GM01260

GM01260 Fibroblast

Description:

GAUCHER DISEASE, TYPE II
GLUCOSIDASE, ACID BETA; GBA

Affected:

Yes

Sex:

Female

Age:

11 MO (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

Relation to Proband

proband

Confirmation

Molecular characterization after cell line submission to CCR

Species

Homo sapiens

Common Name

Human

Remarks

Splenomegaly; opisthotonos: expired at age 1; 3% of control fibro glucocerebrosidase activity; donor subject is a compound heterozygote: one allele has a T>C transition at nucleotide 1448 in exon 10 of the GBA gene (1448T>C) resulting in the substitution of proline for leucine at codon 444 [Leu444Pro (L444P)]; the second allele has a C>G transversion at nucleotide 1361 in exon 9 (1361C>G) resulting in the substitution of arginine for proline at codon 415 [Pro415Arg (P415R)] [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

IDENTIFICATION OF SPECIES OF ORIGIN

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

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. Reiner et al (DNA 7:107-116 1988) employed a human glucocerebrosidase cDNA in a Northern blot analysis to show that mRNA from this type II Gaucher disease patient had the same three RNA species (6 2.6 & 2.2 kb transcripts) as found in normal placenta. 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. GM01260 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 the presence of two mutant alleles. One allele contains a C to G transversion at codon 415 which causes substitution of arginine for proline and creates a new HhaI restriction site. The other 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. 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 heterozygous for two mutant alleles: the T to C transition in exon 10 (Leu 444 to Pro 444) and the C to G transversion in exon 9 (Pro 415 to Arg 415). The T to C transition had previously been described by Tsuji et al (N Engl J Med 316: 570-575 1987).

glucosylceramidase

According to the submitter, biochemical test results for this subject showed decreased enzyme activity. EC Number: 3.2.1.45; 3% 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

606463.0002; GAUCHER DISEASE, NEURONOPATHIC

Identified Mutation

PRO415ARG, 5976C>G; Wigderson et al. [Am J Hum Genet 44: 365 (1989)] characterized mutations in the human glucocerebrosidase gene in 9 patients with Gaucher disease: 5 with type I, 3 with type II, and 1 with type III disease. Two mutant alleles were described; one was the T-to-C transition resulting in substitution of proline for leucine at position 444 (230800.0001), and the other was a C-to-G transversion resulting in a substitution of arginine for proline at position 415. One type II patient was heterozygous for both mutations (GM01260). The substitution at position 444, which creates a new NciI restriction site, was observed in 3 of the patients with type I disease and in the patient with type III disease. One additional patient with type II disease was homozygous for the leu444-to-pro mutation.

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

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 EBioMedicine1867:102735 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

Fink JK, Correll PH, Perry LK, Brady RO, Karlsson S, Correction of glucocerebrosidase deficiency after retroviral-mediated gene transfer into hematopoietic progenitor cells from patients with Gaucher disease. Proc Natl Acad Sci U S A87:2334-8 1990

PubMed ID: 2315324

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

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

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

PubMed ID: 3359914

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

Pentchev PG, Comly ME, Kruth HS, Patel S, Proestel M, Weintroub H, The cholesterol storage disorder of the mutant BALB/c mouse. A primary genetic lesion closely linked to defective esterification of exogenously derived cholesterol and its relationship to human type C Niemann-Pick disease. J Biol Chem261:2772-7 1986

PubMed ID: 3949747

Ginns EI, Choudary PV, Tsuji S, Martin B, Stubblefield B, Sawyer J, Hozier J, Barranger JA, Gene mapping and leader polypeptide sequence of human glucocerebrosidase: implications for Gaucher disease. Proc Natl Acad Sci U S A82:7101-5 1985

PubMed ID: 3863141

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

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

Michels VV, Berseth CL, O'Brien JF, Dewald G, Duplication of part of chromosome 1q: clinical report and review of literature. Am J Med Genet18:125-34 1984

PubMed ID: 6430083

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