SMPD1 Mutation Update: Database and Comprehensive Analysis of Published and Novel Variants.
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.
Regional Coordinator Centre for Rare Diseases, University Hospital Santa Maria della Misericordia, Udine, Italy.
Stefania
S
Zampieri
Centro di Diagnostica Genetica e Biochimica delle Malattie Metaboliche, Istituto G. Gaslini, Genova, Italy.
Mirella
M
Filocamo
Regional Coordinator Centre for Rare Diseases, University Hospital Santa Maria della Misericordia, Udine, Italy.
Annalisa
A
Pianta
Centro di Diagnostica Genetica e Biochimica delle Malattie Metaboliche, Istituto G. Gaslini, Genova, Italy.
Susanna
S
Lualdi
Sección Errores Congénitos del Metabolismo-IBC, Serv Bioquímica y Genética Molecular, Hospital Clínic; IDIBAPS; CIBERER, Barcelona, Spain.
Laura
L
Gort
Sección Errores Congénitos del Metabolismo-IBC, Serv Bioquímica y Genética Molecular, Hospital Clínic; IDIBAPS; CIBERER, Barcelona, Spain.
Maria Jose
MJ
Coll
Department of Computing and Information Systems, University of Melbourne, Melbourne, Australia.
Richard
R
Sinnott
University of Birmingham and Queen Elizabeth Hospital, Birmingham, UK.
Tarekegn
T
Geberhiwot
Regional Coordinator Centre for Rare Diseases, University Hospital Santa Maria della Misericordia, Udine, Italy.
Bruno
B
Bembi
Regional Coordinator Centre for Rare Diseases, University Hospital Santa Maria della Misericordia, Udine, Italy.
Andrea
A
Dardis
D030541:Databases, Genetic; D005091:Exons; D015870:Gene Expression; D005808:Genes, Recessive; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007438:Introns; D009154:Mutation; D052536:Niemann-Pick Disease, Type A / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D052537:Niemann-Pick Disease, Type B / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D016366:Open Reading Frames; D010641:Phenotype; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics*; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics*
D012333:RNA, Messenger; C543066:SMPD1 protein, human; D013108:Sphingomyelin Phosphodiesterase
Niemann-Pick; SMPD1; acid sphingomyelinase; lysosomal storage disorder