Molecular basis of acid ceramidase deficiency in a neonatal form of Farber disease: Identification of the first large deletion in ASAH1 gene

Alves, Marta; Trionnaire, Emmanuelle Le; Ribeiro, Isaura; Carpentier, Stéphane; Harzer, K.; Levade, Thierry; Ribeiro, Maria Gil

doi:10.1016/j.ymgme.2013.04.019

Cited by 28 publications

(16 citation statements)

References 32 publications

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“…Panel ( a ) (top) shows diagrammatic representation of location of each mutation with respect to the ASAH1 exons; location of mutations discovered in this study are shown at the top and those discovered in other studies are shown at the bottom. The large ASAH1 deletion identified recently in a type IV Farber disease ( FD ) patient is shown separately as a broken line. Mutation type is color coded: missense, black; splice, red; in/del, blue.…”

Section: Resultsmentioning

confidence: 99%

Molecular analyses of novel ASAH1 mutations causing Farber lipogranulomatosis: analyses of exonic splicing enhancer inactivating mutation

et al. 2013

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Farber lipogranulomatosis is a rare autosomal recessive lysosomal storage disorder caused by mutations in the ASAH1 gene. In the largest ever study, we identified and characterized ASAH1 mutations from 11 independent Farber disease (FD) families. A total of 13 different mutations were identified including 1 splice, 1 polypyrimidine tract (PPT) deletion and 11 missense mutations. Eleven mutations were exclusive to the Indian population. The IVS6+4A>G splice and IVS5-16delTTTTC PPT deletion mutations resulted in skipping of exon 6 precluding thereby the region responsible for cleavage of enzyme precursor. A missense mutation (p.V198A) resulted in skipping of exon 8 due to inactivation of an exonic splicing enhancer (ESE) element. This is the first report of mutations affecting PPT and ESE in the ASAH1 gene resulting in FD.

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Section: Resultsmentioning

confidence: 99%

Molecular analyses of novel ASAH1 mutations causing Farber lipogranulomatosis: analyses of exonic splicing enhancer inactivating mutation

et al. 2013

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“…33 Farber lipogranulomatosis (MIM 228000) is a lysosomal storage disorder due to autosomal recessive ASAH1 variants 34,35 that leads to accumulation of ceramide in tissues due to enzymatic deficiency, and is primarily characterized by subcutaneous nodules, joint deformities and hoarseness, although severe and atypical forms such as hydrops fetalis, failure to thrive and congenital heart disease have also been reported. 36,37 Autosomal recessive ASAH1 variants can also cause spinal muscular atrophy with progressive myoclonic epilepsy. 38 The occurrence of hydrops fetalis in a child who is compound heterozygous for a splice variant and a large deletion mirrors the embryonic lethal phenotype in Asah1 −/− mice.…”

Section: Discussionmentioning

confidence: 99%

Identification of ASAH1 as a susceptibility gene for familial keloids

Santos‐Cortez

Sun

et al. 2017

Eur J Hum Genet

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Keloids result from abnormal proliferative scar formation with scar tissue expanding beyond the margin of the original wound and are mostly found in individuals of sub-Saharan African descent. The etiology of keloids has not been resolved but previous studies suggest that keloids are a genetically heterogeneous disorder. Although possible candidate genes have been suggested by genome-wide association studies using common variants, by upregulation in keloids or their involvement in syndromes that include keloid formation, rare coding variants that contribute to susceptibility in non-syndromic keloid formation have not been previously identified. Through analysis of whole-genome data we mapped a locus to chromosome 8p23.3-p21.3 with a statistically significant maximum multipoint LOD score of 4.48. This finding was followed up using exome sequencing and led to the identification of a c.1202T>C (p.(Leu401Pro)) variant in the N-acylsphingosine amidohydrolase (ASAH1) gene that co-segregates with the keloid phenotype in a large Yoruba family. ASAH1 is an acid ceramidase known to be involved in tumor formation by controlling the ratio of ceramide and sphingosine. ASAH1 is also involved in cell proliferation and inflammation, and may affect the development of keloids via multiple mechanisms. Functional studies need to clarify the role of the ASAH1 variant in wound healing.

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“…A variety of mutations in the ASAH1 gene have been detected, but as of yet no clear association between genotype and clinical phenotypes of FD has been established . Researchers reported the results on the first allogeneic HCTs in 1989 and 2000 .…”

Section: Introductionmentioning

confidence: 99%

“…A variety of mutations in the ASAH1 gene have been detected, but as of yet no clear association between genotype and clinical phenotypes of FD has been established. [7][8][9] Researchers reported the results on the first allogeneic HCTs in 1989 and 2000. 10,11 These procedures did not prove to be beneficial for these children, and the authors attributed the unfavourable post-transplant course to the CNS involvement observed.…”

Section: Introductionmentioning

confidence: 99%

Allogeneic hematopoietic cell transplantation in Farber disease

Ehlert

Levade

Rocco

et al. 2019

J of Inher Metab Disea

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Background Farber disease (FD) is a rare, lysosomal storage disorder caused by deficient acid ceramidase activity. FD has long been considered a fatal disorder with death in the first three decades of life resulting either from respiratory insufficiency as a consequence of airway involvement or from progressive neurodegeneration because of nervous system involvement. Peripheral symptoms associated with FD, including inflammatory joint disease, have been described to improve relatively rapidly after hematopoietic cell transplantation (HCT). Aims To evaluate the disease‐specific status and limitations in the long‐term follow‐up after HCT, investigate genotype/phenotype correlations and the benefit of allogeneic HCT in FD patients with nervous system involvement. Patients and methods Transplant‐ and disease‐related information of ten FD patients was obtained by using a questionnaire, physicians' letters and additional telephone surveys. ASAH1 gene mutations were identified to search for genotype/phenotype correlations. Results After mainly busulfan‐based preparative regimens, all patients engrafted with one late graft loss. The inflammatory symptoms resolved completely in all patients. Abnormal neurologic findings were present pre‐transplant in 4/10 patients, post‐transplant in 6/10 patients. Mutational analyses revealed new mutations in the ASAH1 gene and a broad diversity of phenotypes without a genotype/phenotype correlation. With a median follow‐up of 10.4 years, overall survival was 80% with two transplant‐related deaths. Conclusion Allogeneic HCT leads to complete and persistent resolution of the inflammatory aspects in FD patients. It appears to have no beneficial effect on progression of nervous system involvement. New mutations in the acid ceramidase gene were identified. A genotype/phenotype correlation could not be established.

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Molecular basis of acid ceramidase deficiency in a neonatal form of Farber disease: Identification of the first large deletion in ASAH1 gene

Cited by 28 publications

References 32 publications

Molecular analyses of novel ASAH1 mutations causing Farber lipogranulomatosis: analyses of exonic splicing enhancer inactivating mutation

Molecular analyses of novel ASAH1 mutations causing Farber lipogranulomatosis: analyses of exonic splicing enhancer inactivating mutation

Identification of ASAH1 as a susceptibility gene for familial keloids

Allogeneic hematopoietic cell transplantation in Farber disease

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