Spectrum of SMPD1 mutations in Asian-Indian patients with acid sphingomyelinase (ASM)-deficient Niemann-Pick disease

Am J Med Genet A. 2016 Oct;170(10):2719-30. doi: 10.1002/ajmg.a.37817. Epub 2016 Jun 24.


Acid sphingomyelinase (ASM)-deficient Niemann-Pick disease is an autosomal recessive lysosomal storage disorder caused by biallelic mutations in the SMPD1 gene. To date, around 185 mutations have been reported in patients with ASM-deficient NPD world-wide, but the mutation spectrum of this disease in India has not yet been reported. The aim of this study was to ascertain the mutation profile in Indian patients with ASM-deficient NPD. We sequenced SMPD1 in 60 unrelated families affected with ASM-deficient NPD. A total of 45 distinct pathogenic sequence variants were found, of which 14 were known and 31 were novel. The variants included 30 missense, 4 nonsense, and 9 frameshift (7 single base deletions and 2 single base insertions) mutations, 1 indel, and 1 intronic duplication. The pathogenicity of the novel mutations was inferred with the help of the mutation prediction software MutationTaster, SIFT, Polyphen-2, PROVEAN, and HANSA. The effects of the identified sequence variants on the protein structure were studied using the structure modeled with the help of the SWISS-MODEL workspace program. The p. (Arg542*) (c.1624C>T) mutation was the most commonly identified mutation, found in 22% (26 out of 120) of the alleles tested, but haplotype analysis for this mutation did not identify a founder effect for the Indian population. To the best of our knowledge, this is the largest study on mutation analysis of patients with ASM-deficient Niemann-Pick disease reported in literature and also the first study on the SMPD1 gene mutation spectrum in India. © 2016 Wiley Periodicals, Inc.

Keywords: India; Niemann-Pick disease; SMPD1 gene mutation; acid sphingomyelinase deficiency.

MeSH terms

  • Adolescent
  • Alleles
  • Amino Acid Substitution
  • Biomarkers
  • Child
  • Child, Preschool
  • Computational Biology / methods
  • Consanguinity
  • DNA Mutational Analysis
  • Enzyme Activation
  • Exons
  • Facies
  • Genotype
  • Haplotypes
  • Humans
  • India
  • Infant
  • Infant, Newborn
  • Models, Molecular
  • Mutation*
  • Niemann-Pick Diseases / diagnosis*
  • Niemann-Pick Diseases / genetics*
  • Niemann-Pick Diseases / metabolism
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Prenatal Diagnosis
  • Protein Conformation
  • Sphingomyelin Phosphodiesterase / chemistry
  • Sphingomyelin Phosphodiesterase / genetics*
  • Sphingomyelin Phosphodiesterase / metabolism
  • Splenomegaly


  • Biomarkers
  • SMPD1 protein, human
  • Sphingomyelin Phosphodiesterase