GM00110

GM00110 Fibroblast

Description:

NIEMANN-PICK DISEASE, TYPE C1; NPC1
NPC1 GENE; NPC1

Affected:

Yes

Sex:

Male

Age:

9 YR (At Sampling)

Overview

Repository

NIGMS Human Genetic Cell Repository

Subcollection

Heritable Diseases
Lysosomal Storage Diseases

Class

Disorders of Lipid Metabolism

Cell Type

Fibroblast

Transformant

Untransformed

Race

White

Relation to Proband

proband

Confirmation

Clinical summary/Case history

Species

Homo sapiens

Common Name

Human

Remarks

Variant; 24% - 50% of normal sphingomyelinase activity; a brother died of Niemann-Pick at age 11; fibroblasts show impaired cholesterol esterification; the donor subject is a compound heterozygote; one allele carries a missense mutation C>T at nucleotide 709 (709C>T) in exon 6 of the NPC1 gene, resulting in a substitution of a serine for a proline at codon 237 [Pro237Ser (P237S)]; the second allele carries a 6 bp deletion in exon 14: 2215(or 2217)delTCCTTT(or CTTTTC) which results in the in frame deletion of 2 amino acids (740F,741S)

Characterizations

PDL at Freeze

4.01

Passage Frozen

IDENTIFICATION OF SPECIES OF ORIGIN

Species of Origin Confirmed by Nucleoside Phosphorylase, Glucose-6-Phosphate Dehydrogenase, and Lactate Dehydrogenase Isoenzyme Electrophoresis

sphingomyelin phosphodiesterase

According to the submitter, biochemical test results for this subject showed decreased enzyme activity. EC Number: 3.1.4.12; 50% activity.

Gene

NPC1

Chromosomal Location

18q11-q12

Allelic Variant 1

607623.0010; NIEMANN-PICK DISEASE, TYPE C1

Identified Mutation

ILE1061THR; In an initial study of 25 patients with type C1 Niemann-Pick disease, Millat et al. [Am. J. Hum. Genet. 65: 1321-1329 (1999)] identified a T-to-C transition at nucleotide 3182 of the NPC1 gene that led to an ile1061-to-thr substitution (I1061T) in 3 patients. The mutation, located in exon 21, affected a putative transmembrane domain of the protein. The mutation was particularly frequent in patients with NPC from western Europe, especially France and the U.K. and in Hispanic patients whose roots were in the Upper Rio Grande valley of the U.S. Millat et al. [Am. J. Hum. Genet. 65: 1321-1329 (1999)] concluded that the I1061T mutation originated in Europe and that the high frequency in northern Rio Grande Hispanics resulted from a founder effect.

Gene

NPC1

Chromosomal Location

18q11-q12

Allelic Variant 2

del740F-741S; NIEMANN-PICK DISEASE, TYPE C1

Identified Mutation

2215(or 2217)delTCCTTT(or CTTTTC)

Phenotypic Data

Remarks

Publications

Umeda A, Fujita H, Kuronita T, Hirosako K, Himeno M, Tanaka Y, Distribution and trafficking of MPR300 is normal in cells with cholesterol accumulated in late endocytic compartments: evidence for early endosome-to-TGN trafficking of MPR300. J Lipid Res44(10):1821-32 2003

PubMed ID: 12867541

Kruth HS, Ifrim I, Chang J, Addadi L, Perl-Treves D, Zhang WY, Monoclonal antibody detection of plasma membrane cholesterol microdomains responsive to cholesterol trafficking. J Lipid Res42(9):1492-500 2001

PubMed ID: 11518770

Yamamoto T, Ninomiya H, Matsumoto M, Ohta Y, Nanba E, Tsutsumi Y, Yamakawa K, Millat G, Vanier MT, Pentchev PG, Ohno K, Genotype-phenotype relationship of Niemann-Pick disease type C: a possible correlation between clinical onset and levels of NPC1 protein in isolated skin fibroblasts. J Med Genet37(9):707-12 2000

PubMed ID: 11182931

Akaboshi S, Yano T, Miyawaki S, Ohno K, Takeshita K, A C57BL/KsJ mouse model of Niemann-Pick disease (spm) belongs to the same complementation group as the major childhood type of Niemann-Pick disease type C. Hum Genet99:350-3 1997

PubMed ID: 9050921

Slotte JP, Hedstrom G, Bierman EL, Intracellular transport of cholesterol in type C Niemann-Pick fibroblasts. Biochim Biophys Acta1005:303-9 1989

PubMed ID: 2804059

Pentchev PG, Comly ME, Kruth HS, Patel S, Proestel M, Weintroub H, The cholesterol storage disorder of the mutant BALB/c mouse. A primary genetic lesion closely linked to defective esterification of exogenously derived cholesterol and its relationship to human type C Niemann-Pick disease. J Biol Chem261:2772-7 1986

PubMed ID: 3949747

Pentchev PG, Comly ME, Kruth HS, Vanier MT, Wenger DA, Patel S, Brady RO, A defect in cholesterol esterification in Niemann-Pick disease (type C) patients. Proc Natl Acad Sci U S A82:8247-51 1985

PubMed ID: 3865225

Sakuragawa N, Sato M, Yoshida Y, Kamo I, Arima M, Satoyoshi E, Effects of dimethylsulfoxide on sphingomyelinase in cultured human fibroblasts and correction of sphingomyelinase deficiency in fibroblasts from Niemann-Pick patients. Biochem Biophys Res Commun126:756-62 1985

PubMed ID: 2983689

Maziere JC, Maziere C, Mora L, Routier JD, Polonovski J, In situ degradation of sphingomyelin by cultured normal fibroblasts and fibroblasts from patients with Niemann-Pick disease type A and C. Biochem Biophys Res Commun108:1101-6 1982

PubMed ID: 7181884

Besley GT, Hoogeboom AJ, Hoogeveen A, Kleijer WJ, Galjaard H, Somatic cell hybridisation studies showing different gene mutations in Niemann-Pick variants. Hum Genet54:409-12 1980

PubMed ID: 6249719

Besley GT, Diagnosis of Niemann-Pick disease using a simple and sensitive fluorimetric assay of sphingomyelinase activity. Clin Chim Acta90:269-78 1978

PubMed ID: 31994

Besley GT, Sphingomyelinase defect in Niemann-Pick disease, type C, fibroblasts. FEBS Lett80:71-4 1977

PubMed ID: 19295