Identification and characterization of eight novel SMPD1 mutations causing types A and B Niemann-Pick disease

Mol Med. 2010 Jul-Aug;16(7-8):316-21. doi: 10.2119/molmed.2010.00017. Epub 2010 Apr 6.


Types A and B Niemann-Pick disease (NPD) result from the deficient activity of acid sphingomyelinase (ASM), due to mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene. Here we report the identification, characterization and genotype/phenotype correlations of eight novel mutations in six unrelated NPD patients. These mutations included seven missense mutations: c.631T>C (p.W211R), c.757G>C (p.D253H), c.940G>A (p.V314M), c.1280A>G (p.H427R), c.1564A>G (p.N522S), c.1575G>C (p.Q525H) and c.1729A>G (p.H577R), and a novel frameshift mutation, c.1657delACCGCCT (fsT553). Each missense mutation was expressed in 293T or COS-7 cells; mutant enzymes p.W211R, p.D253H, p.H427R and p.H577R had <1% of expressed wild-type activity, whereas p.V314M, p.N522S and p.Q525H had 21.7%, 10.1% and 64% of expressed wild-type activity, respectively. The c.1564A>G mutation obliterated a known N-glycosylation site and its p.N522S mutant enzyme had ~10% of expressed wild-type activity. Western blot analysis revealed that each mutant protein was expressed at near wild-type amounts, despite their differences in residual activity. The novel seven-base deletion occurred at codon 553, leading to a premature truncation after residue 609. The expression studies predicted the clinical phenotypes of the six patients: two type A patients had genotypes with only type A alleles [c.631T>C (p.W211R), c.757G>C (p.D253H) and c.1729A>G (p.H577R)], and the other four type B disease patients had at least one neuroprotective mutant type B allele [c.940G>A (p.V314M), c.1280A>G (p.H427R), c.1564A>G (p.N522S) and c.1575G>C (p.Q525H)] that expressed >5% residual ASM activity. Thus, these new mutations provide novel genotype/phenotype correlations and further document the genetic heterogeneity in types A and B NPD.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Blotting, Western
  • COS Cells
  • Cell Line
  • Child
  • Child, Preschool
  • Chlorocebus aethiops
  • Cloning, Molecular
  • DNA Mutational Analysis
  • Female
  • Frameshift Mutation*
  • Humans
  • Male
  • Molecular Sequence Data
  • Mutation, Missense*
  • Niemann-Pick Disease, Type A / genetics*
  • Niemann-Pick Disease, Type B / genetics*
  • Phenotype
  • Sequence Alignment
  • Sphingomyelin Phosphodiesterase / genetics*
  • Sphingomyelin Phosphodiesterase / metabolism
  • Transfection


  • SMPD1 protein, human
  • Sphingomyelin Phosphodiesterase