Dataset Information

Polymorphisms of the Niemann-Pick C1-like 1 gene in a Japanese population.

ABSTRACT: The Niemann-Pick C1 like 1 (NPC1L1) protein is a polytopic transmembrane protein responsible for dietary cholesterol absorption. Genetic variation in the NPC1L1 gene affects cholesterol absorption and serum cholesterol levels. However, NCP1L1 genotypes have not previously been invesigated. In this study, genotyping of the NPC1L1 gene was examined in healthy individuals as well as patients with hepatitis C virus (HCV) and inflammatory bowel disease (IBD). A total of 541 individuals were enrolled in the study, including 80 patients with HCV hepatitis, 205 with ulcerative colitis (UC) and 127 with Crohn's disease (CD). Genotyping was performed using TaqMan® SNP assays. Minor allelic frequencies of the 17345C>G (rs2072183) and 19031G>A (rs4720470) SNPs were found to be 0.40 and 0.30, respectively. No significant differences were detected in serum HCV levels in the 1735C>G or 19031G>A SNPs. The 1735C>G SNPs were not associated with total cholesterol (TC) levels in the healthy controls and/or HCV patients. However, statistically significant associations between the 1735GG variant and TC levels were detected in CD patients, with 1735GG carriers having the highest TC levels compared to the 1735CC and 1735CG carriers (P=0.048). Similar trends were noted in UC patients, but did not reach statistical significance (P= 0.19). The 19031G>A SNPs were not associated with TC levels in the healthy controls or patients. This study showed the allelic and genotypic distribution of 1735C>G and 19031G>ASNPs of the NPC1L1 gene in a large number of subjects. The NPC1L1 1735GG variant may therefore be favorable for CD accompanied with malnutrition.

SUBMITTER: Osaki R

PROVIDER: S-EPMC3956618 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Polymorphisms of the Niemann-Pick C1-like 1 gene in a Japanese population.

Osaki Rie R Imaeda Hirotsugu H Takahashi Kenichiro K Fujimoto Takehide T Takeuchi Takayuki T Fujiyama Yoshihide Y Andoh Akira A

Biomedical reports 20121017 1

The Niemann-Pick C1 like 1 (NPC1L1) protein is a polytopic transmembrane protein responsible for dietary cholesterol absorption. Genetic variation in the NPC1L1 gene affects cholesterol absorption and serum cholesterol levels. However, NCP1L1 genotypes have not previously been invesigated. In this study, genotyping of the NPC1L1 gene was examined in healthy individuals as well as patients with hepatitis C virus (HCV) and inflammatory bowel disease (IBD). A total of 541 indiv ...[more]

PMID: 24648913

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Project description:OBJECTIVES:The aim of this study was to comprehensively evaluate the auditory phenotype in Niemann-Pick disease, type C1 (NPC1), to understand better the natural history of this complex, heterogeneous disorder, and to define further the baseline auditory deficits associated with NPC1 so that use of potentially ototoxic interventions (e.g., 2-hydroxypropyl-ß-cyclodextrin) may be more appropriately monitored and understood. DESIGN:Fifty patients with NPC1 ranging in age from 4 months to 21 years (mean = 9.3 years) enrolled in a natural history/observational study at the National Institutes of Health. The auditory test battery included, when possible, immittance audiometry, pure-tone and speech audiometry, otoacoustic emission testing, and a neurotologic auditory brainstem response study. Longitudinal data were collected on a subset of patients. RESULTS:Over half of the cohort exhibited hearing loss involving the high frequencies ranging from a slight to moderate degree, and 74% of patients presented with clinically significant hearing loss involving the frequencies most important to speech understanding (0.5, 1, 2, 4 kHz). Despite the heterogeneity of the sample, results among patients were sufficiently consistent to implicate retrocochlear dysfunction in the majority (66%) of individuals, with (22%) or without (44%) accompanying cochlear involvement. Some patients (10%) presented with a profile for auditory neuropathy spectrum disorder. The combination of cross-sectional and longitudinal data indicates these patients are at risk for a progressive decline in auditory function. CONCLUSIONS:This is the largest cohort of patients with NPC1 evaluated comprehensively for auditory dysfunction, and results implicate the pathological processes of NPC1 in the manifestation of hearing loss. Patients with NPC1 should be monitored audiologically throughout their lives, beginning at the time of diagnosis. Clinicians and researchers should be aware of this historically overlooked aspect of the phenotype.

Project description:Niemann-Pick disease type C1 (NPC1) is a fatal congenital neurodegenerative disorder caused by mutations in the NPC1 gene, which is involved in cholesterol transport in lysosomes. Broad clinical manifestations of NPC1 include liver failure, pulmonary disorder, neurological deficits, and psychiatric symptoms. The main cause of death in NPC1 patients involves central nervous system (CNS) dysfunction; there is no essential treatment. We generated a tyrosine-mutant adeno-associated virus (AAV) 9/3 vector that expresses human NPC1 under a cytomegalovirus (CMV) promoter (AAV-CMV-hNPC1) and injected it into the left lateral ventricle (5 μL) and cisterna magna (10 μL) of Npc1 homo-knockout (Npc1-/-) mice. Each mouse received total 1.35 × 1011 vector genome on days 4 or 5 of life. AAV-treated Npc1-/- mice (n = 11) had an average survival of >28 weeks, while all saline-treated Npc1-/- mice (n = 11) and untreated Npc1-/- mice (n = 6) died within 16 weeks. Saline-treated and untreated Npc1-/- mice lost body weight from 7 weeks until death. However, the average body weight of AAV-treated Npc1-/- mice increased until 15 weeks. AAV-treated Npc1-/- mice also showed a significant improvement in the rotarod test performance. A pathological analysis at 11 weeks showed that cerebellar Purkinje cells were preserved in AAV-treated Npc1-/- mice. In contrast, untreated Npc1-/- mice showed an almost total loss of cerebellar Purkinje cells. Combined injection into both the lateral ventricle and cisterna magna achieved broader delivery of the vector to the CNS, leading to better outcomes than noted in previous reports, with injection into the lateral ventricles or veins alone. In AAV-treated Npc1-/- mice, vector genome DNA was detected widely in the CNS and liver. Human NPC1 RNA was detected in the brain, liver, lung, and heart. Accumulated unesterified cholesterol in the liver was reduced in the AAV-treated Npc1-/- mice. Our results suggest the feasibility of gene therapy for patients with NPC1.

Dataset Information

Polymorphisms of the Niemann-Pick C1-like 1 gene in a Japanese population.

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Polymorphisms of the Niemann-Pick C1-like 1 gene in a Japanese population.

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