Institut for Biomedicin

Lars Bolund

A rare disease-associated mutation in the medium-chain acyl-CoA dehydrogenase (MCAD) gene changes a conserved arginine, previously shown to be functionally essential in short-chain acyl-CoA dehydrogenase (SCAD)

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A rare disease-associated mutation in the medium-chain acyl-CoA dehydrogenase (MCAD) gene changes a conserved arginine, previously shown to be functionally essential in short-chain acyl-CoA dehydrogenase (SCAD). / Andresen, B S; Bross, P; Jensen, T G; Winter, V; Knudsen, I; Kølvraa, S; Jensen, Uffe Birk; Bolund, L; Duran, M; Kim, J J.

I: American Journal of Human Genetics, Bind 53, Nr. 3, 01.09.1993, s. 730-9.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

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@article{19b3f99c67a44426b39af56cd01a86e7,
title = "A rare disease-associated mutation in the medium-chain acyl-CoA dehydrogenase (MCAD) gene changes a conserved arginine, previously shown to be functionally essential in short-chain acyl-CoA dehydrogenase (SCAD)",
abstract = "Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is a serious and potentially fatal inherited defect in the beta-oxidation of fatty acids. Approximately 80% of patients with MCAD deficiency are homozygous for a single disease-causing mutation (G985). The remaining patients (except for a few cases worldwide) are compound heterozygous with G985 in one allele. By sequencing of cloned PCR-amplified MCAD cDNA from a G985 compound heterozygous patient, we identified a C-to-T transition at position 157 as the only change in the entire coding sequence of the non-G985 allele. The presence of the T157 mutation was verified in genomic DNA from the patient and her mother by a PCR-based assay. The mutation changes conserved arginine at position 28 (R28C) of the mature MCAD protein. The effect of the T157 mutation on MCAD protein was investigated by expression of mutant MCAD cDNA in COS-7 cells. On the basis of knowledge about the three-dimensional structure of the MCAD protein, we suggest that the mutation destroys a salt bridge between arginine28 and glutamate86, thereby affecting the formation of enzymatically active protein. Twenty-two additional families with compound heterozygous patients were tested in the PCR-based assay. The T157 mutation was identified in one of these families, which had an MCAD-deficient child who died unexpectedly in infancy. Our results indicate that the mutation is rare. It is, however, noteworthy that a homologous mutation has previously been identified in the short-chain acyl-CoA dehydrogenase (SCAD) gene of a patient with SCAD deficiency, suggesting that the conserved arginine is crucial for formation of active enzyme in the straight-chain acyl-CoA dehydrogenases.",
keywords = "Acyl-CoA Dehydrogenase, Acyl-CoA Dehydrogenases, Arginine, Base Sequence, Cells, Cultured, Cysteine, DNA Mutational Analysis, Female, Heterozygote, Humans, Infant, Infant, Newborn, Lipid Metabolism, Inborn Errors, Male, Molecular Sequence Data, Mutagenesis, Site-Directed, Oxidation-Reduction, Pedigree, Point Mutation, Polymerase Chain Reaction, Polymorphism, Restriction Fragment Length, Protein Structure, Secondary, Recombinant Proteins, Structure-Activity Relationship",
author = "Andresen, {B S} and P Bross and Jensen, {T G} and V Winter and I Knudsen and S K{\o}lvraa and Jensen, {Uffe Birk} and L Bolund and M Duran and Kim, {J J}",
year = "1993",
month = sep,
day = "1",
language = "English",
volume = "53",
pages = "730--9",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "3",

}

RIS

TY - JOUR

T1 - A rare disease-associated mutation in the medium-chain acyl-CoA dehydrogenase (MCAD) gene changes a conserved arginine, previously shown to be functionally essential in short-chain acyl-CoA dehydrogenase (SCAD)

