Apolipoprotein L1

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Apolipoprotein L, 1
Identifiers
Symbols APOL1 ; APO-L; APOL; APOL-I; FSGS4
External IDs OMIM603743 GeneCards: APOL1 Gene
RNA expression pattern
PBB GE APOL1 209546 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 8542 n/a
Ensembl ENSG00000100342 n/a
UniProt O14791 n/a
RefSeq (mRNA) NM_001136540 n/a
RefSeq (protein) NP_001130012 n/a
Location (UCSC) Chr 22:
36.65 – 36.66 Mb
n/a
PubMed search [1] n/a

Apolipoprotein L1 is a protein that in humans is encoded by the APOL1 gene.[1][2][3][4] Two transcript variants encoding two different isoforms have been found for this gene.[4]

Species distribution[edit]

This gene is only found in humans, African green monkeys, and gorillas.[5][6]

Structure[edit]

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.[2][7]

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[edit]

Two transcript variants, G1 and G2, have been recently identified. G1 is caused by two non-synonymous single nucleotide polymorphisms (SNPs). G2 is caused by an in-frame deletion of the two amino acid residues, N388 and Y389.

Function[edit]

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,[5] podocytes, proximal tubules, and arterial cells.[8] The protein has a secreted form that allows it to circulate in the blood. It forms a complex with high-density lipoprotein 3 (HDL3) particles that also contain apolipoprotein A1 (APOA1) and the hemoglobin-binding, haptoglobin-related protein (HPR). It 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.[9]

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.[9]

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.[3][10]

Clinical significance[edit]

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.[11] 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.

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,[12] consistent with the reported protection from forms of kidney disease known to be associated with the APOL1 variants.[13] In the Yoruba people of Nigeria (West Africa) the prevalence of G1 and G2 risk alleles are 40% and 8% respectively.[11][14] 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%.[11] 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, 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.[15][16] Studies have also determined the prevalence of each individual allele in FSGS cases as well. 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.[11][16] 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.[17]

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.[18] 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.[16]

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.[17][19] 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.[17][19] 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.[17]

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.[16]

Kidneys from donors containing two APOL1 variants experience allograft failure more rapidly than donors with 0 or 1 variants.[20] 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.[21] These observations together suggest that the genotype of the donor only affects allograft survival.

References[edit]

  1. ^ Duchateau PN, Pullinger CR, Orellana RE, Kunitake ST, Naya-Vigne J, O'Connor PM, Malloy MJ, Kane JP (Nov 1997). "Apolipoprotein L, a new human high density lipoprotein apolipoprotein expressed by the pancreas. Identification, cloning, characterization, and plasma distribution of apolipoprotein L". J Biol Chem 272 (41): 25576–82. doi:10.1074/jbc.272.41.25576. PMID 9325276. 
  2. ^ a b 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. 
  3. ^ a b 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 (Jul 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. 
  4. ^ a b "Entrez Gene: APOL1 apolipoprotein L, 1". 
  5. ^ a b Monajemi H, Fontijn RD, Pannekoek H, Horrevoets AJ (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. 
  6. ^ Poelvoorde P, Vanhamme L, Van Den Abbeele J, Switzer WM, Pays E (2004). "Distribution of apolipoprotein L-I and trypanosome lytic activity among primate sera". Mol. Biochem. Parasitol. 134 (1): 155–7. doi:10.1016/j.molbiopara.2003.11.006. PMID 14747153. 
  7. ^ Duchateau PN, Pullinger CR, Cho MH, Eng C, Kane JP (2001). "Apolipoprotein L gene family: tissue-specific expression, splicing, promoter regions; discovery of a new gene.". J Lipid Res 42 (4): 620–30. PMID 11290834. 
  8. ^ Madhavan SM, O'Toole JF, Konieczkowski M, Ganesan S, Bruggeman LA, Sedor JR (2011). "APOL1 localization in normal kidney and nondiabetic kidney disease.". J Am Soc Nephrol 22 (11): 2119–28. doi:10.1681/ASN.2011010069. PMC 3231786. PMID 21997392. 
  9. ^ a b Wan G, Zhaorigetu S, Liu Z, Kaini R, Jiang Z, Hu CA (2008). "Apolipoprotein L1, a novel Bcl-2 homology domain 3-only lipid-binding protein, induces autophagic cell death". J. Biol. Chem. 283 (31): 21540–9. doi:10.1074/jbc.M800214200. PMC 2490785. PMID 18505729. 
  10. ^ Vanhamme L, Paturiaux-Hanocq F, Poelvoorde P, Nolan DP, Lins L, Van Den Abbeele J et al. (2003). "Apolipoprotein L-I is the trypanosome lytic factor of human serum.". Nature 422 (6927): 83–7. doi:10.1038/nature01461. PMID 12621437. 
  11. ^ a b c d 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 (Jul 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. 
  12. ^ Tzur S, Rosset S, Shemer R, Yudkovsky G, Selig S, Tarekegn A, Bekele E, Bradman N, Wasser WG, Behar DM, Skorecki K (Jul 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. 
  13. ^ Behar DM, Shlush LI, Maor C, Lorber M, Skorecki K (2006). "Absence of HIV-associated nephropathy in Ethiopians". Am J Kidney Dis. 47 (1): 88–94. doi:10.1053/j.ajkd.2005.09.023. PMID 16377389. 
  14. ^ Rosset S, Tzur S, Behar DM, Wasser WG, Skorecki K (2011). "The population genetics of chronic kidney disease: insights from the MYH9-APOL1 locus". Nat Rev Nephrol 7 (6): 313–26. doi:10.1038/nrneph.2011.52. PMID 21537348. 
  15. ^ 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 (2011). "Differential effects of MYH9 and APOL1 risk variants on FRMD3 Association with Diabetic ESRD in African Americans". PLoS Genet. 7 (6): e1002150. doi:10.1371/journal.pgen.1002150. PMC 3116917. PMID 21698141. 
  16. ^ a b c d 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 (2011). "APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy". J. Am. Soc. Nephrol. 22 (11): 2129–37. doi:10.1681/ASN.2011040388. PMC 3231787. PMID 21997394. 
  17. ^ a b c d Tzur S, Rosset S, Skorecki K, Wasser WG (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". Nephrol. Dial. Transplant. 27 (4): 1498–505. doi:10.1093/ndt/gfr796. PMID 22357707. 
  18. ^ 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 (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 Int. 82 (7): 805–11. doi:10.1038/ki.2012.217. PMC 3443536. PMID 22695330. 
  19. ^ a b 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 (2011). "Genetic variation in APOL1 associates with younger age at hemodialysis initiation". J. Am. Soc. Nephrol. 22 (11): 2091–7. doi:10.1681/ASN.2010121234. PMC 3231784. PMID 21997398. 
  20. ^ 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 (2011). "The APOL1 gene and allograft survival after kidney transplantation". Am. J. Transplant. 11 (5): 1025–30. doi:10.1111/j.1600-6143.2011.03513.x. PMC 3083491. PMID 21486385. 
  21. ^ 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 (2012). "The APOL1 genotype of African American kidney transplant recipients does not impact 5-year allograft survival". Am. J. Transplant. 12 (7): 1924–8. doi:10.1111/j.1600-6143.2012.04033.x. PMC 3387301. PMID 22487534. 

Further reading[edit]