GM18398

GM18398 Fibroblast

Description:

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

Affected:

Yes

Sex:

Male

Age:

No Data

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

Molecular characterization before cell line submission to CCR

Species

Homo sapiens

Common Name

Human

Remarks

Clinically affected; diagnosed at 3 years 1 month; alive at 11 year; Caucasian; sclera were yellow during neonatal development; hepatosplenomegay at birth; walked at 11.5 mo; clumsy; learning difficulties; ataxia beginning 7 years; walked with assistance at age 11 years; vertical gaze palsy beginning at 6 years; dysarthria beginning at 4 years; cataplexy beginning at 7-8 years; fibroblasts showed 439 pmol CE/mg protein/6 hr activity in a cholesterol esterification assay [normal mean was 1855 +/- 1327 pmol CE/mg protein/6 hr, see Park et al. Hum Mut 22:313-325 (2003)]; fibroblasts were scored as npc-like in a filipin staining assay (see Park et al., 2003); a complementation test showed that the cells were type 1 (see Park et al., 2003); the donor subject is a compound heterozygote at the NPC1 gene locus: allele 1 carries a substitution (G>T) at nucleotide 2018 (c.2018G>T) in exon 13, resulting in a missense mutation at codon 673 [G673V (Gly673Val)]; allele 2 carries a substitution (T>C) at nucleotide 3182 (c.3182T>C) in exon 21, resulting in a missense mutation at codon 1061 [I1061T (Ile1061Thr)]; the subject also carries the following polymorphism in the NPC1 gene: (A>G) at nucleotide 2572 (c.2572A>G) resulting in a missense mutation (I>V) at codon 858 [I858V (Ile858Val)]; the first nucleotide of the initiating Met codon is numbered +1.

Characterizations

IDENTIFICATION OF SPECIES OF ORIGIN

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

Gene

NPC1

Chromosomal Location

18q11-q12

Allelic Variant 1

G673V; NIEMANN-PICK DISEASE, TYPE C1

Identified Mutation

GLY673VAL

Gene

NPC1

Chromosomal Location

18q11-q12

Allelic Variant 2

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.

Phenotypic Data

Remarks

Publications

Wang C, Scott SM, Subramanian K, Loguercio S, Zhao P, Hutt DM, Farhat NY, Porter FD, Balch WE, Quantitating the epigenetic transformation contributing to cholesterol homeostasis using Gaussian process Nature communications10:5052 2018

PubMed ID: 31699992