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GALC
galactosylceramidase
The GALC gene provides instructions for producing galactosylceramidase, an enzyme vital for the breakdown of specific fats within the nervous system. The GALC gene is responsible for encoding galactosylceramidase, an enzyme primarily located in lysosomes.
GALC is located on the long (q) arm of chromosome 14, at band 14q31.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The GALC gene contains the genetic blueprint for galactosylceramidase, an enzyme essential for cellular metabolism, particularly within the nervous system. This enzyme's primary function is to break down complex lipids, known as galactolipids, through a process called hydrolysis. Proper functioning of galactosylceramidase is critical for maintaining healthy nerve cells and the protective myelin sheath surrounding them. Dysfunction of the GALC gene can lead to the accumulation of toxic substances, resulting in severe neurological conditions.
What the gene does
The galactosylceramidase enzyme, encoded by the GALC gene, is situated within lysosomes, which are cellular compartments responsible for waste breakdown. Its main role involves hydrolysing specific galactolipids, such as galactosylceramide and psychosine, by using water molecules. Galactosylceramide is a key component of myelin, the insulating layer that enables rapid nerve signal transmission. The enzyme's breakdown of galactosylceramide is part of the continuous process of myelin turnover throughout an individual's life. Psychosine, a substance that is harmful to cells, is generated during myelin production and is normally rapidly degraded by galactosylceramidase. Consequently, healthy tissues typically contain minimal amounts of psychosine; impaired enzyme function can lead to its accumulation, causing cellular damage.
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Chromosome location
The GALC gene is located on chromosome 14, specifically at band 14q31.3. This genomic position indicates its precise address within the human genome, helping researchers understand its context and potential interactions with other genes on the chromosome.
Protein structure
The GALC gene encodes a protein of 685 amino acids. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants within the GALC gene can impact the structure and function of the galactosylceramidase enzyme. Over 200 distinct genetic changes in GALC have been identified as causes of associated conditions. These variants can range from small point mutations to larger deletions, all of which may reduce or eliminate the enzyme's activity.
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.1034-1G>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Galactosylceramide beta-galactosidase deficiency |
c.1034-2A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Galactosylceramide beta-galactosidase deficiency |
c.1127_1131delinsACTGAT | p.Gly376_Leu377delinsAspTer | Pathogenic/Likely pathogenic | ★★☆☆ | Galactosylceramide beta-galactosidase deficiency |
c.1230del | p.Phe411fs | Pathogenic/Likely pathogenic | ★★☆☆ | Galactosylceramide beta-galactosidase deficiency |
c.1251+1G>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Galactosylceramide beta-galactosidase deficiency |
c.1717dup | p.Thr573fs | Pathogenic/Likely pathogenic | ★★☆☆ | Galactosylceramide beta-galactosidase deficiency |
c.236G>A | p.Arg79His | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
c.246A>G | p.Ile82Met | Pathogenic | ★★☆☆ | Galactosylceramide beta-galactosidase deficiency |
c.328+2T>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Galactosylceramide beta-galactosidase deficiency |
c.516_517del | p.Tyr173fs | Pathogenic/Likely pathogenic | ★★☆☆ | Galactosylceramide beta-galactosidase 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 GALC gene are primarily associated with Krabbe disease. This is an inherited neurological disorder that typically manifests in infancy, leading to significant developmental delays, movement difficulties, feeding problems, and seizures. Krabbe disease is characterised by the build-up of harmful substances due to the impaired function of the galactosylceramidase enzyme.
Inheritance pattern
Conditions caused by pathogenic GALC 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 GALC gene is included in several UK NHS national genomic testing panels, indicating its clinical relevance for diagnosing various conditions. It has a 'green' status on panels such as DDG2P, Early onset or syndromic epilepsy, Foetal anomalies (R21), Hereditary neuropathy (R78), Hereditary spastic paraplegia (R61), Inherited white matter disorders, Intellectual disability, Krabbe disease - GALC deficiency (R280), Leukodystrophy (R62), Likely inborn error of metabolism (R98), Lysosomal storage disorder (R276), and Undiagnosed metabolic disorders, among others. This widespread inclusion underscores its importance in diagnosing inherited neurological and metabolic conditions within the UK healthcare system.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is Krabbe disease?
Krabbe disease is a severe, inherited neurological disorder caused by pathogenic variants in the GALC gene. It leads to the impaired breakdown of specific fats, causing harmful substances to accumulate in cells, particularly in the nervous system.
How is Krabbe disease inherited?
Krabbe disease is inherited in an autosomal recessive pattern. This means an individual must inherit two copies of a pathogenic GALC gene variant, one from each parent, to develop the condition. Individuals with only one pathogenic variant are typically carriers and do not show symptoms.
What does galactosylceramidase do?
Galactosylceramidase is an enzyme encoded by the GALC gene that breaks down certain fats called galactolipids, including galactosylceramide and psychosine, in the lysosomes of cells. This process is crucial for maintaining the myelin sheath around nerve cells and preventing the build-up of toxic substances.
References
- Shin D, Feltri ML, Wrabetz L. Altered Trafficking and Processing of GALC Mutants Correlates with Globoid Cell Leukodystrophy Severity. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2016. PMID: 26865610
- Spratley SJ, Hill CH, Viuff AH. Molecular Mechanisms of Disease Pathogenesis Differ in Krabbe Disease Variants. Traffic (Copenhagen, Denmark). 2016. PMID: 27126738
- Wenger DA, Rafi MA, Luzi P. Krabbe disease: One Hundred years from the bedside to the bench to the bedside. Journal of neuroscience research. 2016. PMID: 27638583
- Giri S, Khan M, Rattan R. Krabbe disease: psychosine-mediated activation of phospholipase A2 in oligodendrocyte cell death. Journal of lipid research. 2006. PMID: 16645197
- Zaka M, Wenger DA. Psychosine-induced apoptosis in a mouse oligodendrocyte progenitor cell line is mediated by caspase activation. Neuroscience letters. 2004. PMID: 15039117