Niemann-Pick Disease Type C: Mutation Spectrum and Novel Sequence Variations in the Human NPC1 Gene Márcia Polese-Bonatto 1,2 & Hugo Bock 1,2 & Ana Carolina S. Farias 1 & Rafaella Mergener 1 & Maria Cristina Matte 1 & Mirela S. Gil 1 & Felipe Nepomuceno 3 & Fernanda T. S. Souza 4,5 & Rejane Gus 4 & Roberto Giugliani 1,4,5,6 & Maria Luiza Saraiva-Pereira 1,2,4,6,7 Received: 24 September 2018 /Accepted: 15 February 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Niemann-Pick type C (NP-C) is a rare autosomal recessive disorder characterized by storage of unesterified glycolipids and cholesterol in lysosome and/or late endosome due to mutations in either NPC1 or NPC2 gene. This study aims to identify the spectrum of sequence alterations associated to NP-C in individuals with clinical suspicion of this disease. The entire coding region and flanking sequences of both genes associated to NP-C were evaluated in a total of 265 individuals that were referred to our laboratory. Clinical and/or biochemical suspicion of NP-C was confirmed by molecular analysis in 54 subjects. In this cohort, 33 different sequence alterations were identified in NPC1 and one in NPC2. Among those, 5 novel alterations in NPC1 gene were identified as follows: one deletion (p.Lys38_Tyr40del), one frameshift (p.Asn195Lysfs*2), and three missense mutations (p.Cys238Arg, p.Ser365Pro and, p.Val694Met) that are likely to be pathogenic through different approaches, including in silico tools as well as multiple sequence alignment throughout different species. We have also reported main clinical symptoms of patients with novel alterations and distribution of frequent symptoms in the cohort. Findings reported here contribute to the knowledge of mutation spectrum of NP-C, defining frequent mutations as well as novel sequence alterations associated to the disease. Keywords Niemann-Pick type C disease . NPC1 gene . NPC2 gene . Mutation spectrum . Novel variation Introduction Niemann-Pick type C disease (NP-C disease; OMIM #257220) is a rare autosomal recessive neurodegenerative dis- order characterized by storage of unesterified glycolipids and cholesterol in lysosome and/or late endosome (LE/L) due to mutations in either NPC1 or NPC2 genes [1]. This disorder causes premature death, and subjects from different ethnic groups can be affected [2–4]. NP-C prevalence is approxi- mately 1/100,000 live births, but incidence can vary among different countries [ 4]. Hepatosplenomegaly, vertical supranuclear ophthalmoplegia, progressive ataxia, dystonia, and dementia are among symptoms characterized as the Bclassic^ phenotype [5–7]. Mutations in genes coding for the large transmembrane endosomal NPC1 and a small solu- ble lysosomal NPC2 proteins result in intracellular sterol Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12035-019-1528-z) contains supplementary material, which is available to authorized users. * Maria Luiza Saraiva-Pereira mlpereira@hcpa.edu.br 1 Laboratório de Identificação Genética, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil 2 Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil 3 Programa de Pós-Graduação em Biologia Celular e Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil 4 Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil 5 Departamento de Genética, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil 6 INAGEMP—Instituto Nacional de Genética Médica Populacional, Porto Alegre, RS, Brazil 7 Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil Molecular Neurobiology https://doi.org/10.1007/s12035-019-1528-z