Alternative titles; symbols
HGNC Approved Gene Symbol: ASAH1
SNOMEDCT: 703524005, 79935000;
Cytogenetic location: 8p22 Genomic coordinates (GRCh38) : 8:18,055,992-18,084,961 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8p22 | Farber lipogranulomatosis | 228000 | Autosomal recessive | 3 |
| Spinal muscular atrophy with progressive myoclonic epilepsy | 159950 | Autosomal recessive | 3 |
N-acylsphingosine amidohydrolase (ASAH1; EC 3.5.1.23), or acid ceramidase (AC), is responsible for the degradation of ceramide into sphingosine and free fatty acids within lysosomes. ASAH1 also has 'reverse' enzymatic activity, in that it can synthesize ceramide from sphingosine and free fatty acids. The ASAH1 synthesis reaction occurs at a pH distinct from that of the hydrolysis reaction (6.0 vs 4.5, respectively), suggesting that ASAH1 may have diverse functions within cells depending on its subcellular location and the local pH (review by Park and Schuchman, 2006).
Koch et al. (1996) purified acid ceramidase from urine and determined the 117 amino acid residues by microsequencing. Degenerative oligonucleotide probes were then constructed and used to screen human fibroblast and pituitary cDNA libraries. Several partial cDNA clones were obtained, and 2 of these combined to construct a full-length cDNA containing a 17-bp 5-prime untranslated sequence, a 1,185-bp open reading frame encoding 395 amino acids, a 110-bp 3-prime untranslated sequence, and an 18-bp poly(A) tail. Lysosomal acid ceramidase is a heterodimeric protein consisting of a nonglycosylated alpha subunit and a glycosylated beta subunit. The cDNA was found to encode both subunits, suggesting that the primary translation product of 395 amino acids is cleaved to the mature enzyme posttranslationally.
Using quantitative RT-PCR, Houben et al. (2006) found that ACDase was expressed in all human tissues examined, with highest expression in heart and kidney. It was also expressed in all mouse tissues examined, with highest expression in kidney, followed by lung, heart, and brain.
Li et al. (1999) determined that the ASAH gene spans about 30 kb and contains 14 exons.
By in situ hybridization and FISH analyses, Li et al. (1999) mapped the ASAH gene to chromosome 8p22-p21.3.
Park and Schuchman (2006) reviewed acid ceramidase and its role in disease.
By combining genetic perturbation of sphingolipid metabolism with quantification of TLR (see 601194) signaling steps and mass spectrometry-based lipidomics in mouse cells, Koberlin et al. (2015) uncovered a circular network of coregulated sphingolipids and glycerophospholipids. Quantitative lipidomics on fibroblasts from patients with mutations in GBA (606463), GALC (606890), ASAH1, or LYST (606897) revealed conservation of the circular organization of lipid coregulation across species, cell types, and genetic perturbations. The functional annotation accurately predicted TLR-mediated inflammatory responses, in terms of changes in lipid abundance and lipid species, in patient cells.
Farber Lipogranulomatosis
In a patient with Farber lipogranulomatosis (FRBRL; 228000), Koch et al. (1996) identified a homoallelic thr222-to-lys (T222K; 613468.0001) mutation in the ASAH gene.
Bar et al. (2001) identified 6 novel mutations in the ASAH gene causing Farber disease: 3 point mutations resulting in single amino acid substitutions, 1 intronic splice site mutation resulting in exon skipping, and 2 point mutations leading to occasional or complete exon skipping. The latter 2 mutations occurred in adjacent nucleotides and led to abnormal splicing of the same exon. Metabolic labeling studies in fibroblasts of 4 patients showed that even though acid ceramidase precursor protein was synthesized in these individuals, rapid proteolysis of the mutated, mature acid ceramidase occurred within the lysosome.
Muramatsu et al. (2002) identified 3 novel mutations in the ASAH gene from 2 Japanese patients with Farber disease.
In 2 Indian sibs with Farber disease, who were born of consanguineous parents, Devi et al. (2006) identified homozygosity for a missense mutation in the ASAH gene (613468.0005).
In 3 Iranian sibs, aged 40, 58 and 60 years, with Farber disease, Bonafe et al. (2016) identified compound heterozygous mutations in the ASAH1 gene (613468.0012-613468.0013). The mutations were identified by whole-exome sequencing and segregated with disease in the family. Acid ceramidase enzyme activity in fibroblasts from 2 of the sibs were reduced to 7 to 8% of control levels. The patients had severe adult-onset peripheral osteolysis and a history of episodic fever and pain in childhood.
