GM00877

GM00877 Fibroblast

Description:

GAUCHER DISEASE, TYPE II
GLUCOSIDASE, ACID BETA; GBA

Affected:

Yes

Sex:

Male

Age:

1 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 after cell line submission to CCR

Species

Homo sapiens

Common Name

Human

Remarks

expired at age 1; hepatosplenomegaly; strabismus; trismus; 4% of cont fibroblast glucocerebrosidase activity; donor subject is homozygous for a T>C transition at nucleotide 1448 (1448T>C) in exon 10 of the GBA gene resulting in a substitution at codon 444, Pro for Leu [Leu444Pro (L444P)]; 1 allele has 2 additional base substitutions: 1483G>C and 1497G>C [codons are numbered from the first codon of the mature protein; the cDNA is numbered from the first initiating AUG]

Characterizations

PDL at Freeze

5.12

Passage Frozen

MUTATION VERIFICATION

Tsuji et al (Proc Natl Acad Sci USA 85:2349-2352 1988) reported that DNA extracted from this culture lacked the Asn-370 to Ser mutation in the glucocerebrosidase gene which was found in 75% of type 1 patients. Bergman and Grabowski (Am J Hum Genet 44:741-750 1989) analyzed the major processing steps in the maturation of the lysosomal hydrolase acid B-glucosidase in this type II Gaucher disease fibroblast culture. In normal fibroblasts remodeling of N-linked oligosaccharides resulted in the temporal appearance of three molecular-weight forms of acid B-glucosidase. An initial 64-KDa form containing high mannose-type oligosaccharide side chains was processed quantitatively within 24h to a sialylated 69-KDa form. During the subsequent 96h some of the 69-KDa form is processed to 59-KDa. GM00877 fibroblasts revealed no processing of the 64-KDa form of the enzyme. In addition the newly synthesized enzyme disappeared by 24h. No conversion to the normally present 59-KDa form was observed. These results confirm those reported by Beutler and Kuhl (Proc Natl Acad Sci USA 83:7472-7474 1986) which described a very unstable glucocerebrosidase enzyme precursor for type II Gaucher disease fibroblasts. 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 that this patient is homozygous for a mutant allele that contains a T to C transition at codon 444 that causes a substitution of proline for leucine and creates a new NciI restriction site. These results were confirmed by Theophilus et al (Am J Hum Genet 45:212-225 1989). These authors reported that this type II patient was homozygous for the mutant allele a T to C transition in exon 10 (Leu 444 to Pro 444). This mutation had been described previously by Tsuji et al (N Engl J Med 316:570-575 1987).

IDENTIFICATION OF SPECIES OF ORIGIN

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

glucosylceramidase

According to the submitter, biochemical test results for this subject showed decreased enzyme activity. EC Number: 3.2.1.45; 4% activity.

Gene

GBA

Chromosomal Location

1q21

Allelic Variant 1

606463.0001; GAUCHER DISEASE, NEURONOPATHIC

Identified Mutation

LEU483PRO (LEU444PRO), 1448T>C; The leu444-to-pro (L444P) substitution in exon 10 of the GBA gene has been reported as resulting from a 1448T-C transition (Zimran et al., 1989) and from a 6433T-C transition (Latham et al., 1990), depending upon the reference sequence cited. This mutation has alternatively been referred to as LEU483PRO (Saranjam et al., 2013).

Gene

GBA

Chromosomal Location

1q21

Allelic Variant 2

606463.0009; GAUCHER DISEASE, TYPE I OR II, DUE TO 'PSEUDOPATTERN' MUTATION

Identified Mutation

LEU444PRO; ALA456PRO; VAL460VAL; In 3 non-Jewish type I and 1 non-Jewish type II patients, Hong et al. [DNA Cell Biol 9: 233 (1990)] found a mutant allele containing 3 single-base substitutions in codons 444, 456, and 460. These mutations were leu444 (CTG) to pro (CCG), ala456 (GCT) to pro (CCT), and val460 (GTG) to val (GTC). This mutant allele was referred to as 'pseudopattern' because it has sequence identical to a small region of exon 10 in the pseudogene {Horowitz et al. [Genomics 4:87 (1989)]}.

