ASPH explained

Aspartyl/asparaginyl beta-hydroxylase (HAAH) is an enzyme that in humans is encoded by the ASPH gene.^{[1] [2] [3]} ASPH is an alpha-ketoglutarate-dependent hydroxylase, a superfamily non-haem iron-containing proteins.

Function

This gene is thought to play an important role in calcium homeostasis. Alternative splicing of this gene results in five transcript variants which vary in protein translation, the coding of catalytic domains, and tissue expression. Variation among these transcripts impacts their functions which involve roles in the calcium storage and release process in the endoplasmic and sarcoplasmic reticulum as well as hydroxylation of aspartic acid and asparagine in epidermal growth factor-like domains of various proteins.

Clinical significance

As early as 1996, the over-expression of HAAH was recognized as an indicator of carcinoma in humans. Further research has correlated elevated HAAH levels (variously in affected tissue or blood serum) with hepatocellular (liver) carcinoma^{[4] [5]} adenocarcinoma (pancreatic cancer),^[6] colorectal cancer,^[7] prostate cancer. and lung cancer.^[8] The pancreatic study showed elevated HAAH only in diseased tissue, but not in adjacent normal and inflamed tissue.

Mutations in ASPH cause Traboulsi syndrome.^[9]

Further reading

• Hirota K, Semenza GL . Regulation of hypoxia-inducible factor 1 by prolyl and asparaginyl hydroxylases . Biochemical and Biophysical Research Communications . 338 . 1 . 610–6 . December 2005 . 16154531 . 10.1016/j.bbrc.2005.08.193 . free .
• Lavaissiere L, Jia S, Nishiyama M, de la Monte S, Stern AM, Wands JR, Friedman PA . Overexpression of human aspartyl(asparaginyl)beta-hydroxylase in hepatocellular carcinoma and cholangiocarcinoma . The Journal of Clinical Investigation . 98 . 6 . 1313–23 . September 1996 . 8823296 . 507557 . 10.1172/JCI118918 .
• Zhang L, Kelley J, Schmeisser G, Kobayashi YM, Jones LR . Complex formation between junctin, triadin, calsequestrin, and the ryanodine receptor. Proteins of the cardiac junctional sarcoplasmic reticulum membrane . The Journal of Biological Chemistry . 272 . 37 . 23389–97 . September 1997 . 9287354 . 10.1074/jbc.272.37.23389 . free .
• Wetzel GT, Ding S, Chen F . Molecular cloning of junctin from human and developing rabbit heart . Molecular Genetics and Metabolism . 69 . 3 . 252–8 . March 2000 . 10767180 . 10.1006/mgme.2000.2966 .
• Dinchuk JE, Henderson NL, Burn TC, Huber R, Ho SP, Link J, O'Neil KT, Focht RJ, Scully MS, Hollis JM, Hollis GF, Friedman PA . 6 . Aspartyl beta -hydroxylase (Asph) and an evolutionarily conserved isoform of Asph missing the catalytic domain share exons with junctin . The Journal of Biological Chemistry . 275 . 50 . 39543–54 . December 2000 . 10956665 . 10.1074/jbc.M006753200 . free .
• Treves S, Feriotto G, Moccagatta L, Gambari R, Zorzato F . Molecular cloning, expression, functional characterization, chromosomal localization, and gene structure of junctate, a novel integral calcium binding protein of sarco(endo)plasmic reticulum membrane . The Journal of Biological Chemistry . 275 . 50 . 39555–68 . December 2000 . 11007777 . 10.1074/jbc.M005473200 . free .
• Kirchhefer U, Neumann J, Baba HA, Begrow F, Kobayashi YM, Reinke U, Schmitz W, Jones LR . 6 . Cardiac hypertrophy and impaired relaxation in transgenic mice overexpressing triadin 1 . The Journal of Biological Chemistry . 276 . 6 . 4142–9 . February 2001 . 11069905 . 10.1074/jbc.M006443200 . free .
• Sepe PS, Lahousse SA, Gemelli B, Chang H, Maeda T, Wands JR, de la Monte SM . Role of the aspartyl-asparaginyl-beta-hydroxylase gene in neuroblastoma cell motility . Laboratory Investigation; A Journal of Technical Methods and Pathology . 82 . 7 . 881–91 . July 2002 . 12118090 . 10.1097/01.lab.0000020406.91689.7f . free .
