The molecular basis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in compound heterozygous patients: is there correlation between genotype and phenotype?

B S Andresen, P Bross, S Udvari, J Kirk, G Gray, S Kmoch, N Chamoles, I Knudsen, V Winter, B Wilcken, I Yokota, K Hart, S Packman, J P Harpey, J M Saudubray, D E Hale, L Bolund, S Kølvraa, N Gregersen

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Resumé

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most commonly recognized defect of mitochondrial beta-oxidation. It is potentially fatal, but shows a wide clinical spectrum. The aim of the present study was to investigate whether any correlation exists between MCAD genotype and disease phenotype. We determined the prevalence of the 14 known and seven previously unknown non-G985 mutations in 52 families with MCAD deficiency not caused by homozygosity for the prevalent G985 mutation. This showed that none of the non-G985 mutations are prevalent, and led to the identification of both disease-causing mutations in 14 families in whom both mutations had not previously been reported. We then evaluated the severity of the mutations identified in these 14 families. Using expression of mutant MCAD in Escherichia coli with or without co-overexpression of the molecular chaperonins GroESL we showed that five of the missense mutations affect the folding and/or stability of the protein, and that the residual enzyme activity of some of them could be modulated to a different extent depending on the amounts of available chaperonins. Thus, some of the missense mutations may result in relatively high levels of residual enzyme activity, whereas the mutations leading to premature stop codons will result in no residual enzyme activity. By correlating the observed types of mutations identified to the clinical/biochemical data in the 14 patients in whom we identified both disease-causing mutations, we show that a genotype/phenotype correlation in MCAD deficiency is not straightforward. Different mutations may contribute with different susceptibilities for disease precipitation, when the patient is subjected to metabolic stress, but other genetic and environmental factors may play an equally important role.

OriginalsprogEngelsk
TidsskriftHuman Molecular Genetics
Vol/bind6
Udgave nummer5
Sider (fra-til)695-707
Antal sider13
ISSN0964-6906
StatusUdgivet - 1997

Fingeraftryk

Genetic Association Studies
Mutation
Chaperonins
Missense Mutation
Enzymes
Nonsense Codon

Citer dette

Andresen, B S ; Bross, P ; Udvari, S ; Kirk, J ; Gray, G ; Kmoch, S ; Chamoles, N ; Knudsen, I ; Winter, V ; Wilcken, B ; Yokota, I ; Hart, K ; Packman, S ; Harpey, J P ; Saudubray, J M ; Hale, D E ; Bolund, L ; Kølvraa, S ; Gregersen, N. / The molecular basis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in compound heterozygous patients : is there correlation between genotype and phenotype?. I: Human Molecular Genetics. 1997 ; Bind 6, Nr. 5. s. 695-707.
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title = "The molecular basis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in compound heterozygous patients: is there correlation between genotype and phenotype?",
abstract = "Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most commonly recognized defect of mitochondrial beta-oxidation. It is potentially fatal, but shows a wide clinical spectrum. The aim of the present study was to investigate whether any correlation exists between MCAD genotype and disease phenotype. We determined the prevalence of the 14 known and seven previously unknown non-G985 mutations in 52 families with MCAD deficiency not caused by homozygosity for the prevalent G985 mutation. This showed that none of the non-G985 mutations are prevalent, and led to the identification of both disease-causing mutations in 14 families in whom both mutations had not previously been reported. We then evaluated the severity of the mutations identified in these 14 families. Using expression of mutant MCAD in Escherichia coli with or without co-overexpression of the molecular chaperonins GroESL we showed that five of the missense mutations affect the folding and/or stability of the protein, and that the residual enzyme activity of some of them could be modulated to a different extent depending on the amounts of available chaperonins. Thus, some of the missense mutations may result in relatively high levels of residual enzyme activity, whereas the mutations leading to premature stop codons will result in no residual enzyme activity. By correlating the observed types of mutations identified to the clinical/biochemical data in the 14 patients in whom we identified both disease-causing mutations, we show that a genotype/phenotype correlation in MCAD deficiency is not straightforward. Different mutations may contribute with different susceptibilities for disease precipitation, when the patient is subjected to metabolic stress, but other genetic and environmental factors may play an equally important role.",
keywords = "Acyl-CoA Dehydrogenase, Acyl-CoA Dehydrogenases, Adolescent, Alleles, Blotting, Western, Chaperonin 10, Chaperonin 60, Child, Child, Preschool, Enzyme Activation, Escherichia coli, Exons, Female, Heterozygote, Humans, Infant, Infant, Newborn, Male, Mutation, Pedigree, Phenotype, Polymerase Chain Reaction, Recombinant Proteins, Restriction Mapping, Sequence Analysis, DNA, