GM01655

GM01655 LCL from B-Lymphocyte

Description:

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

Affected:

Yes

Sex:

Female

Age:

5 YR (At Sampling)

Overview

Repository

NIGMS Human Genetic Cell Repository

Subcollection

Heritable Diseases

Class

Disorders of Amino Acid Metabolism

Biopsy Source

Peripheral vein

Cell Type

B-Lymphocyte

Tissue Type

Blood

Transformant

Epstein-Barr Virus

Sample Source

LCL from B-Lymphocyte

Race

White

Family Member

Relation to Proband

proband

Confirmation

Clinical summary/Case history

Species

Homo sapiens

Common Name

Human

Remarks

See GM01654 Fibro; HLA type A1,A2,B13, Bw17(B23)(Bw40); Mennonite kindred; 2 sisters died of MSUD; deficient BCKD (BCKAD) activity in fibro and lympho; expired at age 5; deficient of BCKD (BCKAD) complex subunit E1B; homozygous for Y438N mutation (formerly designated Y393N) in the BCKDHA gene

Characterizations

IDENTIFICATION OF SPECIES OF ORIGIN

Species of Origin Confirmed by Nucleoside Phosphorylase Isoenzyme Electrophoresis

3-methyl-2-oxobutanoate dehydrogenase

Indo et al (J Clin Invest 80:63-70 1987) reported that lymphoblasts from this patient had BCKDH enzyme activity which showed sigmoidal or near sigmoidal kinetics for overall activity which was reduced from normal activity. Both fibroblasts and lymphoblasts showed a markedly decreased amount of the E1B (branched-chain alpha-keto acid decarboxylase) protein component of the BCKDH complex using an immunoblot analysis. The E1A subunit gave a weakly positive reaction and the E2 (dihydrolipoyl transacylase) and E3 (dihydrolipoyl dehydrogenase) proteins exhibited cross-reactive peptide. Fisher et al (Am J Hum Genet 49:429-434 1991) reported that cDNA from this maple syrup urine disease patient showed a mutation at codon 393 of the mature E1 alpha polypeptide consisting of a base substitution changing a tyrosine (encoded by TAC) to an asparagine residue (encoded by AAC) which is designated Y393N. The patient was found to be homozygous for the mutation. EC Number: 1.2.4.4

GENE MAPPING & DOSAGE STUDIES - Y CHROMOSOME

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

Gene

BCKDHA

Chromosomal Location

19q13.1-q13.2

Allelic Variant 1

Y438N; MAPLE SYRUP URINE DISEASE, CLASSIC TYPE IA, DUE TO DEFICIENCY OF E1A

Identified Mutation

TYR438ASN (FORMERLY TYR393ASN)

Gene

BCKDHA

Chromosomal Location

19q13.1-q13.2

Allelic Variant 2

Y438N; MAPLE SYRUP URINE DISEASE, CLASSIC TYPE IA, DUE TO DEFICIENCY OF E1A

Identified Mutation

TYR438ASN (FORMERLY TYR393ASN)

Phenotypic Data

Remarks

Publications

Fisher CR, Fisher CW, Chuang DT, Cox RP, Occurrence of a Tyr393----Asn (Y393N) mutation in the E1 alpha gene of the branched-chain alpha-keto acid dehydrogenase complex in maple syrup urine disease patients from a Mennonite population. Am J Hum Genet49:429-34 1991

PubMed ID: 1867199

Matsuda I, Nobukuni Y, Mitsubuchi H, Indo Y, Endo F, Asaka J, Harada A, A T-to-A substitution in the E1 alpha subunit gene of the branched- chain alpha-ketoacid dehydrogenase complex in two cell lines derived from Menonite maple syrup urine disease patients. Biochem Biophys Res Commun172:646-51 1990

PubMed ID: 2241958

Indo Y, Kitano A, Endo F, Akaboshi I, Matsuda I, Altered kinetic properties of the branched-chain alpha-keto acid dehydrogenase complex due to mutation of the beta-subunit of the branched-chain alpha-keto acid decarboxylase (E1) component in lymphoblastoid cells derived from patients with maple syrup urine disease. J Clin Invest80:63-70 1987

PubMed ID: 3597778