Molecular genetic characterization of novel sphingomyelin phosphodiesterase 1 mutations causing Niemann–pick disease

B. Tóth, M. Erdős, Annamária Székely, László Ritli, P. Bagossi, János Sümegi, L. Máródi

Research output: Chapter in Book/Report/Conference proceedingChapter

5 Citations (Scopus)

Abstract

Niemann–Pick disease (NPD) types A and B are autosomal recessive disorders caused by acid sphingomyelinase (ASM) deficiency due to mutation in the sphingomyelin phosphodiesterase 1 gene (SMPD1). Although a number of SMPD1 mutations were reported, expression studies were performed for only a small number of missense mutations. We evaluated three unrelated patients with clinical manifestations of NPD. Sequence analysis revealed two previously described (S248R and W391G) and two novel (G247D and F572L) missense mutations. To analyze the effects of the novel mutations on ASM function, cDNA was generated by site-directed mutagenesis and expressed in COS-7 cells. In vitro biochemical assays revealed marked deficiency of ASM activity consistent with the disease phenotype in cells homoallelic for each mutation. We show that each mutation dramatically reduced half-life and catalytic activity of ASM with more pronounced decrease by the G247D mutation. These data suggest that impaired protein stability and decreased enzyme activity are responsible for the disease in sphingomyelinase-deficient patients carrying the G247D and F572L mutations.

Original languageEnglish
Title of host publicationJIMD Reports
PublisherSpringer
Pages125-129
Number of pages5
DOIs
Publication statusPublished - Jan 1 2012

Publication series

NameJIMD Reports
Volume3
ISSN (Print)2192-8304
ISSN (Electronic)2192-8312

Fingerprint

Sphingomyelin Phosphodiesterase
Molecular Biology
Mutation
Type A Niemann-Pick Disease
Acids
Missense Mutation
Genes
Mutagenesis
Protein Stability
COS Cells
Enzyme activity
Site-Directed Mutagenesis
Sequence Analysis
Half-Life
Assays
Catalyst activity
Complementary DNA
Phenotype
Enzymes

Keywords

  • Acid sphingomyelinase
  • G247D Mutation
  • G247S Mutation
  • Missense mutation
  • pCMV6 Vector

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)

Cite this

Molecular genetic characterization of novel sphingomyelin phosphodiesterase 1 mutations causing Niemann–pick disease. / Tóth, B.; Erdős, M.; Székely, Annamária; Ritli, László; Bagossi, P.; Sümegi, János; Máródi, L.

JIMD Reports. Springer, 2012. p. 125-129 (JIMD Reports; Vol. 3).

Research output: Chapter in Book/Report/Conference proceedingChapter

Tóth, B. ; Erdős, M. ; Székely, Annamária ; Ritli, László ; Bagossi, P. ; Sümegi, János ; Máródi, L. / Molecular genetic characterization of novel sphingomyelin phosphodiesterase 1 mutations causing Niemann–pick disease. JIMD Reports. Springer, 2012. pp. 125-129 (JIMD Reports).
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