Document Detail

Niemann-Pick type C disease: novel NPC1 mutations and characterization of the concomitant acid sphingomyelinase deficiency.
MedLine Citation:
PMID:  16143556     Owner:  NLM     Status:  MEDLINE    
Niemann-Pick type C (NPC) disease is an inherited lipid storage disorder characterized by the lysosomal accumulation of free cholesterol in affected cells. Three novel mutations in the NPC1 gene (c.3615delA, c.2000C > T, and c.2240delT) were detected in two unrelated patients with the severe phenotype of NPC. The analyses showed that the c.2240delT mutation, which causes a premature stop at codon 748, resulted in nonsense-mediated decay of the mutant transcripts. Immunoblotting analyses for the NPC1 protein did not detect the mutant proteins in COS-1 cells transiently transfected with the two mutant NPC1 cDNA constructs (c.3615delA and c.2000C > T). In NPC cells, sphingomyelin accumulates with cholesterol, leading to an identical subcellular distribution of both lipids. Acid sphingomyelinase (ASM), which is responsible for the lysosomal hydrolysis of sphingomyelin, is partially reduced in NPC fibroblasts. Therefore, NPC fibroblasts were studied to determine if ASM activity was perturbed due to the accumulation of cholesterol. However, these studies demonstrated that the subcellular localization of ASM was preserved, suggesting that the high content of lysosomal cholesterol was not responsible for the decreased ASM activity.
Hiroaki Tamura; Tsutomu Takahashi; Nobuhiro Ban; Hiroyuki Torisu; Haruaki Ninomiya; Goro Takada; Nobuya Inagaki
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Publication Detail:
Type:  Case Reports; Journal Article     Date:  2005-09-06
Journal Detail:
Title:  Molecular genetics and metabolism     Volume:  87     ISSN:  1096-7192     ISO Abbreviation:  Mol. Genet. Metab.     Publication Date:  2006 Feb 
Date Detail:
Created Date:  2006-02-10     Completed Date:  2006-05-08     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9805456     Medline TA:  Mol Genet Metab     Country:  United States    
Other Details:
Languages:  eng     Pagination:  113-21     Citation Subset:  IM    
Department of Pediatrics, Akita University School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan.
Data Bank Information
Bank Name/Acc. No.:
OMIM/257220;  601015
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MeSH Terms
Blotting, Western
COS Cells
Carrier Proteins / chemistry,  genetics*
Cells, Cultured
Cercopithecus aethiops
Child, Preschool
Cholesterol, LDL / physiology
DNA Mutational Analysis
Fibroblasts / enzymology
Infant, Newborn
Membrane Glycoproteins / chemistry,  genetics*
Niemann-Pick Diseases / classification*,  enzymology,  genetics*
Progesterone / physiology
Sphingomyelin Phosphodiesterase / chemistry,  genetics*
Reg. No./Substance:
0/Carrier Proteins; 0/Cholesterol, LDL; 0/Membrane Glycoproteins; 0/NPC1 protein, human; 480-49-9/Filipin; 57-83-0/Progesterone; EC Phosphodiesterase

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