title: Identification and characterization of eight novel SMPD1 mutations causing types A and B Niemann-Pick disease.
abstract: Types A and B Niemann-Pick disease (NPD) result from the deficient activity of acid sphingomyelinase (ASM), due to mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene. Here we report the identification, characterization and genotype/phenotype correlations of eight novel mutations in six unrelated NPD patients. These mutations included seven missense mutations: c.631T>C (p.W211R), c.757G>C (p.D253H), c.940G>A (p.V314M), c.1280A>G (p.H427R), c.1564A>G (p.N522S), c.1575G>C (p.Q525H) and c.1729A>G (p.H577R), and a novel frameshift mutation, c.1657delACCGCCT (fsT553). Each missense mutation was expressed in 293T or COS-7 cells; mutant enzymes p.W211R, p.D253H, p.H427R and p.H577R had <1% of expressed wild-type activity, whereas p.V314M, p.N522S and p.Q525H had 21.7%, 10.1% and 64% of expressed wild-type activity, respectively. The c.1564A>G mutation obliterated a known N-glycosylation site and its p.N522S mutant enzyme had ~10% of expressed wild-type activity. Western blot analysis revealed that each mutant protein was expressed at near wild-type amounts, despite their differences in residual activity. The novel seven-base deletion occurred at codon 553, leading to a premature truncation after residue 609. The expression studies predicted the clinical phenotypes of the six patients: two type A patients had genotypes with only type A alleles [c.631T>C (p.W211R), c.757G>C (p.D253H) and c.1729A>G (p.H577R)], and the other four type B disease patients had at least one neuroprotective mutant type B allele [c.940G>A (p.V314M), c.1280A>G (p.H427R), c.1564A>G (p.N522S) and c.1575G>C (p.Q525H)] that expressed >5% residual ASM activity. Thus, these new mutations provide novel genotype/phenotype correlations and further document the genetic heterogeneity in types A and B NPD.
authors.affiliation: Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine of New York University, New York, New York 10029, United States of America.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Desnick
authors.forename: Jungmin
authors.initials: J
authors.lastname: Kim
authors.forename: Xingxuan
authors.initials: X
authors.lastname: He
authors.forename: Melissa P
authors.initials: MP
authors.lastname: Wasserstein
authors.forename: Calogera M
authors.initials: CM
authors.lastname: Simonaro
authors.forename: Edward H
authors.initials: EH
authors.lastname: Schuchman
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D019556:COS Cells; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D004252:DNA Mutational Analysis; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D052536:Niemann-Pick Disease, Type A / Q000235:genetics*; D052537:Niemann-Pick Disease, Type B / Q000235:genetics*; D010641:Phenotype; D016415:Sequence Alignment; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: C543066:SMPD1 protein, human; D013108:Sphingomyelin Phosphodiesterase
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