In a 25-year-old woman with Farber disease, Bao et al. (2020) identified compound heterozygous mutations in the ASAH1 gene. The mutations were identified by sequencing of the ASAH1 gene. The patient had osteolytic changes of the hands and toes and a history of nodules since infancy, hoarseness, joint swelling, and bone pain. She had a similarly affected brother who did not undergo genetic testing.
In a review of acid ceramidase deficiency, Yu et al. (2018) noted that most of the mutations in the ASAH1 gene were missense mutations. A majority of the mutations associated with FRBRL were located within the beta subunit; 18 patients had mutations in exon 8, and 9 patients had mutations in exon 13.
Spinal Muscular Atrophy With Progressive Myoclonic Epilepsy
In 5 children from 2 families with spinal muscular atrophy with progressive myoclonic epilepsy (SMAPME; 159950), Zhou et al. (2012) identified a homozygous mutation in the ASAH1 gene (T42M; 613468.0006). The mutation was identified by genomewide linkage analysis followed by exome sequencing. Another patient from a third family was found to be compound heterozygous for the T42M mutation and a deletion of the ASAH1 gene (613468.0007). The T42M mutant protein was expressed in various patient tissues and showed decreased enzymatic activity (32% of controls) in in vitro functional studies, although the mutant enzyme still showed activity toward ceramide. The phenotype was characterized by childhood onset of proximal muscle weakness and muscular atrophy due to degeneration of spinal motor neurons, followed by the onset of myoclonic seizures. The disorder was progressive, and all patients died in the teenage years. Despite the severe phenotype, the disease course was less severe than that observed in Farber disease and symptoms appeared to be restricted to the central nervous system. Zhou et al. (2012) postulated that the different phenotype in the SMAPME patients was related to residual levels of ASAH1 activity.
In a girl with onset of SMAPME manifest as seizures at age 10 years, Dyment et al. (2014) identified compound heterozygous mutations in the ASAH1 gene (613468.0010 and 613468.0011). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Patient fibroblasts showed about 5.5% residual acid ceramidase activity and barely detectable levels of the beta subunit.
Associations Pending Confirmation
For discussion of a possible association between keloid formation (KLDF; 148100) and variation in the ASAH1 gene, see 613468.0016.
Zhou et al. (2012) observed that morpholino knockdown of the zebrafish ASAH1 ortholog Asah1b caused a significant increase of apoptosis specifically in the spinal cord, resulting in a curved body. In addition, morphant zebrafish showed decreased numbers of collateral branches in motor axons compared to controls. The morphant zebrafish had a decrease in, but not abrogation of, acid-ceramidase activity (about 26% of controls).
In a patient with Farber lipogranulomatosis (FRBRL; 228000), Koch et al. (1996) identified a homozygous 665C-A transversion in the ASAH1 gene, resulting in a thr222-to-lys (T222K) substitution. The parents were consanguineous and heterozygous for the mutation.
In a patient with Farber lipogranulomatosis (FRBRL; 228000), Li et al. (1999) identified a glu138-to-val (E138V) mutation in the ASAH1 gene as a result of a 413A-T transversion.
In a male offspring of consanguineous Tunisian parents with the severe (classic) subtype of Farber lipogranulomatosis (FRBRL; 228000) (Souillet et al., 1989), Bar et al. (2001) found a tyr36-to-cys (Y36C) mutation of the ASAH1 gene due to a 107A-G transition. The amino acid substitution was located in the alpha subunit.
In a patient with Farber lipogranulomatosis (FRBRL; 228000), Bar et al. (2001) described homozygosity for a 958A-G transition in the ASAH1 gene, resulting in an asn320-to-asp (N320D) substitution in the beta subunit of acid ceramidase.
In 2 Indian sibs with Farber disease (FRBRL; 228000), who were born of consanguineous parents, Devi et al. (2006) identified homozygosity for a C-to-G transversion in exon 8 of the ASAH1 gene, resulting in a leu182-to-val (L182V) substitution. The parents were heterozygous for the mutation, which was not found in 101 ethnically matched controls.
In 5 children from 2 families with spinal muscular atrophy with progressive myoclonic epilepsy (SMAPME; 159950), Zhou et al. (2012) identified a homozygous 125C-T transition in the last nucleotide of exon 2 of the ASAH1 gene, resulting in a thr42-to-met (T42M) substitution at a highly conserved residue in the alpha-subunit. The mutation was not found in 95 controls, and was found at a very low frequency (2 of 10,756 alleles) in the Exome Variant Server database. Haplotype analysis suggested a founder effect. The mutation was identified by genomewide linkage analysis followed by exome sequencing. Another patient from a third family was found to be compound heterozygous for the T42M mutation and a deletion of the ASAH1 gene (613468.0007). The T42M mutant protein was expressed in various patient tissues and showed decreased enzymatic activity (32% of controls) in in vitro functional studies, although the mutant enzyme still showed activity toward ceramide. Immunoblot experiments showed that the amount of the alpha-subunit was mildly lower than the beta subunit, suggesting that the mutation may affect the stability of the alpha-subunit and thus contribute to decreased enzyme activity.
