title: Identification of seven novel SMPD1 mutations causing Niemann-Pick disease types A and B.
abstract: Niemann-Pick disease (NPD) types A and B are autosomal, recessively inherited, lysosomal storage disorders caused by deficient activity of acid sphingomyelinase (E.C. 3.1.4.12) because of mutations in the sphingomyelin phosphodiesterase-1 (SMPD1) gene. Here, we present the molecular analysis and clinical characteristics of 15 NPD type A and B patients. Sequencing the SMDP1 gene revealed eight previously described mutations and seven novel mutations including four missense [c.682T>C (p.Cys228Arg), c.1159T>C (p.Cys387Arg), c.1474G>A (p.Gly492Ser), and c.1795C>T (p.Leu599Phe)], one frameshift [c.169delG (p.Ala57Leufs*20)] and two splicing (c.316+1G>T and c.1341delG). The most frequent mutations were p.Arg610del (21%) and p.Gly247Ser (12%). Two patients homozygous for p.Arg610del and initially classified as phenotype B showed different clinical manifestations. Patients homozygous for p.Leu599Phe had phenotype B, and those homozygous for c.1341delG or c.316+1G>T presented phenotype A. The present results provide new insight into genotype/phenotype correlations in NPD and emphasize the difficulty of classifying patients into types A and B, supporting the idea of a continuum between these two classic phenotypes.
authors.affiliation: Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain; Instituto de Investigación Sanitaria de Aragón (IIS), Zaragoza, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Zaragoza (U752), Barcelona (U719), Spain.
authors.forename: P
authors.initials: P
authors.lastname: Irun
authors.forename: M
authors.initials: M
authors.lastname: Mallén
authors.forename: C
authors.initials: C
authors.lastname: Dominguez
authors.forename: V
authors.initials: V
authors.lastname: Rodriguez-Sureda
authors.forename: L A
authors.initials: LA
authors.lastname: Alvarez-Sala
authors.forename: N
authors.initials: N
authors.lastname: Arslan
authors.forename: N
authors.initials: N
authors.lastname: Bermejo
authors.forename: C
authors.initials: C
authors.lastname: Guerrero
authors.forename: I
authors.initials: I
authors.lastname: Perez de Soto
authors.forename: L
authors.initials: L
authors.lastname: Villalón
authors.forename: P
authors.initials: P
authors.lastname: Giraldo
authors.forename: M
authors.initials: M
authors.lastname: Pocovi
mesh_terms: D019943:Amino Acid Substitution; D023061:Gene Order; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D009154:Mutation; D009542:Niemann-Pick Diseases / Q000175:diagnosis* / Q000235:genetics*; D010641:Phenotype; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics*
chemical_list: C543066:SMPD1 protein, human; D013108:Sphingomyelin Phosphodiesterase