GM00651

GM00651 Fibroblast

Description:

MAPLE SYRUP URINE DISEASE (MSUD), TYPE IA
BRANCHED-CHAIN KETO ACID DEHYDROGENASE E1, ALPHA POLYPEPTIDE; BCKDHA

Affected:

No Data

Sex:

Female

Age:

No Data

Overview

Repository

NIGMS Human Genetic Cell Repository

Subcollection

Heritable Diseases

Class

Disorders of Amino Acid Metabolism

Cell Type

Fibroblast

Transformant

Untransformed

Race

White

Family Member

Relation to Proband

mother

Confirmation

Molecular characterization after cell line submission to CCR

Species

Homo sapiens

Common Name

Human

Remarks

30-60% of normal branched-chain alphaketo acid decarboxylase activity; clinically unaffected mother of GM00649; heterozygous for an 8-bp deletion in exon 7 of the BCKDHA gene

Characterizations

Passage Frozen

GENE MAPPING & DOSAGE STUDIES - Y CHROMOSOME

PCR analysis of DNA from this cell culture gave a negative result with a primer for Yq11, DYS227.

3-methyl-2-oxobutanoate dehydrogenase

According to the submitter, biochemical test results for this subject showed decreased enzyme activity. EC Number: 1.2.4.4; 30-60% activity.

Gene

BCKDHA

Chromosomal Location

19q13.1-q13.2

Allelic Variant 1

608348.0002; MAPLE SYRUP URINE DISEASE, CLASSIC TYPE IA, DUE TO DEFICIENCY OF E1A

Identified Mutation

8-BP DEL, NT887-894, FS255TER; In the compound heterozygote with the tyr393-to-asn mutation (248600.0001) reported by Zhang et al. [J Clin Invest 83: 1425 (1989)], Chuang et al. [Am. J. Hum. Genet. 55: 297 (1994)] demonstrated that the other allele carried an 8-bp deletion involving bases 887 through 894. The deletion resulted in a nonsense codon 255 of the mature E1-alpha subunit. The deletion abolished an SmaI restriction site in exon 7. This alteration in restriction was used to study segregation of the deletion in the family. The mother was found to be heterozygous. (When the tyr393-to-asn mutation was reported in 1989, the second allele was postulated to be a regulatory mutation, on the basis of a reduced mRNA level for this allele. Studies of the promoter regulatory region of the gene from this patient (GM00649) revealed that the patient and the mother were heterozygous for an A-to-T transversion at base -284. Using the luciferase reporter assay, however, Chuang et al. [Am. J. Hum. Genet. 55: 297 (1994)] found that the A-to-T transversion was associated with normal activity, indicating that it represents a normal polymorphism.)

Phenotypic Data

Remarks

30-60% of normal branched-chain alphaketo acid decarboxylase activity; clinically unaffected mother of GM00649; heterozygous for an 8-bp deletion in exon 7 of the BCKDHA gene

Publications

Love-Gregory LD, Grasela J, Hillman RE, Phillips CL, Evidence of common ancestry for the maple syrup urine disease (MSUD) Y438N allele in non-Mennonite MSUD patients. Mol Genet Metab75(1):79-90 2002

PubMed ID: 11825067

Chuang JL, Fisher CR, Cox RP, Chuang DT, Molecular basis of maple syrup urine disease: novel mutations at the E1 alpha locus that impair E1(alpha 2 beta 2) assembly or decrease steady- state E1 alpha mRNA levels of branched-chain alpha-keto acid dehydrogenase complex. Am J Hum Genet55:297-304 1994

PubMed ID: 8037208

Chuang DT, Ku LS, Kerr DS, Cox RP, Detection of heterozygotes in maple-syrup-urine disease: measurements of branched-chain alpha-ketoacid dehydrogenase and its components in cell cultures. Am J Hum Genet34:416-24 1982

PubMed ID: 7081220

Fensom AH, Benson PF, Baker JE, A rapid method for assay of branched-chain keto acid decarboxylation in cultured cells and its application to prenatal diagnosis of maple syrup urine disease. Clin Chim Acta87:169-74 1978

PubMed ID: 668138