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Expression of aspartoacylase (ASPA) and Canavan disease


Sommer, Anke; Sass, Jörn Oliver (2012). Expression of aspartoacylase (ASPA) and Canavan disease. Gene, 505(2):206-210.

Abstract

Canavan disease (CD) is a neurodegenerative disorder usually presenting in the first six months of life. CD patients can be identified via elevated levels of N-acetyl-l-aspartate in the pattern of urinary organic acids assessed by gas chromatography-mass spectrometry. They are characterized by deficiency of aspartoacylase (aminoacylase 2; ASPA) due to mutations in the ASPA gene. Information on the molecular basis of CD is rather sparse. A lack of expression studies of ASPA mutant proteins in appropriate expression systems has prompted this investigation. Studies with overexpressed ASPA mutant proteins were carried out in the HEK293 cell line, which provides the authentic human machinery for posttranslational modifications. All ASPA mutants tested (ASPA Arg168His, ASPA Pro181Thr, ASPA Tyr288Cys, ASPA Phe295Ser, and ASPA Ala305Glu) showed loss of ASPA activity, which can be explained by the intramolecular effects of the mutations in the enzyme. The mutation p.Phe295Ser even leads to absent ASPA mRNA expression, as revealed by quantitative real-time PCR. Using this approach, ASPA gene expression analysis yielded high levels of human ASPA gene expression not only in brain and kidney, but also in lung and liver. More information of ASPA localization in human organs and detailed characterization of mutations leading to a deficiency of ASPA can contribute to a better understanding of this inborn error of metabolism.

Abstract

Canavan disease (CD) is a neurodegenerative disorder usually presenting in the first six months of life. CD patients can be identified via elevated levels of N-acetyl-l-aspartate in the pattern of urinary organic acids assessed by gas chromatography-mass spectrometry. They are characterized by deficiency of aspartoacylase (aminoacylase 2; ASPA) due to mutations in the ASPA gene. Information on the molecular basis of CD is rather sparse. A lack of expression studies of ASPA mutant proteins in appropriate expression systems has prompted this investigation. Studies with overexpressed ASPA mutant proteins were carried out in the HEK293 cell line, which provides the authentic human machinery for posttranslational modifications. All ASPA mutants tested (ASPA Arg168His, ASPA Pro181Thr, ASPA Tyr288Cys, ASPA Phe295Ser, and ASPA Ala305Glu) showed loss of ASPA activity, which can be explained by the intramolecular effects of the mutations in the enzyme. The mutation p.Phe295Ser even leads to absent ASPA mRNA expression, as revealed by quantitative real-time PCR. Using this approach, ASPA gene expression analysis yielded high levels of human ASPA gene expression not only in brain and kidney, but also in lung and liver. More information of ASPA localization in human organs and detailed characterization of mutations leading to a deficiency of ASPA can contribute to a better understanding of this inborn error of metabolism.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2012
Deposited On:16 Nov 2012 14:08
Last Modified:17 Feb 2018 00:05
Publisher:Elsevier
ISSN:0378-1119
OA Status:Closed
Publisher DOI:https://doi.org/10.1016/j.gene.2012.06.036
PubMed ID:22750302

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