Abstract
Rare loss-of-function mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene are known to dramatically decrease the catalytic activity of acid sphingomyelinase (ASM), resulting in an autosomal recessive lysosomal storage disorder known as Niemann-Pick disease (NPD) type A and B. In contrast to the general low frequency of those deleterious mutations, we found a relatively high frequency for the proposed type B NPD variant c.1460C>T (p.A487V) in our sample of 58 patients suffering from Major Depressive Disorder. We therefore investigated the biochemical consequences of this variant more closely. Our in vivo data derived from blood cell analyses indicated cellular ASM activity levels in the normal range. The secreted ASM activity levels in blood plasma were slightly lower, but still above those levels reported for type B NPD patients. In vitro expression studies of this ASM variant in different cell lines confirmed these results, showing cellular and secreted enzymatic activities equivalent to those of wild-type ASM and similar expression levels. Thus, we conclude that the ASM variant c.1460C>T (p.A487V) is not a rare missense mutation but an SMPD1 sequence variant that yields a protein with functional catalytic characteristics.
Competing interests: None declared
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- 1.
According to Schuchman et al. (1991) numbered as A485V, here numbered according to GenBank Accession Number NM_000543.4 as A487V. The difference is due to the polymorphic region coding for the signal peptide of ASM.
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Acknowledgements
We thank Alice Konrad, Michaela Henkel, Sabine Müller, Stefan Hofmann and Michael Kathrein for excellent technical assistance. We are grateful to Sibylle Schwab for helpful discussions.
This work was supported by the German Federal Ministry for Education and Research BMBF (01GI0219; German Research Network on Depression and Suicidality) and by the Scholarship Programme ‘Equality for Women in Research and Teaching’, University Erlangen-Nuremberg (to CR).
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Communicated by: Robert Steiner
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Conception and design: CR, MR, JK; Analysis of data: CR, JN, CM, PZ, MR; Interpretation of data: CR, JN, CM, PZ, MR; Drafting of article: CR, MR; Revising manuscript: JN, CM, PZ, UH, CH, RM, HJM, JK; Intellectual input: MA, UH, CH, RM, HJM, JK
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Rhein, C. et al. (2012). The Acid Sphingomyelinase Sequence Variant p.A487V Is Not Associated With Decreased Levels of Enzymatic Activity. In: Zschocke, J., Gibson, K., Brown, G., Morava, E., Peters, V. (eds) JIMD Reports - Case and Research Reports, 2012/5. JIMD Reports, vol 8. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2012_147
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DOI: https://doi.org/10.1007/8904_2012_147
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