL1 associated kidney diseases. The frequency of the risk alleles in African Americans is more than 30%.[16] The existence of these alleles has been shown to increase the risk of developing diseases such as Focal Segmental Glomerulosclerosis(FSGS), Hypertension Attributed-End Stage Kidney Disease (ESKD), and HIV-Associated Nephropathy(HIVAN).

The prevalence of the risk alleles in African Americans with these kidney diseases shown in recent studies are 67% in HIVAN, 66% in FSGS, and 47% in hypertension-attributed ESKD.[21][22] Hispanic populations such as Dominicans and Puerto Ricans demonstrate a mixture of genetic influences that include African ancestry resulting in a prevalence of the APOL1 variants as well.[23] Studies have also determined the prevalence of each individual allele in FSGS cases as well.

Focal segmental glomerulosclerosis (FSGS)

The prevalence of the G1 risk allele in African Americans with FSGS is 52% and 18-23% in those without FSGS. The prevalence of the G2 risk allele in African Americans with FSGS is 23% and 15% in those without FSGS.[16][22] FSGS is a kidney disease that affects younger individuals therefore, its effects are slightly different from the effects of general non-diabetic ESKD. In a recent study, the mean ages of onset of FSGS for African Americans with 2, 1, and 0 APOL1 risk alleles was 32yrs, 36yrs and 39yrs, respectively. APOL1 variants also have a tendency to manifest FSGS at relatively young ages; FSGS begins between the ages of 15 to 39 in 70% of individuals with two APOL1 risk alleles and 42% of individuals with of 0 or 1 risk alleles.[22]

Pathogenesis

Although possession of the APOL1 risk variants increases susceptibility to non-diabetic kidney disease, not all people who possess these variants develop kidney disease, which indicates another factor may initiate progression of kidney disease.[24] Similarly in HIV positive patients, although the majority of African-American patients with HIVAN have two APOL1 risk alleles other as yet unknown factors in the host, including genetic risk variants and environmental or viral factors, may influence the development of this disorder in those with zero or one APOL1 risk allele. Kidney Int. 2012 Aug;82(3):338-43. The African American population has a total lifetime risk of developing FSGS of 0.8%. For those with 0 risk alleles the risk of developing FSGS is 0.2%, 0.3% with 1 risk allele, 4.25% with 2 risk alleles and a 50% chance of developing HIVAN for untreated HIV infected individuals.[22]

People with these allelic variants who develop ESKD begin dialysis at an earlier age than ESKD patients without the risk alleles. On average, those with two risk alleles begin dialysis approximately 10 years earlier than ESKD patients without the risk variants.[23][25] The mean ages of initiation of dialysis of African American ESKD patients with two risk alleles, one risk allele, or no risk alleles are approximately 48yrs, 53yrs, and 58 yrs, respectively.[23][25] Compared to African American ESKD patients, Hispanic ESKD patients with two APOL1 risk variants start dialysis at an earlier age, 41 yrs.

Although, the age of initiation of dialysis is earlier with one risk allele this effect is only seen in those with the G1 variant. In a study, ~96% of patients with two risk alleles started dialysis before the age of 75 compared to 94% for G1 heterozygotes, and 84% for those with no risk alleles.[23]

Kidneys from donors containing two APOL1 variants experience allograft failure more rapidly than donors with 0 or 1 variants.[26] Kidney recipients who have copies of the APOL1 risk variants, but do not receive kidneys from donors with the risk variants do not have decreased survival rates of the donated kidneys.[27] These observations together suggest that the genotype of the donor only affects allograft survival.