Phenotypic Data

Remarks

Publications

Yañez MJ, Campos F, Marín T, Klein AD, Futerman AH, Alvarez AR, Zanlungo S, c-Abl activates RIPK3 signaling in Gaucher disease Biochimica et biophysica acta Molecular basis of disease1867:166089 2020

PubMed ID: 33549745

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

Basgalupp SP, Siebert M, Ferreira C, Behringer S, Spiekerkoetter U, Hannibal L, Schwartz IVD, Assessment of cellular cobalamin metabolism in Gaucher disease BMC medical genetics21:12 2019

PubMed ID: 31931749

Sun Y, Liou B, Chu Z, Fannin V, Blackwood R, Peng Y, Grabowski GA, Davis HW, Qi X, Systemic enzyme delivery by blood-brain barrier-penetrating SapC-DOPS nanovesicles for treatment of neuronopathic Gaucher disease EBioMedicine21:102735 2019

PubMed ID: 32279952

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

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

Firon N, Eyal N, Kolodny EH, Horowitz M, Genotype assignment in Gaucher disease by selective amplification of the active glucocerebrosidase gene. Am J Hum Genet46:527-32 1990

PubMed ID: 2309702

Latham T, Grabowski GA, Theophilus BD, Smith FI, Complex alleles of the acid beta-glucosidase gene in Gaucher disease. Am J Hum Genet47:79-86 1990

PubMed ID: 2349952

Zimran A, Gelbart T, Beutler E, Linkage of the PvuII polymorphism with the common Jewish mutation for Gaucher disease. Am J Hum Genet46:902-5 1990

PubMed ID: 1971142

Bergmann JE, Grabowski GA, Posttranslational processing of human lysosomal acid beta-glucosidase: a continuum of defects in Gaucher disease type 1 and type 2 fibroblasts. Am J Hum Genet44:741-50 1989

PubMed ID: 2495719

Theophilus B, Latham T, Grabowski GA, Smith FI, Gaucher disease: molecular heterogeneity and phenotype-genotype correlations. Am J Hum Genet45:212-25 1989

PubMed ID: 2502917

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

Tsuji S, Martin BM, Barranger JA, Stubblefield BK, LaMarca ME, Ginns EI, Genetic heterogeneity in type 1 Gaucher disease: multiple genotypes in Ashkenazic and non-Ashkenazic individuals [published erratum appears in Proc Natl Acad Sci U S A 1988 Aug;85(15):5708] Proc Natl Acad Sci U S A85:2349-52 1988

PubMed ID: 3353383

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

Tsuji S, Choudary PV, Martin BM, Stubblefield BK, Mayor JA, Barranger JA, Ginns EI, A mutation in the human glucocerebrosidase gene in neuronopathic Gaucher's disease. N Engl J Med316:570-5 1987

PubMed ID: 2880291

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

Grabowski GA, Dinur T, Osiecki KM, Kruse JR, Legler G, Gatt S, Gaucher disease types 1, 2, and 3: differential mutations of the acid beta-glucosidase active site identified with conduritol B epoxide derivatives and sphingosine. Am J Hum Genet37:499-510 1985

PubMed ID: 4003396

Grabowski GA, Goldblatt J, Dinur T, Kruse J, Svennerholm L, Gatt S, Desnick RJ, Genetic heterogeneity in Gaucher disease: physicokinetic and immunologic studies of the residual enzyme in cultured fibroblasts from non-neuronopathic and neuronopathic patients. Am J Med Genet21:529-49 1985

PubMed ID: 3927728

Saito M, Rosenberg A, The fate of glucosylceramide (glucocerebroside) in genetically impaired (lysosomal beta-glucosidase deficient) Gaucher disease diploid human fibroblasts. J Biol Chem260:2295-300 1985

PubMed ID: 3919000

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

Silverstein E, Friedland J, Angiotensin converting enzyme in cultured fibroblasts in Gaucher and Niemann-Pick diseases. Proc Soc Exp Biol Med170:251-3 1982

PubMed ID: 6283559

Turner BM, Hirschhorn K, Properties of beta-glucosidase in cultured skin fibroblasts from controls and patients with Gaucher disease. Am J Hum Genet30:346-58 1978

PubMed ID: 102189