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ALAS2 gene
URL of this page: https://medlineplus.gov/genetics/gene/alas2/

ALAS2 gene

5'-aminolevulinate synthase 2

Normal Function

The ALAS2 gene provides instructions for making an enzyme called 5'-aminolevulinate synthase 2 or erythroid ALA-synthase. This version of the enzyme is found only in developing red blood cells called erythroblasts.

ALA-synthase plays an important role in the production of heme. Heme is a component of iron-containing proteins called hemoproteins, including hemoglobin (the protein that carries oxygen in the blood). Heme is vital for all of the body's organs, although it is most abundant in the blood, bone marrow, and liver.

The production of heme is a multi-step process that requires eight different enzymes. ALA-synthase is responsible for the first step in this process, the formation of a compound called delta-aminolevulinic acid (ALA). In subsequent steps, seven other enzymes produce and modify compounds that ultimately lead to heme.

Health Conditions Related to Genetic Changes

Porphyria

At least two ALAS2 gene mutations have been found in people with a form of porphyria known as X-linked dominant erythropoietic protoporphyria. Each of these mutations deletes a small amount of genetic material near the end of the ALAS2 gene. These changes overactivate erythroid ALA-synthase, which increases the production of ALA within red blood cells. The excess ALA is converted by other enzymes to compounds called porphyrins. If these compounds build up in erythroblasts, they can leak out and be transported through the bloodstream to the skin and other tissues. High levels of porphyrins in the skin cause the oversensitivity to sunlight that is characteristic of this condition.

More About This Health Condition

X-linked sideroblastic anemia

At least 50 mutations that cause X-linked sideroblastic anemia have been identified in the ALAS2 gene. Almost all of these mutations change single protein building blocks (amino acids) in erythroid ALA-synthase. These changes impair the activity of the enzyme, which disrupts the normal production of heme in developing red blood cells. A reduction in the amount of heme prevents these cells from making enough hemoglobin. Because almost all of the iron transported into erythroblasts is normally incorporated into heme, the reduced production of heme leads to a buildup of excess iron in these cells. Additionally, the body attempts to compensate for the hemoglobin shortage by absorbing more iron from the diet. This buildup of excess iron can damage the body's organs. Low hemoglobin levels and the resulting accumulation of iron in the body's organs lead to the characteristic features of X-linked sideroblastic anemia.

More About This Health Condition

Other Names for This Gene

  • 5-aminolevulinate synthase, erythroid-specific, mitochondrial
  • ALAS, erythroid
  • ALAS-E
  • aminolevulinate, delta-, synthase 2
  • ANH1
  • ASB
  • HEM0_HUMAN

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Gene and Variant Databases

References

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  • Astner I, Schulze JO, van den Heuvel J, Jahn D, Schubert WD, Heinz DW. Crystal structure of 5-aminolevulinate synthase, the first enzyme of heme biosynthesis, and its link to XLSA in humans. EMBO J. 2005 Sep 21;24(18):3166-77. doi: 10.1038/sj.emboj.7600792. Epub 2005 Aug 25. Citation on PubMed or Free article on PubMed Central
  • Bekri S, May A, Cotter PD, Al-Sabah AI, Guo X, Masters GS, Bishop DF. A promoter mutation in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene causes X-linked sideroblastic anemia. Blood. 2003 Jul 15;102(2):698-704. doi: 10.1182/blood-2002-06-1623. Epub 2003 Mar 27. Citation on PubMed
  • Bottomley SS. Congenital sideroblastic anemias. Curr Hematol Rep. 2006 Mar;5(1):41-9. Citation on PubMed
  • Cox TC, Sadlon TJ, Schwarz QP, Matthews CS, Wise PD, Cox LL, Bottomley SS, May BK. The major splice variant of human 5-aminolevulinate synthase-2 contributes significantly to erythroid heme biosynthesis. Int J Biochem Cell Biol. 2004 Feb;36(2):281-95. doi: 10.1016/s1357-2725(03)00246-2. Citation on PubMed
  • Furuyama K, Harigae H, Heller T, Hamel BC, Minder EI, Shimizu T, Kuribara T, Blijlevens N, Shibahara S, Sassa S. Arg452 substitution of the erythroid-specific 5-aminolaevulinate synthase, a hot spot mutation in X-linked sideroblastic anaemia, does not itself affect enzyme activity. Eur J Haematol. 2006 Jan;76(1):33-41. doi: 10.1111/j.1600-0609.2005.00541.x. Citation on PubMed
  • May A, Bishop DF. The molecular biology and pyridoxine responsiveness of X-linked sideroblastic anaemia. Haematologica. 1998 Jan;83(1):56-70. Citation on PubMed
  • Nakajima O, Okano S, Harada H, Kusaka T, Gao X, Hosoya T, Suzuki N, Takahashi S, Yamamoto M. Transgenic rescue of erythroid 5-aminolevulinate synthase-deficient mice results in the formation of ring sideroblasts and siderocytes. Genes Cells. 2006 Jun;11(6):685-700. doi: 10.1111/j.1365-2443.2006.00973.x. Citation on PubMed
  • Nemeth E. Iron regulation and erythropoiesis. Curr Opin Hematol. 2008 May;15(3):169-75. doi: 10.1097/MOH.0b013e3282f73335. Citation on PubMed
  • Sadlon TJ, Dell'Oso T, Surinya KH, May BK. Regulation of erythroid 5-aminolevulinate synthase expression during erythropoiesis. Int J Biochem Cell Biol. 1999 Oct;31(10):1153-67. doi: 10.1016/s1357-2725(99)00073-4. Citation on PubMed
  • Shoolingin-Jordan PM, Al-Daihan S, Alexeev D, Baxter RL, Bottomley SS, Kahari ID, Roy I, Sarwar M, Sawyer L, Wang SF. 5-Aminolevulinic acid synthase: mechanism, mutations and medicine. Biochim Biophys Acta. 2003 Apr 11;1647(1-2):361-6. doi: 10.1016/s1570-9639(03)00095-5. Citation on PubMed
  • Whatley SD, Ducamp S, Gouya L, Grandchamp B, Beaumont C, Badminton MN, Elder GH, Holme SA, Anstey AV, Parker M, Corrigall AV, Meissner PN, Hift RJ, Marsden JT, Ma Y, Mieli-Vergani G, Deybach JC, Puy H. C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload. Am J Hum Genet. 2008 Sep;83(3):408-14. doi: 10.1016/j.ajhg.2008.08.003. Epub 2008 Sep 4. Citation on PubMed or Free article on PubMed Central

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