• Ho SP, Scully MS, Krauthauser CM, Wexler EJ, Stow MD, Dinchuk JE, Kerr JS, Friedman PA . 6 . Antisense oligonucleotides selectively regulate aspartyl beta-hydroxylase and its truncated protein isoform in vitro but distribute poorly into A549 tumors in vivo . The Journal of Pharmacology and Experimental Therapeutics . 302 . 2 . 795–803 . August 2002 . 12130746 . 10.1124/jpet.302.2.795 . 7167890 .
• Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, Wagner L, Shenmen CM, Schuler GD, Altschul SF, Zeeberg B, Buetow KH, Schaefer CF, Bhat NK, Hopkins RF, Jordan H, Moore T, Max SI, Wang J, Hsieh F, Diatchenko L, Marusina K, Farmer AA, Rubin GM, Hong L, Stapleton M, Soares MB, Bonaldo MF, Casavant TL, Scheetz TE, Brownstein MJ, Usdin TB, Toshiyuki S, Carninci P, Prange C, Raha SS, Loquellano NA, Peters GJ, Abramson RD, Mullahy SJ, Bosak SA, McEwan PJ, McKernan KJ, Malek JA, Gunaratne PH, Richards S, Worley KC, Hale S, Garcia AM, Gay LJ, Hulyk SW, Villalon DK, Muzny DM, Sodergren EJ, Lu X, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madan A, Young AC, Shevchenko Y, Bouffard GG, Blakesley RW, Touchman JW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Krzywinski MI, Skalska U, Smailus DE, Schnerch A, Schein JE, Jones SJ, Marra MA . 6 . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences . Proceedings of the National Academy of Sciences of the United States of America . 99 . 26 . 16899–903 . December 2002 . 12477932 . 139241 . 10.1073/pnas.242603899 . 2002PNAS...9916899M . free .
• Maeda T, Sepe P, Lahousse S, Tamaki S, Enjoji M, Wands JR, de la Monte SM . Antisense oligodeoxynucleotides directed against aspartyl (asparaginyl) beta-hydroxylase suppress migration of cholangiocarcinoma cells . Journal of Hepatology . 38 . 5 . 615–22 . May 2003 . 12713872 . 10.1016/S0168-8278(03)00052-7 .
• Treves S, Franzini-Armstrong C, Moccagatta L, Arnoult C, Grasso C, Schrum A, Ducreux S, Zhu MX, Mikoshiba K, Girard T, Smida-Rezgui S, Ronjat M, Zorzato F . 6 . Junctate is a key element in calcium entry induced by activation of InsP3 receptors and/or calcium store depletion . The Journal of Cell Biology . 166 . 4 . 537–48 . August 2004 . 15302852 . 1868564 . 10.1083/jcb.200404079 .
• Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP . 6 . Large-scale characterization of HeLa cell nuclear phosphoproteins . Proceedings of the National Academy of Sciences of the United States of America . 101 . 33 . 12130–5 . August 2004 . 15302935 . 514446 . 10.1073/pnas.0404720101 . 2004PNAS..10112130B . free .
• Xian ZH, Zhang SH, Cong WM, Yan HX, Wang K, Wu MC . Expression of aspartyl beta-hydroxylase and its clinicopathological significance in hepatocellular carcinoma . Modern Pathology . 19 . 2 . 280–6 . February 2006 . 16341145 . 10.1038/modpathol.3800530 . free .
• de la Monte SM, Tamaki S, Cantarini MC, Ince N, Wiedmann M, Carter JJ, Lahousse SA, Califano S, Maeda T, Ueno T, D'Errico A, Trevisani F, Wands JR . 6 . Aspartyl-(asparaginyl)-beta-hydroxylase regulates hepatocellular carcinoma invasiveness . Journal of Hepatology . 44 . 5 . 971–83 . May 2006 . 16564107 . 10.1016/j.jhep.2006.01.038 .
• Feldmann G, Nattermann J, Nischalke HD, Gorschlüter M, Kuntzen T, Ahlenstiel G, Gerhardt T, Wolff M, Sauerbruch T, Spengler U, Dumoulin FL . 6 . Detection of human aspartyl (asparaginyl) beta-hydroxylase and homeobox B7 mRNA in brush cytology specimens from patients with bile duct cancer . Endoscopy . 38 . 6 . 604–9 . June 2006 . 16673309 . 10.1055/s-2006-925065 . 33900440 .
• Gundogan F, Elwood G, Greco D, Rubin LP, Pinar H, Carlson RI, Wands JR, de la Monte SM . 6 . Role of aspartyl-(asparaginyl) beta-hydroxylase in placental implantation: Relevance to early pregnancy loss . Human Pathology . 38 . 1 . 50–9 . January 2007 . 16949909 . 10.1016/j.humpath.2006.06.005 .

