Type C Niemann-Pick disease: spectrum of phenotypic variation in disruption of intracellular LDL-derived cholesterol processing

Vanier, Marie T.; Rodriguez-Lafrasse, Claire; Rousson, Robert; Gazzah, Noureddine; Juge, Marie-Christine; Pentchev, Peter G.; Revol, A; Louisot, Pierre

doi:10.1016/0925-4439(91)90069-l

Cited by 207 publications

(195 citation statements)

References 26 publications

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“…In these patients, the known biochemical assays do not allow adequate diagnosis and cannot be applied for prenatal diagnosis. 21,28 Thus, molecular diagnosis of the specific mutation aids both in direct diagnosis of affected individuals and in accurate detection of carriers among this highly consanguineous population.…”

Section: Discussionmentioning

confidence: 99%

Clinical-biochemical correlation in molecularly characterized patients with Niemann-Pick type C

Meiner

Shpitzen

Mandel³

et al. 2001

Genetics in Medicine

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Purpose: Niemann-Pick disease type C (NP-C) is an autosomal recessive lipid storage disease manifested by an impairment in cellular cholesterol homeostasis. The clinical phenotype of NP-C is extremely variable, ranging from an acute neonatal form to an adult late-onset presentation. To facilitate phenotype-genotype studies, we have analyzed multiple Israeli NP-C families. Methods: The severity of the disease was assessed by the age at onset, hepatic involvement, neurological deterioration, and cholesterol esterification studies. Screening of the entire NPC1 coding sequence allowed for molecular characterization and identification of disease causing mutations.Results: A total of nine NP-C index cases with mainly neurovisceral involvement were characterized. We demon-

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Section: Discussionmentioning

confidence: 99%

Clinical-biochemical correlation in molecularly characterized patients with Niemann-Pick type C

Meiner

Shpitzen

Mandel³

et al. 2001

Genetics in Medicine

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“…The filipin staining and LDL-induced cholesteryl ester formation tests were performed in cultured fibroblasts as described (Vanier et al 1991). Genomic DNA amplification and sequencing of exons and corresponding intronic flanking regions were performed for the detection of mutations in the NPC 1 and NPC 2 genes.…”

Section: Methodsmentioning

confidence: 99%

The Spectrum of Niemann-Pick Type C Disease in Greece

Mavridou

Dimitriou²,

Vanier

et al. 2017

JIMD Reports

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Niemann-Pick type C disease (NPC) is a neurovisceral lysosomal storage disease caused by mutations in either the NPC1 or the NPC2 gene. It is a cellular lipid trafficking disorder characterized by the accumulation of unesterified cholesterol and various sphingolipids in the lysosomes and late endosomes, and it exhibits a broad clinical spectrum. Today, over 420 disease-causing mutations have been identified in the NPC1 and the NPC2

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“…Filipin staining was performed in adipocytes treated with U18666a, as described previously (23,24). U18666a is a widely used inhibitor of cholesterol trafficking and synthesis.…”

Section: Filipin Stainingmentioning

confidence: 99%

Niemann-Pick type C2 deficiency impairs autophagy-lysosomal activity, mitochondrial function, and TLR signaling in adipocytes

Guo

Zhao

Qiu

et al. 2016

Journal of Lipid Research

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Aging is a risk factor for the development of chronic metabolic diseases such as type 2 diabetes, cardiovascular disease, neurodegenerative disease, and cancer. These aging-related diseases are known to be clustered together; aging-associated neurodegenerative disorders frequently coincide with type 2 diabetes, insulin resistance, obesity, and metabolic syndrome. This suggests that neurodegenerative disorders and type 2 diabetes share common genetic and metabolic features. Therefore, studying the role of the gene that contributes to neurodegenerative diseases in obesity and diabetes is of particular importance, as it may provide a clue for the pathological mechanism of the development of aging-related diseases. Intensive investigation on the underlying mechanisms of cellular aging has suggested that autophagy-lysosome and mitochondrial function plays an essential role in the regulation of cellular homeostasis and health (1). The autophagy-lysosome system is one of the main intracellular proteolytic systems that is responsible for the clearance of unwanted intracellular macromolecules and organelles (2). Cellular aging is associated with the disruption of this homeostatic mechanism, leading to the accumulation of oxidized/misfolded proteins, lipids, and damaged organelles (3). However, the genes and proteins that regulate autophagy-lysosomal activation and contribute to cellular aging remain largely unidentified.Autophagy is a highly regulated process that is inducible by nutrient deprivation and cellular stress. During nutrient deprivation, multiple signaling pathways cooperate to Abstract In this study, we investigated the role and mechanism of Niemann-Pick type C (NPC)2 in regulating lysosomal activity, mitophagy, and mitochondrial function in adipocytes. We found that knocking down NPC2 impaired lysosomal activity, as evidenced by the reduced mature cathepsin B, the increased accumulation of light chain 3 (LC3) and p62, and the decreased autophagic flux. In NPC2-knockdown (kd) adipocytes, the starvation-induced conversion of LC3-I to LC3-II was abolished. More interestingly, the majority of NPC2 was found in the mitochondrial fraction, and NPC2 deficiency led to impaired autophagic flux and decreased induction of LC3-II in the mitochondrial fraction during mitochondrial stress. Moreover, cellular respiration profiling revealed that NPC2-kd adipocytes had significantly decreased basal/maximal respiration and mitochondrial gene expression compared with scrambled cells, suggesting mitochondrial dysfunction. Additionally, we found that the mitochondrial recruitment of LC3-II induced by lipopolysaccharide (LPS), but not TNF, was blunted in NPC2-kd adipocytes. Most intriguingly, NPC2-kd selectively diminished LPS-induced NFB and ERK1/2 phosphorylation and the expression of pro-inflammatory genes, indicating that tolllike receptor signaling activation is impaired in the absence of NPC2. Our results suggest that NPC2 is in a mitochondrially associated autophagosome and plays an important role in regulating mitophag...

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Type C Niemann-Pick disease: spectrum of phenotypic variation in disruption of intracellular LDL-derived cholesterol processing

Cited by 207 publications

References 26 publications

Clinical-biochemical correlation in molecularly characterized patients with Niemann-Pick type C

Clinical-biochemical correlation in molecularly characterized patients with Niemann-Pick type C

The Spectrum of Niemann-Pick Type C Disease in Greece

Niemann-Pick type C2 deficiency impairs autophagy-lysosomal activity, mitochondrial function, and TLR signaling in adipocytes

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