GM00372

GM00372 Fibroblast from Skin, Arm

Description:

GAUCHER DISEASE, TYPE I
GLUCOSIDASE, ACID BETA; GBA

Affected:

Yes

Sex:

Male

Age:

29 YR (At Sampling)

Overview

Repository

NIGMS Human Genetic Cell Repository

Subcollection

Heritable Diseases
Lysosomal Storage Diseases

Class

Disorders of Lipid Metabolism

Biopsy Source

Arm

Cell Type

Fibroblast

Tissue Type

Skin

Transformant

Untransformed

Sample Source

Fibroblast from Skin, Arm

Race

White

Country of Origin

USA

Relation to Proband

proband

Confirmation

Clinical summary/Case history

Species

Homo sapiens

Common Name

Human

Remarks

Clinically affected; varying percentages of glucocerebrosidase activity (6%, 11.1%), B-glucosidase activity(4.1%, 16.1%), and glucosylsphingosine activity(9.6%) in this cell line have been reported in several publications - please refer to the publications tab on this sample page for more info; donor subject is a compound heterozygote for mutations in the gene encoding acid-beta glucosidase (GBA): one allele carries a single-base mutation (adenosine to guanosine transition) in exon 9 at position 1226 (1226A>G)of the glucocerebrosidase gene which results in the amino acid substitution of serine for asparagine [Asn370Ser (N370S)]; the second allele carries an insertion of a second guanine at cDNA nucleotide 84 (84GG).

Characterizations

PDL at Freeze

4.47

Passage Frozen

MUTATION VERIFICATION

Reiner et al (DNA 7:107-116 1988) employed a glucocerebrosidase cDNA in a Northern blot analysis to show that the mRNA from this type III Gaucher disease patient had the same three RNA species (6 2.6 & 2.2 kb transcripts) as found in normal placenta. Wigderson et al (Am J Hum Genet 44:365-377 1989) characterized the human glucocerebrosidase gene from Gaucher disease patients. The results obtained with DNA from this cell culture showed this patient to be heterozygous for a mutant allele. The mutant allele has a T to C transition at codon 444 that causes a substitution of proline for leucine and creates a new NciI restriction site.

IDENTIFICATION OF SPECIES OF ORIGIN

Species of Origin confirmed by LINE assay

glucosylceramidase

According to the submitter, biochemical test results for this subject showed decreased enzyme activity. EC Number: 3.2.1.45; 6% activity.

Gene

GBA

Chromosomal Location

1q21

Allelic Variant 1

606463.0003; GAUCHER DISEASE, TYPE I

Identified Mutation

ASN370SER; By nucleotide sequence analysis of a genomic clone from an Ashkenazi Jewish patient with type I, Tsuji et al. [Proc. Nat. Acad. Sci. 85: 2349-2352 (1988] found a single-base mutation (adenosine to guanosine transition) in exon 9 of the glucocerebrosidase gene. This change resulted in the amino acid substitution of serine for asparagine. Transient expression studies following oligonucleotide-directed mutagenesis of the normal cDNA confirmed that the mutation results in loss of glucocerebrosidase activity. This mutation [1226G (N370S)] accounts for approximately 70% of mutations in the Jewish population.

Gene

GBA

Chromosomal Location

1q21

Allelic Variant 2

606463.0014; GAUCHER DISEASE, TYPE I

Identified Mutation

1-BP INS, 84G; Beutler et al. [Proc. Nat. Acad. Sci. 88: 10544-10547 (1991)] found a second common Jewish Gaucher disease mutation in addition to the A-to-G mutation of nucleotide 1226, which accounts for about 75% of mutant alleles in Ashkenazi Jews (606463.0003). The new mutation consisted of insertion of a second guanine at cDNA nucleotide 84 and was referred to as the 84GG mutation. The 84GG and A1226G mutations, along with the less-common mutation at nucleotide 1448 (606463.0001), account for 95% of all Gaucher disease-producing alleles in Ashkenazi Jews.

Phenotypic Data

Remarks

Publications

Tuyaa-Boustugue P, Jantzen I, Zhang H, Young SP, Broqua P, Tallandier M, Entchev E, Reduction of lysosome abundance and GAG accumulation after odiparcil treatment in MPS I and MPS VI models Molecular genetics and metabolism reports37:101011 2023

PubMed ID: 38053941

Akiyama T, Sato S, Ko SBH, Sano O, Sato S, Saito M, Nagai H, Ko MSH, Iwata H, Synthetic mRNA-based differentiation method enables early detection of Parkinson's phenotypes in neurons derived from Gaucher disease-induced pluripotent stem cells Stem cells translational medicine37:101011 2020

PubMed ID: 33342090

Zheng J, Jeon S, Jiang W, Burbulla LF, Ysselstein D, Oevel K, Krainc D, Silverman RB, Conversion of Quinazoline Modulators from Inhibitors to Activators of ß-Glucocerebrosidase Journal of medicinal chemistry37:101011 2019

PubMed ID: 30645117

Fog CK, Zago P, Malini E, Solanko LM, Peruzzo P, Bornaes C, Magnoni R, Mehmedbasic A, Petersen NHT, Bembi B, Aerts JFMG, Dardis A, Kirkegaard T, The heat shock protein amplifier arimoclomol improves refolding, maturation and lysosomal activity of glucocerebrosidase EBioMedicine38:142-153 2018

PubMed ID: 30497978

Cheng WC, Weng CY, Yun WY, Chang SY, Lin YC, Tsai FJ, Huang FY, Chen YR., Rapid modifications of N-substitution in iminosugars: development of new β-glucocerebrosidase inhibitors and pharmacological chaperones for Gaucher disease. Bioorg Med Chem.21(17):5021-8 2013

PubMed ID: 23880081

Sasagasako N, Kobayashi T, Yamaguchi Y, Shinnoh N, Goto I, Glucosylceramide and glucosylsphingosine metabolism in cultured fibroblasts deficient in acid beta-glucosidase activity. J Biochem (Tokyo)115:113-9 1994

PubMed ID: 8188616

Wigderson M, Firon N, Horowitz Z, Wilder S, Frishberg Y, Reiner O, Horowitz M, Characterization of mutations in Gaucher patients by cDNA cloning. Am J Hum Genet44:365-77 1989

PubMed ID: 2464926

Reiner O, Wigderson M, Horowitz M, Structural analysis of the human glucocerebrosidase genes. DNA7:107-16 1988

PubMed ID: 3359914

Reiner O, Wilder S, Givol D, Horowitz M, Efficient in vitro and in vivo expression of human glucocerebrosidase cDNA. DNA6:101-8 1987

PubMed ID: 2438102

Beutler E, Kuhl W, Glucocerebrosidase processing in normal fibroblasts and in fibroblasts from patients with type I, type II, and type III Gaucher disease. Proc Natl Acad Sci U S A83:7472-4 1986

PubMed ID: 3463977

Beutler E, Kuhl W, Sorge J, Cross-reacting material in Gaucher disease fibroblasts. Proc Natl Acad Sci U S A81:6506-10 1984

PubMed ID: 6593712

Choy FY, Gaucher disease: the effects of phosphatidylserine on glucocerebrosidase from normal and Gaucher fibroblasts. Hum Genet67:432-6 1984

PubMed ID: 6436168