Identification of seven novel SMPD1 mutations causing Niemann–Pick disease types A and B

Authors

  • P Irun,

    Corresponding author
    1. Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain
    2. Instituto de Investigación Sanitaria de Aragón (IIS), Zaragoza, Spain
    3. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Zaragoza (U752), Barcelona (U719), Spain
    • Corresponding author: Dr Pilar Irún, Departamento de Bioquímica y Biología, Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, C. Pedro, Cerbuna 12, 50009 Zaragoza, Spain.

      Tel.: +34 976761224;

      fax: +34 976762123;

      e-mail: mpirun@unizar.es

    Search for more papers by this author
  • M Mallén,

    1. Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain
    Search for more papers by this author
  • C Dominguez,

    1. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Zaragoza (U752), Barcelona (U719), Spain
    2. Biochemistry and Molecular Biology Research Centre for Nanomedicine, Area T2 Nanomedicina, Vall Hebron University Hospital, Barcelona, Spain
    Search for more papers by this author
  • V Rodriguez-Sureda,

    1. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Zaragoza (U752), Barcelona (U719), Spain
    2. Biochemistry and Molecular Biology Research Centre for Nanomedicine, Area T2 Nanomedicina, Vall Hebron University Hospital, Barcelona, Spain
    Search for more papers by this author
  • LA Alvarez-Sala,

    1. Lipids Unit, Medicina Interna, Gregorio Marañón University Hospital, Madrid, Spain
    2. Medicine Faculty, Complutense Madrid University, Madrid, Spain
    Search for more papers by this author
  • N Arslan,

    1. Deparment of Pediatrics, Division of Pediatric Gastroenterology, Nutrition and Metabolism, Dokuz Eylul University Medical Faculty, Alsancak, Izmir, Turkey
    Search for more papers by this author
  • N Bermejo,

    1. Servicio de Hematología y Hemoterapia, Hospital San Pedro de Alcántara, Complejo Hospitalario de Cáceres, Cáceres, Spain
    Search for more papers by this author
  • C Guerrero,

    1. Servicio de Pediatria, Hospital de Alcañiz, Alcañiz, Spain
    Search for more papers by this author
  • I Perez de Soto,

    1. Servicio de Hematología, Hospital Universitario Virgen del Rocío, Sevilla, Spain
    Search for more papers by this author
  • L Villalón,

    1. Servicio de Hematología, Hospital Universitario Fundación Alcorcón, Madrid, Spain
    Search for more papers by this author
  • P Giraldo,

    1. Instituto de Investigación Sanitaria de Aragón (IIS), Zaragoza, Spain
    2. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Zaragoza (U752), Barcelona (U719), Spain
    3. Departamento de Hematología, Hospital Universitario Miguel Servet, Zaragoza, Spain
    Search for more papers by this author
  • M Pocovi

    1. Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain
    2. Instituto de Investigación Sanitaria de Aragón (IIS), Zaragoza, Spain
    3. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Zaragoza (U752), Barcelona (U719), Spain
    Search for more papers by this author

  • The authors declare no conflict of interests related to this study.

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.

Ancillary