Notes and References

1. Korioth F, Gieffers C, Frey J . Cloning and characterization of the human gene encoding aspartyl beta-hydroxylase . Gene . 150 . 2 . 395–9 . December 1994 . 7821814 . 10.1016/0378-1119(94)90460-X .
2. Lim KY, Hong CS, Kim DH . cDNA cloning and characterization of human cardiac junctin . Gene . 255 . 1 . 35–42 . September 2000 . 10974562 . 10.1016/S0378-1119(00)00299-7 .
3. Web site: Entrez Gene: ASPH aspartate beta-hydroxylase.
4. Ince N, de la Monte SM, Wands JR . Overexpression of human aspartyl (asparaginyl) beta-hydroxylase is associated with malignant transformation . Cancer Research . 60 . 5 . 1261–6 . March 2000 . 10728685 .
5. Xue T, Xue XP, Huang QS, Wei L, Sun K, Xue T . Monoclonal antibodies against human aspartyl (asparaginyl) beta-hydroxylase developed by DNA immunization . Hybridoma . 28 . 4 . 251–7 . August 2009 . 19663697 . 10.1089/hyb.2009.0017 .
6. Palumbo KS, Wands JR, Safran H, King T, Carlson RI, de la Monte SM . Human aspartyl (asparaginyl) beta-hydroxylase monoclonal antibodies: potential biomarkers for pancreatic carcinoma . Pancreas . 25 . 1 . 39–44 . July 2002 . 12131769 . 10.1097/00006676-200207000-00010 . 2098747 .
7. Web site: CC Detect - Serum-Based Diagnostic Test For Colon Cancer Available . 2011-11-29 . 2021-02-08 . https://web.archive.org/web/20210208135602/https://www.emaxhealth.com/100/18177.html . dead .
8. Hampton T . New screening techniques show potential for early detection of lung cancer . JAMA . 298 . 17 . 1997 . November 2007 . 17986689 . 10.1001/jama.298.17.1997 .
9. Patel N, Khan AO, Mansour A, Mohamed JY, Al-Assiri A, Haddad R, Jia X, Xiong Y, Mégarbané A, Traboulsi EI, Alkuraya FS . 6 . Mutations in ASPH cause facial dysmorphism, lens dislocation, anterior-segment abnormalities, and spontaneous filtering blebs, or Traboulsi syndrome . American Journal of Human Genetics . 94 . 5 . 755–9 . May 2014 . 24768550 . 4067561 . 10.1016/j.ajhg.2014.04.002 .