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HLCS gene

holocarboxylase synthetase
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Normal Function

The HLCS gene provides instructions for making an enzyme called holocarboxylase synthetase. This enzyme is important for the effective use of biotin, a B vitamin found in foods such as liver, egg yolks, and milk. In many of the body's tissues, holocarboxylase synthetase turns on (activates) enzymes called biotin-dependent carboxylases by attaching biotin to them. These carboxylases are involved in many critical cellular functions, including the production and breakdown of proteins, fats, and carbohydrates.

Holocarboxylase synthetase plays a role in regulating the activity (transcription) of genes. Transcription is the first step in the process of producing proteins. Specifically, the enzyme regulates genes that play a role in the transport and use of biotin in cells. Biotin is needed for the normal function of many tissues, including the brain, muscles, liver, and kidneys.

Health Conditions Related to Genetic Changes

Holocarboxylase synthetase deficiency

About 50 mutations in the HLCS gene have been identified in people with holocarboxylase synthetase deficiency, which is characterized by the body's inability to use biotin effectively. Affected infants often have difficulty feeding, breathing problems, a skin rash, hair loss (alopecia), and a lack of energy (lethargy). If left untreated, the disorder can lead to delayed development, seizures, and coma. These medical problems may be life-threatening in some cases.

Most of the HLCS gene mutations change a single protein building block (amino acid) in the holocarboxylase synthetase enzyme. Many of the known mutations occur in a region of the enzyme that binds to biotin. These genetic changes reduce the enzyme's ability to attach biotin to carboxylases. Without biotin, carboxylases remain inactive and are unable to process proteins, fats, and carbohydrates effectively. A lack of holocarboxylase synthetase activity may also alter the regulation of certain genes that are needed to transport and use biotin in cells. Researchers believe that these defects in enzyme function underlie the signs and symptoms of holocarboxylase synthetase deficiency.

More About This Health Condition

Other Names for This Gene

  • biotin apo-protein ligase
  • biotin-protein ligase
  • BPL1_HUMAN
  • HCS
  • holocarboxylase synthetase (biotin-(proprionyl-CoA-carboxylase (ATP-hydrolysing)) ligase)
  • holocarboxylase synthetase (biotin-(proprionyl-Coenzyme A-carboxylase (ATP-hydrolysing)) ligase)

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Research Resources

References

  • Baumgartner MR. Vitamin-responsive disorders: cobalamin, folate, biotin, vitamins B1 and E. Handb Clin Neurol. 2013;113:1799-810. doi: 10.1016/B978-0-444-59565-2.00049-6. Review. Citation on PubMed
  • Dupuis L, Campeau E, Leclerc D, Gravel RA. Mechanism of biotin responsiveness in biotin-responsive multiple carboxylase deficiency. Mol Genet Metab. 1999 Feb;66(2):80-90. Citation on PubMed
  • Healy S, Perez-Cadahia B, Jia D, McDonald MK, Davie JR, Gravel RA. Biotin is not a natural histone modification. Biochim Biophys Acta. 2009 Nov-Dec;1789(11-12):719-33. doi: 10.1016/j.bbagrm.2009.09.003. Epub 2009 Sep 18. Citation on PubMed
  • León-Del-Río A, Valadez-Graham V, Gravel RA. Holocarboxylase Synthetase: A Moonlighting Transcriptional Coregulator of Gene Expression and a Cytosolic Regulator of Biotin Utilization. Annu Rev Nutr. 2017 Aug 21;37:207-223. doi: 10.1146/annurev-nutr-042617-104653. Epub 2017 May 31. Review. Citation on PubMed
  • Morrone A, Malvagia S, Donati MA, Funghini S, Ciani F, Pela I, Boneh A, Peters H, Pasquini E, Zammarchi E. Clinical findings and biochemical and molecular analysis of four patients with holocarboxylase synthetase deficiency. Am J Med Genet. 2002 Jul 22;111(1):10-8. Citation on PubMed
  • Pacheco-Alvarez D, Solórzano-Vargas RS, Gravel RA, Cervantes-Roldán R, Velázquez A, León-Del-Río A. Paradoxical regulation of biotin utilization in brain and liver and implications for inherited multiple carboxylase deficiency. J Biol Chem. 2004 Dec 10;279(50):52312-8. Epub 2004 Sep 28. Citation on PubMed
  • Streaker ED, Beckett D. Nonenzymatic biotinylation of a biotin carboxyl carrier protein: unusual reactivity of the physiological target lysine. Protein Sci. 2006 Aug;15(8):1928-35. Epub 2006 Jul 5. Citation on PubMed or Free article on PubMed Central
  • Suzuki Y, Yang X, Aoki Y, Kure S, Matsubara Y. Mutations in the holocarboxylase synthetase gene HLCS. Hum Mutat. 2005 Oct;26(4):285-90. Review. Citation on PubMed
  • Tang NL, Hui J, Yong CK, Wong LT, Applegarth DA, Vallance HD, Law LK, Fung SL, Mak TW, Sung YM, Cheung KL, Fok TF. A genomic approach to mutation analysis of holocarboxylase synthetase gene in three Chinese patients with late-onset holocarboxylase synthetase deficiency. Clin Biochem. 2003 Mar;36(2):145-9. Citation on PubMed
  • Yang X, Aoki Y, Li X, Sakamoto O, Hiratsuka M, Kure S, Taheri S, Christensen E, Inui K, Kubota M, Ohira M, Ohki M, Kudoh J, Kawasaki K, Shibuya K, Shintani A, Asakawa S, Minoshima S, Shimizu N, Narisawa K, Matsubara Y, Suzuki Y. Structure of human holocarboxylase synthetase gene and mutation spectrum of holocarboxylase synthetase deficiency. Hum Genet. 2001 Nov;109(5):526-34. Epub 2001 Oct 5. Citation on PubMed
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