GM17913

GM17913 Fibroblast

Description:

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

Affected:

Yes

Sex:

Male

Age:

23 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

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 21 year; alive at 35 year; splenomegaly discovered at age 4 year; clumsy; learning difficulties; hearing problems; wears bilateral hearing aids; ataxia; vertical gaze palsy; dysarthria; dysphagia; gastrostomy; epilepsy; psychiatric disorders; sleeping problems; wheelchair bound; severe difficulty with movement; absence of communication; severe spasticity; fibroblasts showed 117 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)]; 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 (G>A) at nucleotide 3493 (c.3493G>A) in exon 23, resulting in a missense mutation at codon 1165 [V1165M (Val1165Met)]; the subject also carries the following polymporphism: T>C at nucleotide 387 (c.387T>C) resulting in no change (Y>Y) at codon 129 [Y129Y, (Tyr129Tyr)]; the first nucleotide of the initiating Met codon is numbered +1.

Characterizations

PDL at Freeze

6.27

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

V1165M; NIEMANN-PICK DISEASE, TYPE C1

Identified Mutation

VAL1165MET

Phenotypic Data

Remarks

Publications

Yañez MJ, Marín T, Balboa E, Klein AD, Alvarez AR, Zanlungo S, Finding pathogenic commonalities between Niemann-Pick type C and other lysosomal storage disorders: Opportunities for shared therapeutic interventions Biochimica et biophysica acta Molecular basis of disease1866:165875 2020

PubMed ID: 32522631

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

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