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

Prajnya Ranganath, Divya Matta, Gandham Sri Lakshmi Bhavani, Savita Wangnekar, Jamal Mohammed Nurul Jain, Ishwar C. Verma, Madhulika Kabra, Ratna Dua Puri, Sumita Danda, Neerja Gupta, Katta M. Girisha, Vaikom H. Sankar, Siddaramappa J. Patil, Akella Radha Ramadevi, Meenakshi Bhat, Kalpana Gowrishankar, Kausik Mandal, Shagun Aggarwal, Parag Mohan Tamhankar, Preetha TilakShubha R. Phadke, Ashwin Dalal

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2719-2730
Number of pages12
JournalAmerican Journal of Medical Genetics, Part A
Volume170
Issue number10
DOIs
Publication statusPublished - 01-10-2016

Fingerprint

Sphingomyelin Phosphodiesterase
Mutation
Acids
India
Founder Effect
Insertional Mutagenesis
Haplotypes
Genes
Virulence
Software
Alleles

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Ranganath, P., Matta, D., Bhavani, G. S. L., Wangnekar, S., Jain, J. M. N., Verma, I. C., ... Dalal, A. (2016). Spectrum of SMPD1 mutations in Asian-Indian patients with acid sphingomyelinase (ASM)-deficient Niemann–Pick disease. American Journal of Medical Genetics, Part A, 170(10), 2719-2730. https://doi.org/10.1002/ajmg.a.37817
Ranganath, Prajnya ; Matta, Divya ; Bhavani, Gandham Sri Lakshmi ; 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. / Spectrum of SMPD1 mutations in Asian-Indian patients with acid sphingomyelinase (ASM)-deficient Niemann–Pick disease. In: American Journal of Medical Genetics, Part A. 2016 ; Vol. 170, No. 10. pp. 2719-2730.
@article{b77a5f80297d4792879dd9db65349d9d,
title = "Spectrum of SMPD1 mutations in Asian-Indian patients with acid sphingomyelinase (ASM)-deficient Niemann–Pick disease",
abstract = "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.",
author = "Prajnya Ranganath and Divya Matta and Bhavani, {Gandham Sri Lakshmi} and Savita Wangnekar and Jain, {Jamal Mohammed Nurul} and Verma, {Ishwar C.} and Madhulika Kabra and Puri, {Ratna Dua} and Sumita Danda and Neerja Gupta and Girisha, {Katta M.} and Sankar, {Vaikom H.} and Patil, {Siddaramappa J.} and Ramadevi, {Akella Radha} and Meenakshi Bhat and Kalpana Gowrishankar and Kausik Mandal and Shagun Aggarwal and Tamhankar, {Parag Mohan} and Preetha Tilak and Phadke, {Shubha R.} and Ashwin Dalal",
year = "2016",
month = "10",
day = "1",
doi = "10.1002/ajmg.a.37817",
language = "English",
volume = "170",
pages = "2719--2730",
journal = "American Journal of Medical Genetics, Part A",
issn = "1552-4825",
publisher = "Wiley-Liss Inc.",
number = "10",

}

Ranganath, P, Matta, D, Bhavani, GSL, Wangnekar, S, Jain, JMN, Verma, IC, Kabra, M, Puri, RD, Danda, S, Gupta, N, Girisha, KM, Sankar, VH, Patil, SJ, Ramadevi, AR, Bhat, M, Gowrishankar, K, Mandal, K, Aggarwal, S, Tamhankar, PM, Tilak, P, Phadke, SR & Dalal, A 2016, 'Spectrum of SMPD1 mutations in Asian-Indian patients with acid sphingomyelinase (ASM)-deficient Niemann–Pick disease', American Journal of Medical Genetics, Part A, vol. 170, no. 10, pp. 2719-2730. https://doi.org/10.1002/ajmg.a.37817

Spectrum of SMPD1 mutations in Asian-Indian patients with acid sphingomyelinase (ASM)-deficient Niemann–Pick disease. / Ranganath, Prajnya; Matta, Divya; Bhavani, Gandham Sri Lakshmi; 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.

In: American Journal of Medical Genetics, Part A, Vol. 170, No. 10, 01.10.2016, p. 2719-2730.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Spectrum of SMPD1 mutations in Asian-Indian patients with acid sphingomyelinase (ASM)-deficient Niemann–Pick disease

AU - Ranganath, Prajnya

AU - Matta, Divya

AU - Bhavani, Gandham Sri Lakshmi

AU - Wangnekar, Savita

AU - Jain, Jamal Mohammed Nurul

AU - Verma, Ishwar C.

AU - Kabra, Madhulika

AU - Puri, Ratna Dua

AU - Danda, Sumita

AU - Gupta, Neerja

AU - Girisha, Katta M.

AU - Sankar, Vaikom H.

AU - Patil, Siddaramappa J.

AU - Ramadevi, Akella Radha

AU - Bhat, Meenakshi

AU - Gowrishankar, Kalpana

AU - Mandal, Kausik

AU - Aggarwal, Shagun

AU - Tamhankar, Parag Mohan

AU - Tilak, Preetha

AU - Phadke, Shubha R.

AU - Dalal, Ashwin

PY - 2016/10/1

Y1 - 2016/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84987933018&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84987933018&partnerID=8YFLogxK

U2 - 10.1002/ajmg.a.37817

DO - 10.1002/ajmg.a.37817

M3 - Article

C2 - 27338287

AN - SCOPUS:84987933018

VL - 170

SP - 2719

EP - 2730

JO - American Journal of Medical Genetics, Part A

JF - American Journal of Medical Genetics, Part A

SN - 1552-4825

IS - 10

ER -