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Molecular analysis of 30 Niemann–Pick type C patients from Spain

Authors

  • J Macías-Vidal,

    1. Institut de Bioquímica Clínica, Servei de Bioquímica i Genètica Molecular, Hospital Clínic, Barcelona, Spain
    2. CIBER de Enfermedades Raras (CIBERER), Barcelona, Spain
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  • L Rodríguez-Pascau,

    1. CIBER de Enfermedades Raras (CIBERER), Barcelona, Spain
    2. Departament de Genètica, Universitat de Barcelona, Barcelona, Spain
    3. Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain
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  • G Sánchez-Ollé,

    1. CIBER de Enfermedades Raras (CIBERER), Barcelona, Spain
    2. Departament de Genètica, Universitat de Barcelona, Barcelona, Spain
    3. Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain
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  • M Lluch,

    1. Institut de Bioquímica Clínica, Servei de Bioquímica i Genètica Molecular, Hospital Clínic, Barcelona, Spain
    2. CIBER de Enfermedades Raras (CIBERER), Barcelona, Spain
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  • L Vilageliu,

    1. CIBER de Enfermedades Raras (CIBERER), Barcelona, Spain
    2. Departament de Genètica, Universitat de Barcelona, Barcelona, Spain
    3. Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain
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  • D Grinberg,

    1. CIBER de Enfermedades Raras (CIBERER), Barcelona, Spain
    2. Departament de Genètica, Universitat de Barcelona, Barcelona, Spain
    3. Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain
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  • MJ Coll,

    Corresponding author
    1. Institut de Bioquímica Clínica, Servei de Bioquímica i Genètica Molecular, Hospital Clínic, Barcelona, Spain
    2. CIBER de Enfermedades Raras (CIBERER), Barcelona, Spain
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  • the Spanish NPC Working Group

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    • The Spanish NPC Working Group includes all physicians who referred patients' samples for the study: A. Alonso (Hospital Virgen del Camino, Pamplona), M. Arellano (Hospital Mútua de Terrassa, Barcelona), O. Blanco de la Barca (Complejo Hospitalario Universitario de Vigo), M. R. Cazorla (Hospital de Fuenlabrada, Madrid), J. Dalmau (Hospital Universitari La Fe, Valencia), R. Domingo (Hospital Universitario Virgen de la Arrixaca, Murcia), M. T. García-Silva and E. Martín (Hospital Universitario 12 de Octubre, Madrid), M. Gil-Campos (Hospital Universitario Reina Sofía, Córdoba), P. Jara (Hospital Universitario La Paz, Madrid), D. Lefeber (Radboud University Medical Centre Nijmegen, Nederland), J. A. Martínez-Matos and L. Romero (Hospital Universitari de Bellvitge, Barcelona), I. Ortiz (Hospital General de Elda, Alicante), G. Ozaita (Complexo Hospitalario de Ourense), M. S. Pérez Poyato and M. Pineda (Hospital Sant Joan de Déu, Barcelona), J. Prieto (Hospital Universitario de Salamanca), S. Roldán (Hospital Virgen de las Nieves, Granada), L. Ruiz del Portal (Hospital Universitario Virgen del Rocío, Sevilla) and A. Verdú Pérez (Hospital Virgen de la Salud, Toledo).


Dr Maria Josep Coll, Institut de Bioquímica Clínica, Servei de Bioquímica i Genètica Molecular, Hospital Clínic, C/Mejía Lequerica s/n, Ed. Helios III Planta baixa, 08028 Barcelona, Spain.
Tel.: +34 932279341;
fax: +34 932275668;
e-mail: mjcoll@clinic.ub.es

Abstract

Macías-Vidal J, Rodríguez-Pascau L, Sánchez-Ollé G, Lluch M, Vilageliu L, Grinberg D, Coll MJ, the Spanish NPC Working Group. Molecular analysis of 30 Niemann–Pick type C patients from Spain.

Mutations in the NPC1 or NPC2 gene are responsible for Niemann–Pick type C (NPC) disease (OMIM #257220), an autosomal recessive neurodegenerative lysosomal storage disorder caused by an incorrect regulation of intracellular lipid trafficking. A molecular analysis carried out in 30 unrelated patients identified 43 distinct mutations in the NPC1 gene, 12 of which had not been previously described. The novel NPC1 alleles were four amino acid substitutions (p.F995L, p.F1079S, p.L1106P and p.G1209E), a nonsense mutation (p.E1089X), a 1-bp insertion (p.L1117PfsX4), an in-frame deletion (p.N916del), four intronic changes (c.58-3280C>G, c.882-28A>T, c.2604+5G>A and c.3591+5G>A) that affect the splicing mechanism, and the first deletion including the whole gene described in NPC disease. In all the splice site mutations, the formation of abnormal spliced transcripts was confirmed by cDNA analysis, and mRNA degradation by the nonsense-mediated mRNA decay process was also assessed. As it has been previously reported in this disease, genotype–phenotype correlations are limited due to the large number of private mutations. We describe for the first time one homozygous patient for p.I1061T mutation, who presented the severe infantile clinical onset, and another patient with the variant biochemical phenotype, whose clinical presentation was the neonatal form of the disease.

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