Universität zu Köln

Acuna, Mariana, Martinez, Pablo, Moraga, Carol, He, Xingxuan, Moraga, Mauricio, Hunter, Bessie, Nuernberg, Peter, Gutierrez, Rodrigo A., Gonzalez, Mauricio, Schuchman, Edward H., Luis Santos, Jose, Francisco Miquel, Juan, Mabe, Paulina and Zanlungo, Silvana (2016). Epidemiological, clinical and biochemical characterization of the p.(Ala359Asp) SMPD1 variant causing Niemann-Pick disease type B. Eur. J. Hum. Genet., 24 (2). S. 208 - 214. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-5438

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Abstract

Niemann-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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Acuna, Mariana UNSPECIFIED UNSPECIFIED UNSPECIFIED Martinez, Pablo UNSPECIFIED UNSPECIFIED UNSPECIFIED Moraga, Carol UNSPECIFIED UNSPECIFIED UNSPECIFIED He, Xingxuan UNSPECIFIED UNSPECIFIED UNSPECIFIED Moraga, Mauricio UNSPECIFIED UNSPECIFIED UNSPECIFIED Hunter, Bessie UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Gutierrez, Rodrigo A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gonzalez, Mauricio UNSPECIFIED UNSPECIFIED UNSPECIFIED Schuchman, Edward H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Luis Santos, Jose UNSPECIFIED UNSPECIFIED UNSPECIFIED Francisco Miquel, Juan UNSPECIFIED UNSPECIFIED UNSPECIFIED Mabe, Paulina UNSPECIFIED UNSPECIFIED UNSPECIFIED Zanlungo, Silvana UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-285414
DOI:	10.1038/ejhg.2015.89
Journal or Publication Title:	Eur. J. Hum. Genet.
Volume:	24
Number:	2
Page Range:	S. 208 - 214
Date:	2016
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1476-5438
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ACID SPHINGOMYELINASE DEFICIENCY; MUTATIONS CAUSING TYPES; INTERMEDIATE PHENOTYPE; SOUTHERN CONE; PREVALENCE; SEQUENCE; HISTORY Multiple languages Biochemistry & Molecular Biology; Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/28541