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HMGCL
3-hydroxy-3-methylglutaryl-CoA lyase
The HMGCL gene provides instructions for an enzyme crucial in breaking down proteins and fats, particularly during periods of fasting. The HMGCL gene codes for 3-hydroxy-3-methylglutaryl-CoA lyase (HMG-CoA lyase), an enzyme located in mitochondria.
HMGCL is located on the short (p) arm of chromosome 1, at band 1p36.11. Arm ratio per GRCh38 - banding schematic.
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Overview
The HMGCL gene is responsible for producing the enzyme 3-hydroxy-3-methylglutaryl-CoA lyase, often referred to as HMG-CoA lyase. This enzyme plays a central role in metabolic pathways, specifically in the breakdown of dietary proteins and fats within the body.
Its function is particularly important during states of low glucose availability, such as fasting, when the body relies on alternative energy sources.
What the gene does
The HMGCL gene encodes the mitochondrial enzyme 3-hydroxy-3-methylglutaryl-CoA lyase (HMG-CoA lyase), which is essential for cellular energy production. This enzyme facilitates the processing of the amino acid leucine, a building block of proteins. Moreover, HMG-CoA lyase is involved in ketogenesis, the process of producing ketone bodies from the breakdown of fats. Ketones serve as an important alternative energy source for organs like the brain, especially during periods of fasting or when glucose levels are low. The enzyme's activity ensures the body can efficiently utilise fats and proteins to generate energy when carbohydrates are not readily available.
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Chromosome location
The HMGCL gene is situated on chromosome 1, specifically at position 1p36.11. This location refers to the short (p) arm of chromosome 1, within region 3, band 6, sub-band 11. The gene spans a particular segment of this chromosome, contributing to its overall genomic organisation.
Protein structure
The protein produced from the HMGCL gene, 3-hydroxy-3-methylglutaryl-CoA lyase, consists of 325 amino acids. It features a key structural element known as the Pyruvate carboxyltransferase domain, spanning amino acids 33-300. Additionally, a Microbody targeting signal motif is present at amino acids 323-325, which is involved in directing the protein to its correct cellular location.
Key variants
Variations within the HMGCL gene can lead to changes in the structure and function of the HMG-CoA lyase enzyme. More than 25 different genetic changes have been identified in individuals with conditions associated with this gene. These alterations often involve single amino acid substitutions, which can impair the enzyme's ability to properly metabolise proteins and fats.
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.109G>A | p.Glu37Lys | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of hydroxymethylglutaryl-CoA lyase |
c.230del | p.Val77fs | Pathogenic/Likely pathogenic | ★★☆☆ | Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency |
c.252+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of hydroxymethylglutaryl-CoA lyase |
c.349_361del | - | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of hydroxymethylglutaryl-CoA lyase |
c.477del | p.Ala160fs | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of hydroxymethylglutaryl-CoA lyase |
c.501C>A | p.Tyr167Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency |
c.521G>A | p.Cys174Tyr | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of hydroxymethylglutaryl-CoA lyase |
c.562-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of hydroxymethylglutaryl-CoA lyase |
c.610del | p.Asp204fs | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of hydroxymethylglutaryl-CoA lyase |
c.704_705dup | p.Asp236fs | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of hydroxymethylglutaryl-CoA lyase |
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 HMGCL gene are associated with an inherited metabolic disorder called 3-hydroxy-3-methylglutaryl-CoA lyase deficiency. This condition follows an autosomal recessive inheritance pattern, meaning an individual must inherit two altered copies of the gene (one from each parent) to be affected. The deficiency results in the body's inability to efficiently break down certain fats and proteins, leading to a build-up of toxic substances.
Inheritance pattern
Conditions caused by pathogenic HMGCL 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 HMGCL gene is recognised within several NHS Genomic Medicine Service clinical panels, indicating its significance in diagnosing inherited conditions in the UK. It is listed as 'green' in DDG2P, Early onset or syndromic epilepsy, Hyperammonaemia, Intellectual disability, Likely inborn error of metabolism (R98), and Undiagnosed metabolic disorders, highlighting its clinical relevance across these areas.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main role of the HMGCL gene?
The HMGCL gene provides instructions for creating an enzyme called 3-hydroxy-3-methylglutaryl-CoA lyase. This enzyme is crucial for breaking down certain proteins and fats, particularly when the body needs to use alternative energy sources like during fasting.
How does the HMGCL gene relate to energy production?
The HMGCL gene's enzyme helps produce ketones from fats. These ketones serve as an important energy source for various organs, including the brain, especially when the body's primary energy source, glucose, is not readily available.
What is 3-hydroxy-3-methylglutaryl-CoA lyase deficiency?
This is an inherited metabolic disorder caused by pathogenic variants in the HMGCL gene. It means the body cannot properly process certain fats and proteins, which can lead to a build-up of harmful substances and energy deficiency.
References
- Pié J, López-Viñas E, Puisac B. Molecular genetics of HMG-CoA lyase deficiency. Molecular genetics and metabolism. 2007. PMID: 17692550
- Fu Z, Runquist JA, Forouhar F. Crystal structure of human 3-hydroxy-3-methylglutaryl-CoA Lyase: insights into catalysis and the molecular basis for hydroxymethylglutaric aciduria. The Journal of biological chemistry. 2006. PMID: 16330550
- Al-Sayed M, Imtiaz F, Alsmadi OA. Mutations underlying 3-hydroxy-3-methylglutaryl CoA lyase deficiency in the Saudi population. BMC medical genetics. 2006. PMID: 17173698
- Puisac B, López-Viñas E, Moreno S. Skipping of exon 2 and exons 2 plus 3 of HMG-CoA lyase (HL) gene produces the loss of beta sheets 1 and 2 in the recently proposed (beta-alpha)8 TIM barrel model of HL. Biophysical chemistry. 2005. PMID: 15752612
- Cardoso ML, Rodrigues MR, Leão E. The E37X is a common HMGCL mutation in Portuguese patients with 3-hydroxy-3-methylglutaric CoA lyase deficiency. Molecular genetics and metabolism. 2004. PMID: 15308132
- Casals N, Gómez-Puertas P, Pié J. Structural (betaalpha)8 TIM barrel model of 3-hydroxy-3-methylglutaryl-coenzyme A lyase. The Journal of biological chemistry. 2003. PMID: 12746442
- Pie J, Casals N, Puisac B. Molecular basis of 3-hydroxy-3-methylglutaric aciduria. Journal of physiology and biochemistry. 2003. PMID: 15164951
- Ashmarina LI, Pshezhetsky AV, Branda SS. 3-Hydroxy-3-methylglutaryl coenzyme A lyase: targeting and processing in peroxisomes and mitochondria. Journal of lipid research. 1999. PMID: 9869651