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ASAH1
N-acylsphingosine amidohydrolase 1
The ASAH1 gene encodes the acid ceramidase enzyme, crucial for breaking down lipids called ceramides within lysosomes, and is associated with conditions like Farber disease. The ASAH1 gene provides the blueprint for acid ceramidase, an enzyme located in lysosomes that plays a vital role in lipid metabolism by breaking down ceramides.
ASAH1 is located on the short (p) arm of chromosome 8, at band 8p22. Arm ratio per GRCh38 - banding schematic.
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Overview
The ASAH1 gene, also known as N-acylsphingosine amidohydrolase 1, is responsible for producing an enzyme called acid ceramidase. This enzyme is primarily found in lysosomes, which are cellular compartments dedicated to digesting and recycling various cellular materials.
Acid ceramidase is essential for lipid metabolism, specifically the breakdown of ceramides. Dysregulation of this process due to changes in the ASAH1 gene can lead to the build-up of ceramides, impacting various cellular functions and contributing to inherited conditions.
What the gene does
The acid ceramidase enzyme, produced from the ASAH1 gene, plays a critical role in the lysosomal pathway of lipid degradation. Within lysosomes, acid ceramidase breaks down ceramides, which are a type of fat found in cell membranes and myelin, the protective sheath around nerve cells.
Ceramides are involved in regulating several cellular processes, including cell maturation, growth, division, and programmed cell death. When ceramides need to be recycled, acid ceramidase converts them into sphingosine and a fatty acid. These breakdown products can then be reused by the body to synthesise new ceramides or other complex lipids, highlighting the enzyme's importance in maintaining cellular lipid balance and function.
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Chromosome location
The ASAH1 gene is located on chromosome 8 at position 8p22. This genomic location specifies where the gene resides within the human genome, influencing its expression and potential interactions with other genes and regulatory elements.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants within the ASAH1 gene can alter the function of the acid ceramidase enzyme. These genetic changes can range from single amino acid substitutions to larger deletions or duplications. The specific effect of a variant often depends on its location within the gene and how it impacts the enzyme's ability to break down ceramides.
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.1085C>G | p.Pro362Arg | Pathogenic/Likely pathogenic | ★★☆☆ | Farber lipogranulomatosis |
c.1098+1G>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | Farber lipogranulomatosis |
c.174dup | p.Tyr59fs | Pathogenic | ★★☆☆ | Farber lipogranulomatosis |
c.177C>A | p.Tyr59Ter | Pathogenic/Likely pathogenic | ★★☆☆ | ASAH1-related disorders |
c.185G>A | p.Trp62Ter | Pathogenic | ★★☆☆ | Spinal muscular atrophy-progressive myoclonic epilepsy syndrome |
c.186G>A | p.Trp62Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Farber lipogranulomatosis |
c.412G>T | p.Glu138Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Farber lipogranulomatosis |
c.457+4A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Farber lipogranulomatosis |
c.886C>T | p.Arg296Ter | Pathogenic | ★★☆☆ | Spinal muscular atrophy-progressive myoclonic epilepsy syndrome |
c.997C>T | p.Arg333Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Farber lipogranulomatosis |
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 ASAH1 gene are primarily associated with inherited conditions that result from the accumulation of ceramides. These include Farber disease, a rare lysosomal storage disorder characterised by symptoms affecting the joints, skin, and nervous system. Another associated condition is spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME), which involves muscle weakness, wasting, and neurological symptoms.
UK clinical status
The ASAH1 gene is included in several UK NHS national genomic testing panels, indicating its clinical significance for diagnostic purposes. These panels cover various conditions, including DDG2P, Early onset or syndromic epilepsy, Familial pulmonary fibrosis, Foetal anomalies, Foetal hydrops, Hereditary neuropathy or pain disorder, Intellectual disability, Likely inborn error of metabolism, Lysosomal storage disorder, Paediatric motor neuronopathies, and Undiagnosed metabolic disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the ASAH1 gene?
The ASAH1 gene provides instructions for the acid ceramidase enzyme, which is crucial for breaking down lipids called ceramides within the lysosomes of cells. This process is vital for recycling cellular materials and maintaining lipid balance.
What conditions are associated with variants in the ASAH1 gene?
Variants in the ASAH1 gene are primarily associated with Farber disease, a lysosomal storage disorder, and spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME). Both conditions result from the accumulation of ceramides due to impaired enzyme function.
Where is the ASAH1 gene located?
The ASAH1 gene is located on chromosome 8, specifically at position 8p22.
References
- Dyment DA, Sell E, Vanstone MR. Evidence for clinical, genetic and biochemical variability in spinal muscular atrophy with progressive myoclonic epilepsy. Clinical genetics. 2014. PMID: 24164096
- Sands MS. Farber disease: understanding a fatal childhood disorder and dissecting ceramide biology. EMBO molecular medicine. 2013. PMID: 23666771
- Alayoubi AM, Wang JC, Au BC. Systemic ceramide accumulation leads to severe and varied pathological consequences. EMBO molecular medicine. 2013. PMID: 23681708
- Lucki NC, Bandyopadhyay S, Wang E. Acid ceramidase (ASAH1) is a global regulator of steroidogenic capacity and adrenocortical gene expression. Molecular endocrinology (Baltimore, Md.). 2012. PMID: 22261821
- Park JH, Schuchman EH. Acid ceramidase and human disease. Biochimica et biophysica acta. 2006. PMID: 17064658
- Zhang Z, Mandal AK, Mital A. Human acid ceramidase gene: novel mutations in Farber disease. Molecular genetics and metabolism. 2000. PMID: 10993717