Publication in detail

Sci Rep. 2017 Feb 7;7:41931. doi: 10.1038/srep41931.

New murine Niemann-Pick type C models bearing a pseudoexon-generating mutation recapitulate the main neurobehavioural and molecular features of the disease.

Gómez-Grau, M; Albaigès, J; Casas, J; Auladell, C; Dierssen, M; Vilageliu, L; Grinberg, D

University of Barcelona, 08028 Barcelona, Spain. Institut de Biomedicina de la UB (IBUB)-Institut de Recerca Sant Joan de Déu (IRSJD), 08028 Barcelona, Spain. Centre for Biomedical Research on Rare Diseases (CIBERER), 08028 Barcelona, Spain. Barcelona Institute of Science and Technology, 08003 Barcelona, Spain. Departament de Química Biomèdica, Institut de Química Avançada de Catalunya (IQAC-CSIC), 08034 Barcelona, Spain. Pompeu Fabra University (UPF), 08003 Barcelona, Spain.

Niemann-Pick disease type C (NPC) is a rare neurovisceral disease caused mainly by mutations in the NPC1 gene. This autosomal recessive lysosomal disorder is characterised by the defective lysosomal secretion of cholesterol and sphingolipids. No effective therapy exists for the disease. We previously described a deep intronic point mutation (c.1554-1009 G > A) in NPC1 that generated a pseudoexon, which could be corrected at the cellular level using antisense oligonucleotides. Here, we describe the generation of two mouse models bearing this mutation, one in homozygosity and the other in compound heterozygosity with the c.1920delG mutation. Both the homozygotes for the c.1554-1009 G > A mutation and the compound heterozygotes recapitulated the hallmarks of NPC. Lipid analysis revealed accumulation of cholesterol in the liver and sphingolipids in the brain, with both types of transgenic mice displaying tremor and ataxia at 7-8 weeks of age. Behavioural tests showed motor impairment, hyperactivity, reduced anxiety-like behaviour and impaired learning and memory performances, features consistent with those reported previously in NPC animal models and human patients. These mutant mice, the first NPC models bearing a pseudoexon-generating mutation, could be suitable for assessing the efficacy of specific splicing-targeted therapeutic strategies against NPC.

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