References

1. GRCh38: Ensembl release 89: ENSG00000100342 - Ensembl, May 2017
2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
3. Duchateau PN, Pullinger CR, Orellana RE, Kunitake ST, Naya-Vigne J, O'Connor PM, Malloy MJ, Kane JP (October 1997). "Apolipoprotein L, a new human high density lipoprotein apolipoprotein expressed by the pancreas. Identification, cloning, characterization, and plasma distribution of apolipoprotein L". The Journal of Biological Chemistry. 272 (41): 25576–82. doi:10.1074/jbc.272.41.25576. PMID 9325276.
4. Page NM, Butlin DJ, Lomthaisong K, Lowry PJ (May 2001). "The human apolipoprotein L gene cluster: identification, classification, and sites of distribution". Genomics. 74 (1): 71–8. doi:10.1006/geno.2001.6534. PMID 11374903.
5. Pérez-Morga D, Vanhollebeke B, Paturiaux-Hanocq F, Nolan DP, Lins L, Homblé F, Vanhamme L, Tebabi P, Pays A, Poelvoorde P, Jacquet A, Brasseur R, Pays E (July 2005). "Apolipoprotein L-I promotes trypanosome lysis by forming pores in lysosomal membranes". Science. 309 (5733): 469–72. doi:10.1126/science.1114566. PMID 16020735.
6. "Entrez Gene: APOL1 apolipoprotein L, 1".
7. Monajemi H, Fontijn RD, Pannekoek H, Horrevoets AJ (April 2002). "The apolipoprotein L gene cluster has emerged recently in evolution and is expressed in human vascular tissue". Genomics. 79 (4): 539–46. doi:10.1006/geno.2002.6729. PMID 11944986.
8. Poelvoorde P, Vanhamme L, Van Den Abbeele J, Switzer WM, Pays E (March 2004). "Distribution of apolipoprotein L-I and trypanosome lytic activity among primate sera". Molecular and Biochemical Parasitology. 134 (1): 155–7. doi:10.1016/j.molbiopara.2003.11.006. PMID 14747153.
9. Duchateau PN, Pullinger CR, Cho MH, Eng C, Kane JP (April 2001). "Apolipoprotein L gene family: tissue-specific expression, splicing, promoter regions; discovery of a new gene". Journal of Lipid Research. 42 (4): 620–30. PMID 11290834.
10. Citation Needed.
11. Madhavan SM, O'Toole JF, Konieczkowski M, Ganesan S, Bruggeman LA, Sedor JR (November 2011). "APOL1 localization in normal kidney and nondiabetic kidney disease". Journal of the American Society of Nephrology. 22 (11): 2119–28. doi:10.1681/ASN.2011010069. PMC 3231786. PMID 21997392.
12. Raper J, Fung R, Ghiso J, Nussenzweig V, Tomlinson S (April 1999). "Characterization of a novel trypanosome lytic factor from human serum". Infection and Immunity. 67 (4): 1910–6. PMC 96545. PMID 10085035.
13. Thomson R, Finkelstein A (March 2015). "Human trypanolytic factor APOL1 forms pH-gated cation-selective channels in planar lipid bilayers: relevance to trypanosome lysis". Proceedings of the National Academy of Sciences of the United States of America. 112 (9): 2894–9. doi:10.1073/pnas.1421953112. PMC 4352821. PMID 25730870.
14. Wan G, Zhaorigetu S, Liu Z, Kaini R, Jiang Z, Hu CA (August 2008). "Apolipoprotein L1, a novel Bcl-2 homology domain 3-only lipid-binding protein, induces autophagic cell death". The Journal of Biological Chemistry. 283 (31): 21540–9. doi:10.1074/jbc.M800214200. PMC 2490785. PMID 18505729.
15. Vanhamme L, Paturiaux-Hanocq F, Poelvoorde P, Nolan DP, Lins L, Van Den Abbeele J, Pays A, Tebabi P, Van Xong H, Jacquet A, Moguilevsky N, Dieu M, Kane JP, De Baetselier P, Brasseur R, Pays E (March 2003). "Apolipoprotein L-I is the trypanosome lytic factor of human serum". Nature. 422 (6927): 83–7. doi:10.1038/nature01461. PMID 12621437.
16. Genovese G, Friedman DJ, Ross MD, Lecordier L, Uzureau P, Freedman BI, Bowden DW, Langefeld CD, Oleksyk TK, Uscinski Knob AL, Bernhardy AJ, Hicks PJ, Nelson GW, Vanhollebeke B, Winkler CA, Kopp JB, Pays E, Pollak MR (August 2010). "Association of trypanolytic ApoL1 variants with kidney disease in African Americans". Science. 329 (5993): 841–5. doi:10.1126/science.1193032. PMC 2980843. PMID 20647424.
