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

• Published in: American journal of medical genetics. Part A Vol. 170A; no. 10; pp. 2719 - 2730
• Main Authors: Ranganath, Prajnya, Matta, Divya, Bhavani, Gandham SriLakshmi, Wangnekar, Savita, Jain, Jamal Mohammed Nurul, Verma, Ishwar C., Kabra, Madhulika, Puri, Ratna Dua, Danda, Sumita, Gupta, Neerja, Girisha, Katta M., Sankar, Vaikom H., Patil, Siddaramappa J., Ramadevi, Akella Radha, Bhat, Meenakshi, Gowrishankar, Kalpana, Mandal, Kausik, Aggarwal, Shagun, Tamhankar, Parag Mohan, Tilak, Preetha, Phadke, Shubha R., Dalal, Ashwin
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01-10-2016; Wiley Subscription Services, Inc
• Subjects: acid sphingomyelinase deficiency; 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 disease; Niemann-Pick Diseases - diagnosis; Niemann-Pick Diseases - genetics; Niemann-Pick Diseases - metabolism; Phenotype; Polymorphism, Single Nucleotide; Prenatal Diagnosis; Protein Conformation; SMPD1 gene mutation; Sphingomyelin Phosphodiesterase - chemistry; Sphingomyelin Phosphodiesterase - genetics; Sphingomyelin Phosphodiesterase - metabolism; Splenomegaly; Niemann-Pick disease; acid sphingomyelinase deficiency; SMPD1 gene mutation; India
• ISSN: 1552-4825; 1552-4833
• DOI: 10.1002/ajmg.a.37817

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.