Molecular basis of intermittent maple syrup urine disease: novel mutations in the e2 gene of the branched-chain α-keto acid dehydrogenase complex

ABSTRACT The _E2_ gene of the branched-chain α-keto acid dehydrogenase (BCKDH) complex was studied at the molecular level in three patients with intermittent maple syrup urine disease

(MSUD). All three patients had higher BCKDH activity than did those with the classical phenotype. In the first patient, a single base substitution from A to G in intron 8 created a new 5′

splice site and caused an insertion of 126 nucleotides between exons 8 and 9 by activating an upstream cryptic 3′ splice site in the same intron. The predicted mRNA encoded a truncated

protein with 282 amino acids including 4 novel ones at the carboxyl terminus, compared with the normal protein with 421 amino acids. In vitro, the region from the patient but not from a

normal control was recognized and was recovered as a novel exon, indicating that the single substitution was responsible for incorporation of the region into mRNA. This mutation probably

supports an exon definition model in which the spliceosome recognizes a 3′ splice site and then scans downstream for an acceptable 5′ splice site, thereby defining an exon. The second

patient was homozygous for a G to T transversion at nucleotide 1463 in exon 11, which predicted a substitution of the termination codon by a leucine residue and the addition of 7 extra amino

acids at the carboxyl terminus. For each mutation, these two patients were homozygous and their parents were heterozygous. The third patient was a compound heterozygote for a C to G

transversion at nucleotide 309 in exon 4 and a G to A transition at nucleotide 1165 in exon 9, causing an Ile-to-Met substitution at amino acid 37 and a Gly-to-Ser substitution at amino acid

323, respectively. Taken together, these results indicate that the molecular basis of intermittent phenotype MSUD in some patients can be due to mutations in the _E2_ gene, giving rise to a

low but significant residual activity of the BCKDH complex. SIMILAR CONTENT BEING VIEWED BY OTHERS ALKAPTONURIA IN RUSSIA Article 10 September 2021 HOMOGENTISATE 1,2-DIOXYGENASE (_HGD_)

GENE VARIANTS IN YOUNG EGYPTIAN PATIENTS WITH ALKAPTONURIA Article Open access 01 September 2023 EXPANDING THE GENOTYPIC AND PHENOTYPIC SPECTRUM OF EGYPTIAN CHILDREN WITH MAPLE SYRUP URINE

DISEASE Article Open access 18 November 2024 ARTICLE PDF AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Pediatrics, Kumamoto University School of Medicine, Honjo 1-1-1, Kumamoto

860-8556, Japan Tel. +81-96-373-5191; Fax +81-96-366-3471, Japan Motoko Tsuruta, Hiroshi Mitsubuchi, S. Mardy, Yuichi Miura, Yumi Hayashida, Ichiro Matsuda & Y. Indo * Department of

Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan, Japan Akihiko Kinugasa * Department of Pediatrics, National Saishunso Hospital, Kumamoto, Japan, Japan Takateru Ishitsu

Authors * Motoko Tsuruta View author publications You can also search for this author inPubMed Google Scholar * Hiroshi Mitsubuchi View author publications You can also search for this

author inPubMed Google Scholar * S. Mardy View author publications You can also search for this author inPubMed Google Scholar * Yuichi Miura View author publications You can also search for

this author inPubMed Google Scholar * Yumi Hayashida View author publications You can also search for this author inPubMed Google Scholar * Akihiko Kinugasa View author publications You can

also search for this author inPubMed Google Scholar * Takateru Ishitsu View author publications You can also search for this author inPubMed Google Scholar * Ichiro Matsuda View author

publications You can also search for this author inPubMed Google Scholar * Y. Indo View author publications You can also search for this author inPubMed Google Scholar ADDITIONAL INFORMATION

Received: October 29, 1997 / Accepted: November 27, 1997 RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Tsuruta, M., Mitsubuchi, H., Mardy, S. _et al._

Molecular basis of intermittent maple syrup urine disease: novel mutations in the _E2_ gene of the branched-chain α-keto acid dehydrogenase complex. _J Hum Genet_ 43, 91–100 (1998).

https://doi.org/10.1007/s100380050047 Download citation * Published: 01 June 1998 * Issue Date: June 1998 * DOI: https://doi.org/10.1007/s100380050047 SHARE THIS ARTICLE Anyone you share the

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Nature SharedIt content-sharing initiative * Key words Maple syrup urine disease * Intermittent maple syrup urine disease * Branched-chain α-keto acid dehydrogenase complex * Dihydrolipoyl

transacylase (E2) * Inborn error of metabolism * Mutation analysis of the E2 gene