17. Raper, Jayne; Friedman, David J.; Pollak, Martin R.; Alper, Seth L.; Ayodo, George; Doumatey, Ayo; Adeyemo, Adebowale; Rotimi, Charles; Kopp, Jeffrey (2014-05-20). "Evolution of the primate trypanolytic factor APOL1". Proceedings of the National Academy of Sciences. 111 (20): E2130–E2139. doi:10.1073/pnas.1400699111. ISSN 0027-8424. PMC 4034216. PMID 24808134.
18. Tzur S, Rosset S, Shemer R, Yudkovsky G, Selig S, Tarekegn A, Bekele E, Bradman N, Wasser WG, Behar DM, Skorecki K (September 2010). "Missense mutations in the APOL1 gene are highly associated with end stage kidney disease risk previously attributed to the MYH9 gene". Human Genetics. 128 (3): 345–50. doi:10.1007/s00439-010-0861-0. PMC 2921485. PMID 20635188.
19. Behar DM, Shlush LI, Maor C, Lorber M, Skorecki K (January 2006). "Absence of HIV-associated nephropathy in Ethiopians". American Journal of Kidney Diseases. 47 (1): 88–94. doi:10.1053/j.ajkd.2005.09.023. PMID 16377389.
20. Rosset S, Tzur S, Behar DM, Wasser WG, Skorecki K (June 2011). "The population genetics of chronic kidney disease: insights from the MYH9-APOL1 locus". Nature Reviews. Nephrology. 7 (6): 313–26. doi:10.1038/nrneph.2011.52. PMID 21537348.
21. Freedman BI, Langefeld CD, Lu L, Divers J, Comeau ME, Kopp JB, Winkler CA, Nelson GW, Johnson RC, Palmer ND, Hicks PJ, Bostrom MA, Cooke JN, McDonough CW, Bowden DW (June 2011). "Differential effects of MYH9 and APOL1 risk variants on FRMD3 Association with Diabetic ESRD in African Americans". PLoS Genetics. 7 (6): e1002150. doi:10.1371/journal.pgen.1002150. PMC 3116917. PMID 21698141.
22. Kopp JB, Nelson GW, Sampath K, Johnson RC, Genovese G, An P, Friedman D, Briggs W, Dart R, Korbet S, Mokrzycki MH, Kimmel PL, Limou S, Ahuja TS, Berns JS, Fryc J, Simon EE, Smith MC, Trachtman H, Michel DM, Schelling JR, Vlahov D, Pollak M, Winkler CA (November 2011). "APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy". Journal of the American Society of Nephrology. 22 (11): 2129–37. doi:10.1681/ASN.2011040388. PMC 3231787. PMID 21997394.
23. Tzur S, Rosset S, Skorecki K, Wasser WG (April 2012). "APOL1 allelic variants are associated with lower age of dialysis initiation and thereby increased dialysis vintage in African and Hispanic Americans with non-diabetic end-stage kidney disease". Nephrology, Dialysis, Transplantation. 27 (4): 1498–505. doi:10.1093/ndt/gfr796. PMID 22357707.
24. Freedman BI, Langefeld CD, Turner J, Núñez M, High KP, Spainhour M, Hicks PJ, Bowden DW, Reeves-Daniel AM, Murea M, Rocco MV, Divers J (October 2012). "Association of APOL1 variants with mild kidney disease in the first-degree relatives of African American patients with non-diabetic end-stage renal disease". Kidney International. 82 (7): 805–11. doi:10.1038/ki.2012.217. PMC 3443536. PMID 22695330.
25. Kanji Z, Powe CE, Wenger JB, Huang C, Ankers E, Sullivan DA, Collerone G, Powe NR, Tonelli M, Bhan I, Bernhardy AJ, Dibartolo S, Friedman D, Genovese G, Pollak MR, Thadhani R (November 2011). "Genetic variation in APOL1 associates with younger age at hemodialysis initiation". Journal of the American Society of Nephrology. 22 (11): 2091–7. doi:10.1681/ASN.2010121234. PMC 3231784. PMID 21997398.
26. Reeves-Daniel AM, DePalma JA, Bleyer AJ, Rocco MV, Murea M, Adams PL, Langefeld CD, Bowden DW, Hicks PJ, Stratta RJ, Lin JJ, Kiger DF, Gautreaux MD, Divers J, Freedman BI (May 2011). "The APOL1 gene and allograft survival after kidney transplantation". American Journal of Transplantation. 11 (5): 1025–30. doi:10.1111/j.1600-6143.2011.03513.x. PMC 3083491. PMID 21486385.
27. Lee BT, Kumar V, Williams TA, Abdi R, Bernhardy A, Dyer C, Conte S, Genovese G, Ross MD, Friedman DJ, Gaston R, Milford E, Pollak MR, Chandraker A (July 2012). "The APOL1 genotype of African American kidney transplant recipients does not impact 5-year allograft survival". American Journal of Transplantation. 12 (7): 1924–8. doi:10.1111/j.1600-6143.2012.04033.x. PMC 3387301. PMID 22487534.