For discussion of deletion of the ASAH1 gene that was found in compound heterozygous state in a patient with spinal muscular atrophy with progressive myoclonic epilepsy (SMAPME; 159950) by Zhou et al. (2012), see 613468.0006.
In a patient with a severe form of Farber lipogranulomatosis (FRBRL; 228000) resulting in hydrops fetalis and death at age 3 days (Kattner et al., 1997), Alves et al. (2013) identified compound heterozygous mutations in the ASAH1 gene: an A-to-G transition in intron 11 (c.917+4A-G), predicted to interfere with normal splicing, and a 9.4-kb deletion encompassing exons 3 to 5 (613468.0009). Each unaffected parent was heterozygous for 1 of the mutations. Analysis of patient cells showed about 50% ASAH1 transcript compared to controls, but no detectable full-length transcript and no ASAH1 protein. The major abnormal transcript resulted from the deletion of exons 3 to 5, resulting in premature termination (Tyr42_Leu127delinsArgfsTer10). The patient's severe phenotype correlated with the 2 null ASAH1 mutations.
For discussion of the 9.4-kb deletion in the ASAH1 gene that was found in compound heterozygous state in a patient with a severe form of Farber lipogranulomatosis (FRBRL; 228000) by Alves et al. (2013), see 613468.0008.
In a girl with onset of spinal muscular atrophy with progressive myoclonic epilepsy (SMAPME; 159950) at age 10 years, Dyment et al. (2014) identified compound heterozygous mutations in the ASAH1 gene: a c.850G-T transversion in exon 11, resulting in a gly284-to-ter (G284X) substitution, and a c.456A-C transversion (613468.0011) in exon 6, predicted to result in a lys152-to-asn (K152N) substitution; however, cDNA from patient fibroblasts showed that the latter mutation caused aberrant splicing with the skipping of exon 6. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and were filtered against the 1000 Genomes Project (2012/04 release) and Exome Variant Server (ESP6500) databases, as well as 800 in-house control exomes. Patient fibroblasts showed about 5.5% residual acid ceramidase activity and barely detectable levels of the beta subunit.
For discussion of the c.456A-C mutation in the ASAH1 gene that was found in compound heterozygous state in a patient with SMAPME (159950) by Dyment et al. (2014), see 613468.0010.
In 3 Iranian sibs, aged 40, 58 and 60 years, with Farber lipogranulomatosis (FRBRL; 228000), Bonafe et al. (2016) identified compound heterozygous mutations in the ASAH1 gene: a c.505T-C transition, resulting in a trp169-to-arg (W169R) substitution, and a c.760A-G transition, resulting in an arg254-to-gly (R254G; 613468.0013) substitution. The mutations, which were identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated with disease in the family. Acid ceramidase enzyme activity in fibroblasts from 2 of the sibs was reduced to 7 to 8% of control levels. The patients had severe adult-onset peripheral osteolysis and a history of episodic fever and pain in childhood.
For discussion of the c.760A-G transition in the ASAH1 gene, resulting in an arg254-to-gly (R254G) substitution, that was identified in compound heterozygous state in 3 Iranian sibs with lipogranulomatosis (FRBRL; 228000) by Bonafe et al. (2016), see 613468.0012.
In a 25-year-old woman with Farber lipogranulomatosis (FRBRL; 228000), Bao et al. (2020) identified compound heterozygous mutations in the ASAH1 gene: a c.427T-G transversion (c.427T-G, NM_177924.3), resulting in a cys143-to-gly (C143G) substitution, and a c.358G-C transversion, resulting in an ala120-to-pro (A120P; 613468.0015) substitution. The mutations were identified by sequencing of the ASAH1 gene, and the parents were shown to be mutation carriers. The patient had osteolytic changes of the hands and toes and a history of nodules since infancy, hoarseness, joint swelling, and bone pain.
For discussion of the c.358G-C transversion (c.358G-C, NM_177924.3) in the ASAH1 gene, resulting in an ala120-to-pro (A120P) substitution, that was identified in compound heterozygous state in a patient with Farber lipogranulomatosis (FRBRL; 228000) by Bao et al. (2020), see 613468.0014.
