Epidemiological, clinical and biochemical characterization of the p.(Ala359Asp) SMPD1 variant causing Niemann-Pick disease type B

European Journal of Human Genetics

dc.creatorAcuña-Aravena, Mariana Loreto
dc.creatorMartínez, Pablo
dc.creatorMoraga, Carol
dc.creatorHe, Xingxuan
dc.creatorMoraga, Mauricio
dc.creatorHunter, Bessie
dc.creatorNuernberg, Peter
dc.creatorGutierrez, Rodrigo A
dc.creatorGonzález, Mauricio
dc.creatorSchuchman, Edward H
dc.creatorSantos, José Luis
dc.creatorMiquel, Juan Francisco
dc.creatorMabe, Paulina
dc.creatorZanlungo-Matsuhiro, Silvana
dc.date2021-08-23T22:58:33Z
dc.date2022-07-07T02:46:49Z
dc.date2021-08-23T22:58:33Z
dc.date2022-07-07T02:46:49Z
dc.date2016
dc.date.accessioned2023-08-22T03:14:38Z
dc.date.available2023-08-22T03:14:38Z
dc.identifier1150182
dc.identifier1150182
dc.identifierhttps://hdl.handle.net/10533/252339
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8314047
dc.descriptionNiemann-Pick disease type B (NPDB) is a rare, inherited lysosomal storage disorder that occurs due to variants in the sphingomyelin phosphodiesterase 1 (SMPD1) gene and the resultant deficiency of acid sphingomyelinase (ASM) activity. While numerous variants causing NPDB have been described, only a small number have been studied in any detail. Herein, we describe the frequency of the p.(Ala359Asp) variant in the healthy Chilean population, and determine the haplotype background of homozygous patients to establish if this variant originated from a common founder. Genomic DNA samples from 1691 healthy individuals were analyzed for the p.(Ala359Asp) variant. The frequency of p.(Ala359Asp) was found to be 1/105.7, predicting a disease incidence of 1/44 960 in Chile, higher than the incidence estimated by the number of confirmed NPDB cases. We also describe the clinical characteristics of 13 patients homozygous for p.(Ala359Asp) and all of them had moderate to severe NPDB disease. In addition, a conserved haplotype and shared 280 Kb region around the SMPD1 gene was observed in the patients analyzed, indicating that the variant originated from a common ancestor. The haplotype frequency and mitochondrial DNA analysis suggest an Amerindian origin for the variant. To assess the effect of the p.(Ala359Asp) variant, we transfected cells with the ASM-p.(Ala359Asp) cDNA and the activity was only 4.2% compared with the wild-type cDNA, definitively demonstrating the causative effect of the variant on ASM function. Information on common variants such as p.(Ala359Asp) is essential to guide the successful implementation for future therapies and benefit to patients.
dc.descriptionRegular 2015
dc.descriptionFONDECYT
dc.descriptionFONDECYT
dc.languageeng
dc.relationhandle/10533/111557
dc.relationhandle/10533/111541
dc.relationhandle/10533/108045
dc.relationhttp://revista-agroproductividad.org/index.php/agroproductividad/article/view/115/97
dc.rightsAtribución-NoComercial-SinDerivadas 3.0 Chile
dc.rightshttp://creativecommons.org/licenses/by-nc-nd/3.0/cl/
dc.rightsinfo:eu-repo/semantics/article
dc.rightsinfo:eu-repo/semantics/openAccess
dc.titleEpidemiological, clinical and biochemical characterization of the p.(Ala359Asp) SMPD1 variant causing Niemann-Pick disease type B
dc.titleEuropean Journal of Human Genetics
dc.typeArticulo
dc.typeinfo:eu-repo/semantics/publishedVersion


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