AU - Andresen, B S

AU - Bross, P

AU - Jensen, T G

AU - Winter, V

AU - Knudsen, I

AU - Kølvraa, S

AU - Jensen, Uffe Birk

AU - Bolund, L

AU - Duran, M

AU - Kim, J J

PY - 1993/9/1

Y1 - 1993/9/1

N2 - Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is a serious and potentially fatal inherited defect in the beta-oxidation of fatty acids. Approximately 80% of patients with MCAD deficiency are homozygous for a single disease-causing mutation (G985). The remaining patients (except for a few cases worldwide) are compound heterozygous with G985 in one allele. By sequencing of cloned PCR-amplified MCAD cDNA from a G985 compound heterozygous patient, we identified a C-to-T transition at position 157 as the only change in the entire coding sequence of the non-G985 allele. The presence of the T157 mutation was verified in genomic DNA from the patient and her mother by a PCR-based assay. The mutation changes conserved arginine at position 28 (R28C) of the mature MCAD protein. The effect of the T157 mutation on MCAD protein was investigated by expression of mutant MCAD cDNA in COS-7 cells. On the basis of knowledge about the three-dimensional structure of the MCAD protein, we suggest that the mutation destroys a salt bridge between arginine28 and glutamate86, thereby affecting the formation of enzymatically active protein. Twenty-two additional families with compound heterozygous patients were tested in the PCR-based assay. The T157 mutation was identified in one of these families, which had an MCAD-deficient child who died unexpectedly in infancy. Our results indicate that the mutation is rare. It is, however, noteworthy that a homologous mutation has previously been identified in the short-chain acyl-CoA dehydrogenase (SCAD) gene of a patient with SCAD deficiency, suggesting that the conserved arginine is crucial for formation of active enzyme in the straight-chain acyl-CoA dehydrogenases.

AB - Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is a serious and potentially fatal inherited defect in the beta-oxidation of fatty acids. Approximately 80% of patients with MCAD deficiency are homozygous for a single disease-causing mutation (G985). The remaining patients (except for a few cases worldwide) are compound heterozygous with G985 in one allele. By sequencing of cloned PCR-amplified MCAD cDNA from a G985 compound heterozygous patient, we identified a C-to-T transition at position 157 as the only change in the entire coding sequence of the non-G985 allele. The presence of the T157 mutation was verified in genomic DNA from the patient and her mother by a PCR-based assay. The mutation changes conserved arginine at position 28 (R28C) of the mature MCAD protein. The effect of the T157 mutation on MCAD protein was investigated by expression of mutant MCAD cDNA in COS-7 cells. On the basis of knowledge about the three-dimensional structure of the MCAD protein, we suggest that the mutation destroys a salt bridge between arginine28 and glutamate86, thereby affecting the formation of enzymatically active protein. Twenty-two additional families with compound heterozygous patients were tested in the PCR-based assay. The T157 mutation was identified in one of these families, which had an MCAD-deficient child who died unexpectedly in infancy. Our results indicate that the mutation is rare. It is, however, noteworthy that a homologous mutation has previously been identified in the short-chain acyl-CoA dehydrogenase (SCAD) gene of a patient with SCAD deficiency, suggesting that the conserved arginine is crucial for formation of active enzyme in the straight-chain acyl-CoA dehydrogenases.

KW - Acyl-CoA Dehydrogenase

KW - Acyl-CoA Dehydrogenases

KW - Arginine

KW - Base Sequence

KW - Cells, Cultured

KW - Cysteine

KW - DNA Mutational Analysis

KW - Female

KW - Heterozygote

KW - Humans

KW - Infant

KW - Infant, Newborn

KW - Lipid Metabolism, Inborn Errors

KW - Male

KW - Molecular Sequence Data

KW - Mutagenesis, Site-Directed

KW - Oxidation-Reduction

KW - Pedigree

KW - Point Mutation

KW - Polymerase Chain Reaction

KW - Polymorphism, Restriction Fragment Length

KW - Protein Structure, Secondary

KW - Recombinant Proteins

KW - Structure-Activity Relationship

M3 - Journal article

C2 - 8102510

VL - 53

SP - 730

EP - 739

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 3

ER -