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. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Medical Genetics, Nizam's Institute of Medical Genetics, Hyderabad, Telangana, India.|Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India.
authors.forename: Prajnya
authors.initials: P
authors.lastname: Ranganath
authors.affiliation: Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India.
authors.forename: Divya
authors.initials: D
authors.lastname: Matta
authors.affiliation: Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, Karnataka, India.
authors.forename: Gandham SriLakshmi
authors.initials: GS
authors.lastname: Bhavani
authors.affiliation: Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India.
authors.forename: Savita
authors.initials: S
authors.lastname: Wangnekar
authors.affiliation: Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India.
authors.forename: Jamal Mohammed Nurul
authors.initials: JM
authors.lastname: Jain
authors.affiliation: Center of Medical Genetics, Sir GangaRam Hospital, New Delhi, India.
authors.forename: Ishwar C
authors.initials: IC
authors.lastname: Verma
authors.affiliation: Genetics Unit, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Madhulika
authors.initials: M
authors.lastname: Kabra
authors.affiliation: Center of Medical Genetics, Sir GangaRam Hospital, New Delhi, India.
authors.forename: Ratna Dua
authors.initials: RD
authors.lastname: Puri
authors.affiliation: Department of Clinical Genetics, Christian Medical College and Hospital, Vellore, Tamil Nadu, India.
authors.forename: Sumita
authors.initials: S
authors.lastname: Danda
authors.affiliation: Genetics Unit, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Neerja
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, Karnataka, India.
authors.forename: Katta M
authors.initials: KM
authors.lastname: Girisha
authors.affiliation: Genetic Clinic, Department of Pediatrics, SAT Hospital, Government Medical College, Thiruvananthapuram, Kerala, India.
authors.forename: Vaikom H
authors.initials: VH
authors.lastname: Sankar
authors.affiliation: Clinical Genetics Unit, Mazumdhar Shaw Medical Center, Bengaluru, Karnataka, India.
authors.forename: Siddaramappa J
authors.initials: SJ
authors.lastname: Patil
authors.affiliation: Division of Genetics, Rainbow Children's Hospital, Hyderabad, Telangana, India.
authors.forename: Akella Radha
authors.initials: AR
authors.lastname: Ramadevi
authors.affiliation: Centre for Human Genetics, Bengaluru, Karnataka, India.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Bhat
authors.affiliation: Department of Medical Genetics, CHILDS Trust Medical Research Foundation, Kanchi Kamakoti CHILDS Trust Hospital, Chennai, Tamil Nadu, India.
authors.forename: Kalpana
authors.initials: K
authors.lastname: Gowrishankar
authors.affiliation: Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.
authors.forename: Kausik
authors.initials: K
authors.lastname: Mandal
authors.affiliation: Department of Medical Genetics, Nizam's Institute of Medical Genetics, Hyderabad, Telangana, India.|Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India.
authors.forename: Shagun
authors.initials: S
authors.lastname: Aggarwal
authors.affiliation: Genetic Research Centre, National Institute for Research in Reproductive Health, Mumbai, Maharashtra, India.
authors.forename: Parag Mohan
authors.initials: PM
authors.lastname: Tamhankar
authors.affiliation: Division of Human Genetics, St. John's Medical College, Bengaluru, Karnataka, India.
authors.forename: Preetha
authors.initials: P
authors.lastname: Tilak
authors.affiliation: Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.
authors.forename: Shubha R
authors.initials: SR
authors.lastname: Phadke
authors.affiliation: Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India. ashwindalal@gmail.com.
authors.forename: Ashwin
authors.initials: A
authors.lastname: Dalal
mesh_terms: D000293:Adolescent; D000483:Alleles; D019943:Amino Acid Substitution; D015415:Biomarkers; D002648:Child; D002675:Child, Preschool; D019295:Computational Biology / Q000379:methods; D003241:Consanguinity; D004252:DNA Mutational Analysis; D004789:Enzyme Activation; D005091:Exons; D019066:Facies; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007194:India; D007223:Infant; D007231:Infant, Newborn; D008958:Models, Molecular; D009154:Mutation; D009542:Niemann-Pick Diseases / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011296:Prenatal Diagnosis; D011487:Protein Conformation; D013108:Sphingomyelin Phosphodiesterase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D013163:Splenomegaly
chemical_list: D015415:Biomarkers; C543066:SMPD1 protein, human; D013108:Sphingomyelin Phosphodiesterase
keywords: India; Niemann-Pick disease; SMPD1 gene mutation; acid sphingomyelinase deficiency