SMPD1 Mutation Update: Database and Comprehensive Analysis of Published and Novel Variants

• Published in: Human mutation Vol. 37; no. 2; pp. 139 - 147
• Main Authors: Zampieri, Stefania, Filocamo, Mirella, Pianta, Annalisa, Lualdi, Susanna, Gort, Laura, Coll, Maria Jose, Sinnott, Richard, Geberhiwot, Tarekegn, Bembi, Bruno, Dardis, Andrea
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.02.2016; Hindawi Limited
• Subjects: acid sphingomyelinase; Databases, Genetic; Exons; Gene Expression; Genes, Recessive; Genetic Association Studies; Genetic counseling; Genetic disorders; Genotype; Genotype & phenotype; Humans; Introns; lysosomal storage disorder; Mutation; Niemann-Pick; Niemann-Pick Disease, Type A - diagnosis; Niemann-Pick Disease, Type A - genetics; Niemann-Pick Disease, Type A - pathology; Niemann-Pick Disease, Type B - diagnosis; Niemann-Pick Disease, Type B - genetics; Niemann-Pick Disease, Type B - pathology; Open Reading Frames; Phenotype; RNA Splicing; RNA, Messenger - genetics; SMPD1; Sphingomyelin Phosphodiesterase - genetics; lysosomal storage disorder; SMPD1; acid sphingomyelinase; Niemann-Pick
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/humu.22923

ABSTRACT Niemann–Pick Types A and B (NPA/B) diseases are autosomal recessive lysosomal storage disorders caused by the deficient activity of acid sphingomyelinase (ASM) because of the mutations in the SMPD1 gene. Here, we provide a comprehensive updated review of already reported and newly identified SMPD1 variants. Among them, 185 have been found in NPA/B patients. Disease‐causing variants are equally distributed along the SMPD1 gene; most of them are missense (65.4%) or frameshift (19%) mutations. The most frequently reported mutation worldwide is the p.R610del, clearly associated with an attenuated NP disease type B phenotype. The available information about the impact of 52 SMPD1 variants on ASM mRNA and/or enzymatic activity has been collected and whenever possible, phenotype/genotype correlations were established. In addition, we created a locus‐specific database easily accessible at http://www.inpdr.org/genes that catalogs the 417 SMPD1 variants reported to date and provides data on their in silico predicted effects on ASM protein function or mRNA splicing. The information reviewed in this article, providing new insights into the genotype/phenotype correlation, is extremely valuable to facilitate diagnosis and genetic counseling of families affected by NPA/B. The SMPD1 locus‐specific database provides a comprehensive catalog of the 417 SMPD1 variants reported to date. Among them 185 have been found in NPA/B patients. Disease‐causing mutations are equally distributed along the SMPD1 gene and most of them have been identified within its coding sequence. The vast majority are missense mutations (65.4%). No large deletions or insertions have been reported so far. The most frequently reported mutation worldwide is the p.R610del, clearly associated with a attenuated NP type B phenotype.