This variant is classified as a variant of unknown significance because its contribution to keloid formation (KLDF; see 148100) has not been confirmed.
In a large 3-generation Nigerian Yoruba family (family A) segregating autosomal dominant keloid formation mapping to chromosome 8p23-p21, Santos-Cortez et al. (2017) identified heterozygosity for a c.1202T-C transition (c.1202T-C, NM_004315.5) in the ASAH1 gene resulting in a leu401-to-pro substitution (L401P) that was present in all 9 affected individuals as well as in 3 unaffected family members (III-10, III-12, and III-19). There were also 2 family members of unknown status, with hypertrophic or raised scars, 1 of whom (III-11) did not carry the mutation and 1 of whom (III-7) carried the haplotype but whose mutation status was not reported. Screening for the L401P variant in 318 patients with keloids identified 2 unrelated Nigerian probands with the variant. Analysis of exome variants surrounding the ASAH1 variant defined a 210.4-kb haplotype that was shared by members of family A and the 2 Nigerian probands. The L401P variant was not found in 192 unaffected Yoruba controls with no family history of keloids, but was present in 2 heterozygous African alleles (minor allele frequency, 0.00019) in the ExAC database. The authors noted that in family A, onset of keloid formation ranged from the first to the seventh decade of life; thus the 3 unaffected mutation carriers, who were under 33 years of age, might yet develop keloids. Because 2 family members developed a keloid and a normal scar at around the same age, and some family members developed keloids only at a late age, the authors hypothesized that additional factors that change over time must play a role, including environmental and/or genetic modifiers. The authors also noted that individuals heterozygous for ASAH1 variants causing Farber lipogranulomatosis (228000) or spinal muscular atrophy with progressive myoclonic epilepsy (159950) were not known to have increased risk for keloids.
Alves, M. Q., Le Trionnaire, E., Ribeiro, I., Carpentier, S., Harzer, K., Levade, T., Ribeiro, M. G. Molecular basis of acid ceramidase deficiency in a neonatal form of Farber disease: identification of the first large deletion in ASAH1 gene. Molec. Genet. Metab. 109: 276-281, 2013. [PubMed: 23707712] [Full Text: https://doi.org/10.1016/j.ymgme.2013.04.019]
Bao, X., Ma, M., Zhang, Z., Xu, Y., Qui, Z. Farber disease in a patient from China. Am. J. Med. Genet. 182A: 2184-2186, 2020. [PubMed: 32706452] [Full Text: https://doi.org/10.1002/ajmg.a.61752]
Bar, J., Linke, T., Ferlinz, K., Neumann, U., Schuchman, E. H., Sandhoff, K. Molecular analysis of acid ceramidase deficiency in patients with Farber disease. Hum. Mutat. 17: 199-209, 2001. [PubMed: 11241842] [Full Text: https://doi.org/10.1002/humu.5]
Bonafe, L., Kariminejad, A., Li, J., Royer-Bertrand, B., Garcia, V., Mahdavi, S., Bozorgmehr, B., Lachman, R. L., Mittaz-Crettol, L., Compos-Xavier, B., Nampoothiri, S., Unger, S., Rivolta, C., Levade, T., Superti-Furga, A. Peripheral osteolysis in adults linked to ASAH1 (acid ceramidase) mutations: a new presentation of Farber's disease. Arthritis Rheum. 68: 2323-2327, 2016. [PubMed: 26945816] [Full Text: https://doi.org/10.1002/art.39659]
Devi, A. R. R., Gopikrishna, M., Ratheesh, R., Savithri, G., Swarnalata, G., Bashyam, M. Farber lipogranulomatosis: clinical and molecular genetic analysis reveals a novel mutation in an Indian family. J. Hum. Genet. 51: 811-814, 2006. [PubMed: 16951918] [Full Text: https://doi.org/10.1007/s10038-006-0019-z]
