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ASAH1
N-acylsphingosine amidohydrolase 1
The ASAH1 gene provides instructions for producing acid ceramidase, an enzyme vital for breaking down lipids called ceramides within cellular lysosomes. ASAH1 encodes N-acylsphingosine amidohydrolase 1, also known as acid ceramidase.
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 is responsible for synthesising the enzyme acid ceramidase. This enzyme is primarily found in lysosomes, which are specialised compartments within cells that function to digest and recycle various cellular materials. Acid ceramidase is essential for the metabolism of ceramides, a type of fat molecule involved in cell regulation and nerve cell insulation.
Dysfunction of the ASAH1 gene can lead to the accumulation of ceramides within cells, which is characteristic of several rare inherited conditions. Understanding the role of ASAH1 in lipid metabolism is important for diagnosing and researching these disorders.
What the gene does
The primary function of the ASAH1 gene is to produce acid ceramidase, an enzyme that operates within the lysosomes of cells. Acid ceramidase facilitates the breakdown of ceramides, which are lipid molecules that form part of cell membranes and are involved in regulating processes such as cell maturation, growth, division, and programmed cell death. Ceramides also contribute to myelin, the fatty substance that insulates and protects nerve cells.
Within lysosomes, acid ceramidase breaks down ceramides into sphingosine and a fatty acid. These breakdown products are then recycled by the cell to synthesise new ceramides or other complex lipids as needed. This recycling process is crucial for maintaining cellular homeostasis and proper lipid balance. A reduction in acid ceramidase activity due to ASAH1 variants can disrupt this balance, leading to the accumulation of ceramides and subsequent cellular dysfunction.
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Chromosome location
The ASAH1 gene is located on the short arm of chromosome 8 at position 22, designated as 8p22. This chromosomal location indicates where the gene can be found within the human genome. The specific organisation of exons and introns within ASAH1 dictates the final structure of the acid ceramidase protein.
Protein structure
The ASAH1 gene encodes a protein that is 395 amino acids in length. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants in the ASAH1 gene can alter the function or production of the acid ceramidase enzyme. These genetic changes can range from single nucleotide substitutions to larger deletions or insertions within the gene sequence. The specific impact of a variant often depends on its location and the resulting change in the protein's structure or 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.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 | ★★☆☆ | Farber lipogranulomatosis |
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 associated with several inherited conditions, primarily due to the impaired breakdown of ceramides. One notable condition is Farber disease, an autosomal recessive lysosomal storage disorder characterised by ceramide accumulation, often leading to joint pain, subcutaneous nodules, and hoarseness. Another condition linked to ASAH1 variants is spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME), which involves muscle weakness and seizures.
UK clinical status
The ASAH1 gene is included in several panels within the UK National Health Service (NHS) Genomic Medicine Service's PanelApp. It is listed with a 'green' status on panels such as DDG2P, Early onset or syndromic epilepsy, Familial pulmonary fibrosis, Foetal anomalies (R21), Foetal hydrops, Hereditary neuropathy or pain disorder (R78), Intellectual disability, Likely inborn error of metabolism (R98), Lysosomal storage disorder (R276), Paediatric motor neuronopathies, and Undiagnosed metabolic disorders. A 'green' status indicates that there is strong evidence for the gene's association with the conditions covered by these panels.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the function of the ASAH1 gene?
The ASAH1 gene provides instructions for making acid ceramidase, an enzyme located in cellular lysosomes. This enzyme is crucial for breaking down ceramides, a type of lipid, into sphingosine and fatty acids, which are then recycled by the cell.
What happens if there is a variant in the ASAH1 gene?
Variants in the ASAH1 gene can lead to reduced activity of the acid ceramidase enzyme. This can cause ceramides to build up in cells, leading to various health conditions, such as Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy.
How is ASAH1 relevant to inherited conditions?
ASAH1 variants are associated with several inherited metabolic disorders, particularly those involving the accumulation of lipids. Conditions like Farber disease, a lysosomal storage disorder, arise from insufficient ceramide breakdown due to pathogenic changes in ASAH1.
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