GM17926

GM17926 Fibroblast

Description:

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

Affected:

Yes

Sex:

Female

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

Family Member

Relation to Proband

proband

Confirmation

Molecular characterization before cell line submission to CCR

Species

Homo sapiens

Common Name

Human

Remarks

Clinically affected; diagnosed at age 3 yr 9 mo; deceased at age10 yr 10 mo; premature birth; jaundiced; clumsy; learning difficulties; ataxia; vertical gaze palsy; cataplexy; dysphagia; gastrostomy; seizures; sleeping problems; wheelchair bound; absence of communication; fibroblasts showed 52 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 of the NPC type 1 complementation group (see Park et al., 2003); the donor subject is a compound heterozygote at the NPC1 gene locus: allele 1 carries a substitution (T>C) at nucleotide 3182 (c.3182T>C) in exon 21, resulting in a missense mutation at codon 1061 [I1061T (ILE1061THR)]; allele 2 carries a substitution (A>C) at nucleotide 1526 (c.1526A>C) in exon 9, resulting in a missense mutation at codon 509 [Y509S (TYR509SER)]; the subject also carries the following polymorphisms: A>G at nucleotide 644 (c.644A>G) resulting in the substitution of arginine for histidine (H>R) at codon 215 [H215R (HIS215ARG)]; A>G at nucleotide IVS11+60 (IVS11+60A>G) resulting in no change in the predicted amino acid sequence; C>T at nucleotide 2793 (c.2793C>T) resulting in no change (N>N) at codon 931 [N931N (ASN931ASN)]; T>C at nucleotide IVS19+28 (IVS19+28T>C) resulting in no change in the predicted amino acid sequence; the first nucleotide of the initiating Met codon is numbered +1.

Characterizations

Passage Frozen

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

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

Y509S; NIEMANN-PICK DISEASE, TYPE C1

Identified Mutation

TYR509SER

Phenotypic Data

Remarks

Publications

Pepponi R, De Simone R, De Nuccio C, Visentin S, Matteucci A, Bernardo A, Popoli P, Ferrante A, Repurposing Dipyridamole in Niemann Pick Type C Disease: A Proof of Concept Study International journal of molecular sciences23: 2022

PubMed ID: 35408815

Schultz ML, Krus KL, Kaushik S, Dang D, Chopra R, Qi L, Shakkottai VG, Cuervo AM, Lieberman AP, Coordinate regulation of mutant NPC1 degradation by selective ER autophagy and MARCH6-dependent ERAD Nature communications9:3671 2017

PubMed ID: 30202070

Visentin S, De Nuccio C, Bernardo A, Pepponi R, Ferrante A, Minghetti L, Popoli P, The stimulation of adenosine A2A receptors ameliorates the pathological phenotype of fibroblasts from Niemann-Pick type C patients The Journal of neuroscience : the official journal of the Society for Neuroscience33:15388-93 2013

PubMed ID: 24068806

Park WD, O'Brien JF, Lundquist PA, Kraft DL, Vockley CW, Karnes PS, Patterson MC, Snow K, Identification of 58 novel mutations in Niemann-Pick disease type C: Correlation with biochemical phenotype and importance of PTC1-like domains in NPC1. Hum Mutat22(4):313-25 2003

PubMed ID: 12955717