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Functional characterization of novel variants in SMPD1 in Indian patients with acid sphingomyelinase deficiency
Author(s) -
Deshpande Dipti,
Gupta Shailesh Kumar,
Sarma Asodu Sandeep,
Ranganath Prajnya,
Jain S. Jamal Md Nurul,
Sheth Jayesh,
Mistri Mehul,
Gupta Neerja,
Kabra Madhulika,
Phadke Shubha R.,
Girisha Katta M.,
Dua Puri Ratna,
Aggarwal Shagun,
Datar Chaitanya,
Mandal Kausik,
Tilak Preetha,
Muranjan Mamta,
BijarniaMahay Sunita,
Rama Devi A. Radha,
Tayade Naresh B.,
Ranjan Akash,
Dalal Ashwin B.
Publication year - 2021
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.24263
Subject(s) - missense mutation , biology , acid sphingomyelinase , in silico , sanger sequencing , compound heterozygosity , genetics , medical genetics , disease , gene , phenotype , mutation , sphingomyelin , medicine , pathology , membrane
Pathogenic variations in SMPD1 lead to acid sphingomyelinase deficiency (ASMD), that is, Niemann‐Pick disease (NPD) type A and B (NPA, NPB), which is a recessive lysosomal storage disease. The knowledge of variant spectrum in Indian patients is crucial for early and accurate NPD diagnosis and genetic counseling of families. In this study, we recruited 40 unrelated pediatric patients manifesting symptoms of ASMD and subnormal ASM enzyme activity. Variations in SMPD1 were studied using Sanger sequencing for all exons, followed by interpretation of variants based on American College of Medical Genetics and Genomics & Association for Molecular Pathology (ACMG/AMP) criteria. We identified 18 previously unreported variants and 21 known variants, including missense, nonsense, deletions, duplications, and splice site variations with disease‐causing potential. Eight missense variants were functionally characterized using in silico molecular dynamic simulation and in vitro transient transfection in HEK293T cells, followed by ASM enzyme assay, immunoblot, and immunofluorescence studies. All the variants showed reduced ASM activity in transfected cells confirming their disease‐causing potential. The study provides data for efficient prenatal diagnosis and genetic counseling of families with NPD type A and B.