Gene analysis of mennonite maple syrup urine disease kindred using primer‐specified restriction map modification

Abstract

Maple syrup urine disease (MSUD) is an autosomal recessive inherited disease due to a deficiency of any of the subunits, E1 alpha, E1 beta or E2, of the branched-chain alpha-ketoacid dehydrogenase complex (BCKDH). A large Mennonite kindred of MSUD has been studied in Pennsylvania, USA. In the present investigation, genomes from 70 members, including 12 patients belonging to eight different Mennonite MSUD pedigrees, were examined for possible abnormalities in the E1 alpha gene of BCKDH, by primer-specified restriction map modification. A T-to-A substitution which generates an asparagine in place of a tyrosine at amino acid 394 of the mature E1 alpha subunit was present in both alleles in all the patients and in a single allele in all obligate carriers and several siblings. We describe a new technique for rapid and easy detection of the mutant gene in this population. These family studies provide additional evidence that Mennonite MSUD is caused by a missense mutation of the E1 alpha gene of BCKDH

Human mutations affecting branched chain a-ketoacid dehydrogenase

“…Only one mutation is found with an increased frequency, the 1325T→A transversion that results in a Y393N substitution in E1α. This is the founder mutation responsible for the high incidence of MSUD (1/176) in the Mennonite population (76,79,80). It has been suggested that this mutation may also be found with a high frequency in the general population (81).…”

Maple syrup urine disease (MSUD): Screening for known mutations in Italian patients

“…We have investigated the molecular basis of maple syrup urine disease in Italy by examining genomic DNA from 10 patients and their family members for five previously described mutations in the gene encoding the BCKDH complex. The T to A transversion resulting in a Tyr---~ Asp change at position 394 (Y393N) in the mature EI~ subunit was the first mutation described in BCKDH-deficient patients (Zhang et al 1989;Matsuda et al 1990;Fisher et al 1991a) (Mitsubuchi et al 1992). This mutation was identified in a compound heterozygote of non-Mennonite ethnic background (Zhang et al 1989).…”

“…Thirteen molecular defects have been identified to date in BCKDHdeficient patients. The T to A transversion causing a Tyr to Asp change at codon 393 in the E1~ protein has been identified independently by several groups (Zhang et al 1989;Matsuda et al 1990;Fisher et al 1991a), and then recognized as the only MSUD mutation in the highly inbred Mennonite population (Mitsubuchi et al 1992). An 11 bp deletion in the region encoding the mitochondrial targeting, leader peptide of the EI~ subunit was found in three Japanese siblings of consanguinous parents .…”

Branched Chain Amino Acids and Maple Syrup Urine Disease

“…The second step is an oxidative decarboxylation catalyzed by the branched chain α-keto acid decarboxylase complex (BCKDC). These two enzymes associate as a supramolecular complex effecting effi cient channelling of substrates and control over the initial step of BCAA oxidation [ 10 ]. However this mutation has also been found in non-Mennonite patients not all of whom share common Mennonite haplotypes, suggesting the occurrence of the defect in these families is due to either pre-Mennonite or de novo events [ 11 ].…”