Identification and characterization of SMPD1 mutations causing Niemann-Pick types A and B in Spanish patients

Authors

  • Laura Rodríguez-Pascau,

    1. Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
    2. CIBER de Enfermedades Raras (CIBERER), Barcelona, Spain
    3. Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain
    Search for more papers by this author
    • The first two authors contributed equally to this work.

  • Laura Gort,

    1. CIBER de Enfermedades Raras (CIBERER), Barcelona, Spain
    2. Institut de Bioquímica Clínica, Hospital Clínic, Corporació Sanitària Clínic, Barcelona, Spain
    Search for more papers by this author
    • The first two authors contributed equally to this work.

  • Edward H. Schuchman,

    1. Department of Genetics & Genomic Sciences, Mount Sinai School of Medicine, New York, New York, USA
    Search for more papers by this author
  • Lluïsa Vilageliu,

    1. Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
    2. CIBER de Enfermedades Raras (CIBERER), Barcelona, Spain
    3. Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain
    Search for more papers by this author
  • Daniel Grinberg,

    Corresponding author
    1. Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
    2. CIBER de Enfermedades Raras (CIBERER), Barcelona, Spain
    3. Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain
    • Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
    Search for more papers by this author
  • Amparo Chabás

    1. CIBER de Enfermedades Raras (CIBERER), Barcelona, Spain
    2. Institut de Bioquímica Clínica, Hospital Clínic, Corporació Sanitària Clínic, Barcelona, Spain
    Search for more papers by this author

  • Communicated by William S. Sly

Abstract

Niemann-Pick disease (NPD) types A/B are both caused by a deficiency of lysosomal acid sphingomyelinase and display autosomal recessive inheritance. These two types of the disease were described according to the presence (type A) or absence (type B) of neurological symptoms. We present a molecular analysis of 19 Spanish NPD A/B patients and two from Maghreb. Eight of the patients had type A and 13 had type B NPD. All mutant SMPD1 alleles were identified, including 17 different mutations, 10 of which were novel. The only frequent mutations in the 21 NPD patients were c.1823_1825delGCC (p.R608del) (38%) and c.1445C>A (p.A482E) (9%). Genotype–phenotype correlations were established for most of the mutations and, in particular, the p.R608del-type B association was confirmed. This mutation accounts for 61.5% of the mutant alleles in the type B subgroup of patients. Expression studies performed on six of the identified mutations confirmed them to be disease-causing due to their low enzyme activity. An allele with a mutation affecting a noncanonical donor splice site produced only aberrant mRNAs, corresponding to previously reported nonfunctional SMPD1 minor transcripts. This study is the first exhaustive mutational analysis of Spanish Niemann-Pick A/B disease patients. Hum Mutat 30:1–6, 2009. © 2009 Wiley-Liss, Inc.

Ancillary