External links

• Human APOL1 genome location and APOL1 gene details page in the UCSC Genome Browser.

Further reading

• Duchateau PN, Movsesyan I, Yamashita S, Sakai N, Hirano K, Schoenhaus SA, O'Connor-Kearns PM, Spencer SJ, Jaffe RB, Redberg RF, Ishida BY, Matsuzawa Y, Kane JP, Malloy MJ (August 2000). "Plasma apolipoprotein L concentrations correlate with plasma triglycerides and cholesterol levels in normolipidemic, hyperlipidemic, and diabetic subjects". Journal of Lipid Research. 41 (8): 1231–6. PMID 10946010.
• Duchateau PN, Pullinger CR, Cho MH, Eng C, Kane JP (April 2001). "Apolipoprotein L gene family: tissue-specific expression, splicing, promoter regions; discovery of a new gene". Journal of Lipid Research. 42 (4): 620–30. PMID 11290834.
• Monajemi H, Fontijn RD, Pannekoek H, Horrevoets AJ (April 2002). "The apolipoprotein L gene cluster has emerged recently in evolution and is expressed in human vascular tissue". Genomics. 79 (4): 539–46. doi:10.1006/geno.2002.6729. PMID 11944986.
• Vanhamme L, Paturiaux-Hanocq F, Poelvoorde P, Nolan DP, Lins L, Van Den Abbeele J, Pays A, Tebabi P, Van Xong H, Jacquet A, Moguilevsky N, Dieu M, Kane JP, De Baetselier P, Brasseur R, Pays E (March 2003). "Apolipoprotein L-I is the trypanosome lytic factor of human serum". Nature. 422 (6927): 83–7. doi:10.1038/nature01461. PMID 12621437.
• Kang MK, Kameta A, Shin KH, Baluda MA, Kim HR, Park NH (July 2003). "Senescence-associated genes in normal human oral keratinocytes". Experimental Cell Research. 287 (2): 272–81. doi:10.1016/S0014-4827(03)00061-2. PMID 12837283.
• Anderson NL, Polanski M, Pieper R, Gatlin T, Tirumalai RS, Conrads TP, Veenstra TD, Adkins JN, Pounds JG, Fagan R, Lobley A (April 2004). "The human plasma proteome: a nonredundant list developed by combination of four separate sources". Molecular & Cellular Proteomics. 3 (4): 311–26. doi:10.1074/mcp.M300127-MCP200. PMID 14718574.
• Lugli EB, Pouliot M, del Pilar Molina Portela M, Loomis MR, Raper J (November 2004). "Characterization of primate trypanosome lytic factors". Molecular and Biochemical Parasitology. 138 (1): 9–20. doi:10.1016/j.molbiopara.2004.07.004. PMID 15500911.
• Albert TS, Duchateau PN, Deeb SS, Pullinger CR, Cho MH, Heilbron DC, Malloy MJ, Kane JP, Brown BG (March 2005). "Apolipoprotein L-I is positively associated with hyperglycemia and plasma triglycerides in CAD patients with low HDL". Journal of Lipid Research. 46 (3): 469–74. doi:10.1194/jlr.M400304-JLR200. PMID 15604524.
• Liu T, Qian WJ, Gritsenko MA, Camp DG, Monroe ME, Moore RJ, Smith RD (2006). "Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry". Journal of Proteome Research. 4 (6): 2070–80. doi:10.1021/pr0502065. PMC 1850943. PMID 16335952.
• Vanhollebeke B, Nielsen MJ, Watanabe Y, Truc P, Vanhamme L, Nakajima K, Moestrup SK, Pays E (March 2007). "Distinct roles of haptoglobin-related protein and apolipoprotein L-I in trypanolysis by human serum". Proceedings of the National Academy of Sciences of the United States of America. 104 (10): 4118–23. doi:10.1073/pnas.0609902104. PMC 1820718. PMID 17360487.