GM01935

GM01935 Fibroblast

Description:

GLYCOGEN STORAGE DISEASE II
GLUCOSIDASE, ALPHA, ACID; GAA

Affected:

Yes

Sex:

Female

Age:

30 YR (At Sampling)

Overview

Repository

NIGMS Human Genetic Cell Repository

Subcollection

Heritable Diseases
Lysosomal Storage Diseases

Class

Disorders of Carbohydrate Metabolism

Cell Type

Fibroblast

Transformant

Untransformed

Race

Black/African American

Relation to Proband

proband

Confirmation

Clinical summary/Case history

Species

Homo sapiens

Common Name

Human

Remarks

Adult form; onset of generalized muscle wasting & weakness at age 30; history of amenorrhea & hypertension; normal size and amount of mRNA for GAA, GAA protein detected by antibody, but deficient acid-alpha-1,4 glucosidase (0.14%); donor subject is a compound heterozygote with only one allele expressed: allele one (the silent allele) carries a C>T transition at nucleotide 2560 in exon 18 of the GAA gene (2560C>T) which results in a nonsense codon at amino acid 854 [Arg854Ter (R854X)]; allele two carries three amino acid substitutions: (1) a missense mutation caused by a C>A transversion at nucleotide 1935 in exon 14 (1935C>A) which results in substitution of glutamic acid for aspartic acid at codon 645 [Asp645Glu (D645E)] and accounts for the defects in transport, phosphorylation, and proteolytic processing of the alpha-glucosidase; (2) a G>A transition at nucleotide 2446 (2446G>A) in exon 17 which results in a polymorphism {a substitution of isoleucine for valine at codon 816 [Val816Ile (V816I)]}; and (3) a C>T transition at nucleotide 2780 (2780C>T) in exon 19 which results in a substitution of isoleucine for threonine at codon 927 [Thr927Ile (T927I)].

Characterizations

PDL at Freeze

5.97

Passage Frozen

alpha-glucosidase

According to the submitter, biochemical test results for this subject showed decreased enzyme activity. EC Number: 3.2.1.20; 0.14% activity.

Gene

GAA

Chromosomal Location

17q25.2-q25.3

Allelic Variant 1

606800.0015; GLYCOGEN STORAGE DISEASE TYPE II

Identified Mutation

ARG854TER; Becker et al. [Am. J. Hum. Genet. 62: 991-994 (1998)] found a high frequency of the arg854-to-ter mutation of the GAA gene in compound heterozygous or homozygous state in cases of glycogen storage disease II (232300) in various African populations and in African-American patients.

Gene

GAA

Chromosomal Location

17q25.2-q25.3

Allelic Variant 2

606800.0010; GLYCOGEN STORAGE DISEASE TYPE II, INFANTILE FORM

Identified Mutation

ASP645GLU; Lin and Shieh [Acta Paediat. Sinica 37: 115-121 (1996)] identified a C-to-A transversion at the 5-prime end of exon 14 in the GAA gene (nucleotide 1935) in 4 Chinese patients with the infantile form of Pompe disease (232300) in Taiwan. This change caused substitution of glutamic acid for asparagine-645. The mutation was found in 20 of 25 additional Chinese patients with Pompe disease but in none of 40 normal persons.

Gene

GAA

Chromosomal Location

17q25.2-q25.3

Allelic Variant 2

V816I; GLYCOGEN STORAGE DISEASE TYPE II

Identified Mutation

VAL816ILE

Gene

GAA

Chromosomal Location

17q25.2-q25.3

Allelic Variant 2

T927I; GLYCOGEN STORAGE DISEASE TYPE II

Identified Mutation

THR927ILE

Phenotypic Data

Remarks

Publications

Raben N, Lee E, Lee L, Hirschhorn R, Plotz PH, Novel mutations in African American patients with glycogen storage disease Type II. Mutations in brief no. 209. Online. Hum Mutat13(1):83-4 1999

PubMed ID: 10189220

Becker JA, Vlach J, Raben N, Nagaraju K, Adams EM, Hermans MM, Reuser AJ, Brooks SS, Tifft CJ, Hirschhorn R, Huie ML, Nicolino M, Plotz PH, The African origin of the common mutation in African American patients with glycogen-storage disease type II. Am J Hum Genet62(4):991-4 1998

PubMed ID: 9529346

Chen CS, Bach G, Pagano RE, Abnormal transport along the lysosomal pathway in mucolipidosis, type IV disease. Proc Natl Acad Sci U S A95:6373-8 1998

PubMed ID: 9600972

Adams EM, Becker JA, Griffith L, Segal A, Plotz PH, Raben N, Glycogenosis type II: a juvenile-specific mutation with an unusual splicing pattern and a shared mutation in African Americans. Hum Mutat10(2):128-34 1997

PubMed ID: 9259196

Huie ML, Chen AS, Tsujino S, Shanske S, DiMauro S, Engel AG, Hirschhorn R, Aberrant splicing in adult onset glycogen storage disease type II (GSDII): molecular identification of an IVS1 (-13T-->G) mutation in a majority of patients and a novel IVS10 (+1GT-->CT) mutation. Hum Mol Genet3:2231-6 1994

PubMed ID: 7881425

Hermans MM, de Graaff E, Kroos MA, Wisselaar HA, Willemsen R, Oostra BA, Reuser AJ, The conservative substitution Asp-645-->Glu in lysosomal alpha-glucosidase affects transport and phosphorylation of the enzyme in an adult patient with glycogen-storage disease type II. Biochem J289 ( Pt 3):687-93 1993

PubMed ID: 8094613

Hermans MM, Svetkey LP, Oostra BA, Chen YT, Reuser AJ, The loss of a polymorphic glycosylation site caused by Thr-927-->Ile is linked to a second polymorphic Val-816-->Ile substitution in lysosomal alpha-glucosidase of American blacks. Genomics16(1):300-1 1993

PubMed ID: 8486380

Martiniuk F, Mehler M, Bodkin M, Tzall S, Hirschhorn K, Zhong N, Hirschhorn R, Identification of a missense mutation in an adult-onset patient with glycogenosis type II expressing only one allele. DNA Cell Biol10(9):681-7 1991

PubMed ID: 1684505

Zhong N, Martiniuk F, Tzall S, Hirschhorn R, Identification of a missense mutation in one allele of a patient with Pompe disease, and use of endonuclease digestion of PCR-amplified RNA to demonstrate lack of mRNA expression from the second allele. Am J Hum Genet49:635-45 1991

PubMed ID: 1652892

Martiniuk F, Mehler M, Tzall S, Meredith G, Hirschhorn R, Extensive genetic heterogeneity in patients with acid alpha glucosidase deficiency as detected by abnormalities of DNA and mRNA. Am J Hum Genet47:73-8 1990

PubMed ID: 2112341

Reuser AJ, Kroos M, Oude Elferink RP, Tager JM, Defects in synthesis, phosphorylation, and maturation of acid alpha- glucosidase in glycogenosis type II. J Biol Chem260:8336-41 1985

PubMed ID: 3159730

Beratis NG, LaBadie GU, Hirschhorn K, Genetic heterogeneity in acid alpha-glucosidase deficiency. Am J Hum Genet35:21-33 1983

PubMed ID: 6401921