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HLCS
holocarboxylase synthetase
The HLCS gene provides instructions for producing holocarboxylase synthetase, an enzyme vital for activating biotin-dependent carboxylases involved in key metabolic processes. The HLCS gene is responsible for creating the holocarboxylase synthetase enzyme.
HLCS is located on the long (q) arm of chromosome 21, at band 21q22.13. Arm ratio per GRCh38 - banding schematic.
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Overview
The HLCS gene, also known as holocarboxylase synthetase, is central to the body's metabolic functions. It encodes an enzyme that is necessary for the proper utilisation of biotin, a B vitamin found in various foods such as egg yolks and liver.
Effective biotin use is crucial for numerous cellular processes, including energy production and the synthesis and breakdown of essential molecules. Understanding the HLCS gene is important for conditions where biotin metabolism is impaired.
What the gene does
The holocarboxylase synthetase enzyme, encoded by the HLCS gene, performs a critical function by activating biotin-dependent carboxylases. These carboxylases are enzymes that require biotin to operate effectively.
The activation process involves attaching biotin to these carboxylases, enabling them to participate in vital cellular functions, including the processing of proteins, fats, and carbohydrates. Beyond its role in metabolism, holocarboxylase synthetase also helps regulate gene activity, specifically genes involved in biotin transport and utilisation within cells. Biotin is essential for the normal functioning of many tissues, including the brain, liver, kidneys, and muscles.
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Chromosome location
The HLCS gene is located on chromosome 21 at position 21q22.13. This precise genomic address helps scientists and clinicians pinpoint the gene's position within the human genome and study its relationship to other genes and genetic conditions.
Protein structure
The holocarboxylase synthetase protein is composed of 726 amino acids. Its structure includes a Disordered region spanning amino acids 28-98, and a BPL/LPL catalytic domain found between amino acids 463-652. These domains are crucial for the enzyme's function in binding and utilising biotin.
Key variants
Variants within the HLCS gene can affect the function of the holocarboxylase synthetase enzyme. These genetic changes can lead to impaired biotin metabolism, impacting various bodily systems. More than 50 different variants have been identified in individuals with holocarboxylase synthetase deficiency.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1063_1064del | p.Asp355fs | Pathogenic/Likely pathogenic | ★★☆☆ | Holocarboxylase synthetase deficiency |
c.1133del | p.Gln378fs | Pathogenic/Likely pathogenic | ★★☆☆ | Holocarboxylase synthetase deficiency |
c.1210del | p.Gln403_Val404insTer | Pathogenic/Likely pathogenic | ★★☆☆ | Holocarboxylase synthetase deficiency |
c.1537_1540del | p.Glu513fs | Pathogenic/Likely pathogenic | ★★☆☆ | Holocarboxylase synthetase deficiency |
c.1600_1604del | p.Tyr534fs | Pathogenic/Likely pathogenic | ★★☆☆ | Holocarboxylase synthetase deficiency |
c.1658_1659del | p.His553fs | Pathogenic/Likely pathogenic | ★★☆☆ | Holocarboxylase synthetase deficiency |
c.1769dup | p.Met590fs | Pathogenic/Likely pathogenic | ★★☆☆ | Holocarboxylase synthetase deficiency |
c.2224del | p.Tyr742fs | Pathogenic/Likely pathogenic | ★★☆☆ | Holocarboxylase synthetase deficiency |
c.2369_2373del | p.Val790fs | Pathogenic/Likely pathogenic | ★★☆☆ | Holocarboxylase synthetase deficiency |
c.513dup | p.Thr172fs | Pathogenic/Likely pathogenic | ★★☆☆ | Holocarboxylase synthetase deficiency |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the HLCS gene are associated with Holocarboxylase synthetase deficiency. This condition is inherited in an autosomal recessive manner, meaning an individual must inherit two affected copies of the gene to develop the disorder. The deficiency primarily affects the body's ability to process and utilise biotin effectively, leading to a range of symptoms.
Inheritance pattern
Conditions caused by pathogenic HLCS variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The HLCS gene is recognised within the UK's NHS Genomic Medicine Service. It is listed on several Green panels in PanelApp, indicating strong evidence for its association with various conditions. These include DDG2P, Hyperammonaemia, Intellectual disability, Ketotic hypoglycaemia, Likely inborn error of metabolism, Mitochondrial disorders, Possible mitochondrial disorder (nuclear genes), and Undiagnosed metabolic disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the HLCS gene do?
The HLCS gene provides instructions for making holocarboxylase synthetase, an enzyme that activates biotin-dependent carboxylases. These activated enzymes are essential for the metabolism of proteins, fats, and carbohydrates, and for regulating genes involved in biotin transport.
What is Holocarboxylase synthetase deficiency?
Holocarboxylase synthetase deficiency is an inherited metabolic disorder caused by variants in the HLCS gene. It impairs the body's ability to use biotin effectively, leading to problems with metabolism and potentially affecting various organs, including the brain, muscles, and liver.
How is Holocarboxylase synthetase deficiency inherited?
Holocarboxylase synthetase deficiency follows an autosomal recessive inheritance pattern. This means an individual must inherit two altered copies of the HLCS gene, one from each parent, to develop the condition.
References
- 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. Annual review of nutrition. 2017. PMID: 28564555
- Baumgartner MR. Vitamin-responsive disorders: cobalamin, folate, biotin, vitamins B1 and E. Handbook of clinical neurology. 2013. PMID: 23622402
- Healy S, Perez-Cadahia B, Jia D. Biotin is not a natural histone modification. Biochimica et biophysica acta. 2009. PMID: 19770080
- Streaker ED, Beckett D. Nonenzymatic biotinylation of a biotin carboxyl carrier protein: unusual reactivity of the physiological target lysine. Protein science : a publication of the Protein Society. 2006. PMID: 16823034
- Suzuki Y, Yang X, Aoki Y. Mutations in the holocarboxylase synthetase gene HLCS. Human mutation. 2005. PMID: 16134170
- Pacheco-Alvarez D, Solórzano-Vargas RS, Gravel RA. Paradoxical regulation of biotin utilization in brain and liver and implications for inherited multiple carboxylase deficiency. The Journal of biological chemistry. 2004. PMID: 15456772
- Tang NL, Hui J, Yong CK. A genomic approach to mutation analysis of holocarboxylase synthetase gene in three Chinese patients with late-onset holocarboxylase synthetase deficiency. Clinical biochemistry. 2003. PMID: 12633764
- Morrone A, Malvagia S, Donati MA. Clinical findings and biochemical and molecular analysis of four patients with holocarboxylase synthetase deficiency. American journal of medical genetics. 2002. PMID: 12124727
- Yang X, Aoki Y, Li X. Structure of human holocarboxylase synthetase gene and mutation spectrum of holocarboxylase synthetase deficiency. Human genetics. 2001. PMID: 11735028
- Dupuis L, Campeau E, Leclerc D. Mechanism of biotin responsiveness in biotin-responsive multiple carboxylase deficiency. Molecular genetics and metabolism. 1999. PMID: 10068510