Dyment, D. A., Sell, E., Vanstone, M. R., Smith, A. C., Garandeau, D., Garcia, V., Carpentier, S., Le Trionnaire, E., Sabourdy, F., Beaulieu, C. L., Schwartzentruber, J. A., McMillan, H. J., FORGE Canada Consortium, Majewski, J., Bulman, D. E., Levade, T., Boycott, K. M. Evidence for clinical, genetic and biochemical variability in spinal muscular atrophy with progressive myoclonic epilepsy. Clin. Genet. 86: 558-563, 2014. [PubMed: 24164096] [Full Text: https://doi.org/10.1111/cge.12307]
Houben, E., Holleran, W. M., Yaginuma, T., Mao, C., Obeid, L. M., Rogiers, V., Takagi, Y., Elias, P. M., Uchida, Y. Differentiation-associated expression of ceramidase isoforms in cultured keratinocytes and epidermis. J. Lipid Res. 47: 1063-1070, 2006. [PubMed: 16477081] [Full Text: https://doi.org/10.1194/jlr.M600001-JLR200]
Kattner, E., Schafer, A., Harzer, K. Hydrops fetalis: manifestation in lysosomal storage diseases including Farber disease. Europ. J. Pediat. 156: 292-295, 1997. [PubMed: 9128814] [Full Text: https://doi.org/10.1007/s004310050603]
Koberlin, M. S., Snijder, B., Heinz, L. X., Baumann, C. L., Fauster, A., Vladimer, G. I., Gavin, A.-C., Superti-Furga, G. A conserved circular network of coregulated lipids modulates innate immune responses. Cell 162: 170-183, 2015. [PubMed: 26095250] [Full Text: https://doi.org/10.1016/j.cell.2015.05.051]
Koch, J., Gartner, S., Li, C.-M., Quintern, L. E., Bernardo, K., Levran, O., Schnabel, D., Desnick, R. J., Schuchman, E. H., Sandhoff, K. Molecular cloning and characterization of a full-length complementary DNA encoding human acid ceramidase: identification of the first molecular lesion causing Farber disease. J. Biol. Chem. 271: 33110-33115, 1996. [PubMed: 8955159] [Full Text: https://doi.org/10.1074/jbc.271.51.33110]
Li, C.-M., Park, J.-H., He, X., Levy, B., Chen, F., Arai, K., Adler, D. A., Disteche, C. M., Koch, J., Sandhoff, K., Schuchman, E. H. The human acid ceramidase gene (ASAH): structure, chromosomal location, mutation analysis and expression. Genomics 62: 223-231, 1999. [PubMed: 10610716] [Full Text: https://doi.org/10.1006/geno.1999.5940]
Muramatsu, T., Sakai, N., Yanagihara, I., Yamada, M., Nishigaki, T., Kokubu, C., Tsukamoto, H., Ito, M., Inui, K. Mutation analysis of the acid ceramidase gene in Japanese patients with Farber disease. J. Inherit. Metab. Dis. 25: 585-592, 2002. [PubMed: 12638942] [Full Text: https://doi.org/10.1023/a:1022047408477]
Park, J. H., Schuchman, E. H. Acid ceramidase and human disease. Biochim. Biophys. Acta 1758: 2133-2138, 2006. [PubMed: 17064658] [Full Text: https://doi.org/10.1016/j.bbamem.2006.08.019]
Santos-Cortez, R. L. P., Hu, Y., Sun, F., Benahmed-Miniuk, F., Tao, J., Kanaujiya, J. K., Ademola, S., Fadiora, S., Odesina, V., University of Washington Center for Mendelian Genomics, Nickerson, D. A., Bamshad, M. J., Olaitan, P. B., Oluwatosin, O. M., Leal, S. M., Reichenberger, E. J. Identification of ASAH1 as a susceptibility gene for familial keloids. Europ. J. Hum. Genet. 25: 1155-1161, 2017. [PubMed: 28905881] [Full Text: https://doi.org/10.1038/ejhg.2017.121]
Souillet, G., Guibaud, P., Fensom, A. H., Maire, I., Zabot, M. T. Outcome of displacement bone marrow transplantation in Farber's disease: a report of a case. In: Hobbs, J. R. (ed.): Correction of Certain Genetic Diseases by Transplantation. London: COGENT 1989. Pp. 137-141.
Yu, F. B. S., Amintas, S., Levade, T., Medin, J. A. Acid ceramidase deficiency: Farber disease and SMA-PME. Orphanet J. Rare Dis. 13: 121, 2018. [PubMed: 30029679] [Full Text: https://doi.org/10.1186/s13023-018-0845-z]
Zhou, J., Tawk, M., Tiziano, F. D., Veillet, J., Bayes, M., Nolent, F., Garcia, V., Servidei, S., Bertini, E., Castro-Giner, F., Renda, Y., Carpentier, S., Andrieu-Abadie, N., Gut, I., Levade, T., Topaloglu, H., Melki, J. Spinal muscular atrophy associated with progressive myoclonic epilepsy is caused by mutations in ASAH1. Am. J. Hum. Genet. 91: 5-14, 2012. [PubMed: 22703880] [Full Text: https://doi.org/10.1016/j.ajhg.2012.05.001]