Maple syrup urine disease in Cypriot families

identification of three novel mutations and biochemical characterization of the p.Thr211Met mutation in the E1alpha subunit.

Theodoros Georgiou, Jacinta L. Chuang, R. Max Wynn, Goula Stylianidou, Mark Korson, David T. Chuang, Anthi Drousiotou

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

We report five mutations, three of them novel, responsible for maple syrup urine disease in four unrelated Cypriot families. The five children studied are the first cases of classic maple syrup urine disease to be reported among Cypriots. The first novel mutation identified is a single-base deletion in exon 6 of the Elalpha gene (c.718delG), which leads to a frameshift after Ala240 and to a stop codon 89 residues further downstream. The other two novel mutations identified are in the Elbeta subunit: a two-base deletion in exon 6, c.662_663delCC, which leads to a frameshift after Ala221 and creates a stop codon 17 residues further downstream, as well as a splice mutation, IVS3[+3]delA, which results in the skipping of exon 3. The two known mutations identified are in the Elalpha gene: the G > C transversion at the 3'-splice acceptor site, (IVS5-1G > C), which results in the deletion of the entire exon 6, and the missense mutation in exon 5 (c.632C > T), which corresponds to a p.Thr211Met substitution. The p.Thr211Met substitution is located in a potassium-ion pocket in the E1 component required for stability of the bound cofactor thiamine diphosphate. The mutant E1 protein harboring the p.Thr211Met substitution was shown unable to bind thiamine diphosphate, leading to undetectable E1 activity.

Original languageEnglish (US)
Pages (from-to)657-664
Number of pages8
JournalGenetic Testing and Molecular Biomarkers
Volume13
Issue number5
StatePublished - Oct 2009

Fingerprint

Maple Syrup Urine Disease
Exons
Mutation
Thiamine Pyrophosphate
RNA Splice Sites
Terminator Codon
Missense Mutation
Mutant Proteins
Genes
Potassium
Ions

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

Maple syrup urine disease in Cypriot families : identification of three novel mutations and biochemical characterization of the p.Thr211Met mutation in the E1alpha subunit. / Georgiou, Theodoros; Chuang, Jacinta L.; Wynn, R. Max; Stylianidou, Goula; Korson, Mark; Chuang, David T.; Drousiotou, Anthi.

In: Genetic Testing and Molecular Biomarkers, Vol. 13, No. 5, 10.2009, p. 657-664.

Research output: Contribution to journalArticle

@article{ef1feed9a3e148cd86baea8c2d14f3ce,
title = "Maple syrup urine disease in Cypriot families: identification of three novel mutations and biochemical characterization of the p.Thr211Met mutation in the E1alpha subunit.",
abstract = "We report five mutations, three of them novel, responsible for maple syrup urine disease in four unrelated Cypriot families. The five children studied are the first cases of classic maple syrup urine disease to be reported among Cypriots. The first novel mutation identified is a single-base deletion in exon 6 of the Elalpha gene (c.718delG), which leads to a frameshift after Ala240 and to a stop codon 89 residues further downstream. The other two novel mutations identified are in the Elbeta subunit: a two-base deletion in exon 6, c.662_663delCC, which leads to a frameshift after Ala221 and creates a stop codon 17 residues further downstream, as well as a splice mutation, IVS3[+3]delA, which results in the skipping of exon 3. The two known mutations identified are in the Elalpha gene: the G > C transversion at the 3'-splice acceptor site, (IVS5-1G > C), which results in the deletion of the entire exon 6, and the missense mutation in exon 5 (c.632C > T), which corresponds to a p.Thr211Met substitution. The p.Thr211Met substitution is located in a potassium-ion pocket in the E1 component required for stability of the bound cofactor thiamine diphosphate. The mutant E1 protein harboring the p.Thr211Met substitution was shown unable to bind thiamine diphosphate, leading to undetectable E1 activity.",
author = "Theodoros Georgiou and Chuang, {Jacinta L.} and Wynn, {R. Max} and Goula Stylianidou and Mark Korson and Chuang, {David T.} and Anthi Drousiotou",
year = "2009",
month = "10",
language = "English (US)",
volume = "13",
pages = "657--664",
journal = "Genetic Testing and Molecular Biomarkers",
issn = "1945-0265",
publisher = "Mary Ann Liebert Inc.",
number = "5",

}

TY - JOUR

T1 - Maple syrup urine disease in Cypriot families

T2 - identification of three novel mutations and biochemical characterization of the p.Thr211Met mutation in the E1alpha subunit.

AU - Georgiou, Theodoros

AU - Chuang, Jacinta L.

AU - Wynn, R. Max

AU - Stylianidou, Goula

AU - Korson, Mark

AU - Chuang, David T.

AU - Drousiotou, Anthi

PY - 2009/10

Y1 - 2009/10

N2 - We report five mutations, three of them novel, responsible for maple syrup urine disease in four unrelated Cypriot families. The five children studied are the first cases of classic maple syrup urine disease to be reported among Cypriots. The first novel mutation identified is a single-base deletion in exon 6 of the Elalpha gene (c.718delG), which leads to a frameshift after Ala240 and to a stop codon 89 residues further downstream. The other two novel mutations identified are in the Elbeta subunit: a two-base deletion in exon 6, c.662_663delCC, which leads to a frameshift after Ala221 and creates a stop codon 17 residues further downstream, as well as a splice mutation, IVS3[+3]delA, which results in the skipping of exon 3. The two known mutations identified are in the Elalpha gene: the G > C transversion at the 3'-splice acceptor site, (IVS5-1G > C), which results in the deletion of the entire exon 6, and the missense mutation in exon 5 (c.632C > T), which corresponds to a p.Thr211Met substitution. The p.Thr211Met substitution is located in a potassium-ion pocket in the E1 component required for stability of the bound cofactor thiamine diphosphate. The mutant E1 protein harboring the p.Thr211Met substitution was shown unable to bind thiamine diphosphate, leading to undetectable E1 activity.

AB - We report five mutations, three of them novel, responsible for maple syrup urine disease in four unrelated Cypriot families. The five children studied are the first cases of classic maple syrup urine disease to be reported among Cypriots. The first novel mutation identified is a single-base deletion in exon 6 of the Elalpha gene (c.718delG), which leads to a frameshift after Ala240 and to a stop codon 89 residues further downstream. The other two novel mutations identified are in the Elbeta subunit: a two-base deletion in exon 6, c.662_663delCC, which leads to a frameshift after Ala221 and creates a stop codon 17 residues further downstream, as well as a splice mutation, IVS3[+3]delA, which results in the skipping of exon 3. The two known mutations identified are in the Elalpha gene: the G > C transversion at the 3'-splice acceptor site, (IVS5-1G > C), which results in the deletion of the entire exon 6, and the missense mutation in exon 5 (c.632C > T), which corresponds to a p.Thr211Met substitution. The p.Thr211Met substitution is located in a potassium-ion pocket in the E1 component required for stability of the bound cofactor thiamine diphosphate. The mutant E1 protein harboring the p.Thr211Met substitution was shown unable to bind thiamine diphosphate, leading to undetectable E1 activity.

UR - http://www.scopus.com/inward/record.url?scp=74049157798&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=74049157798&partnerID=8YFLogxK

M3 - Article

VL - 13

SP - 657

EP - 664

JO - Genetic Testing and Molecular Biomarkers

JF - Genetic Testing and Molecular Biomarkers

SN - 1945-0265

IS - 5

ER -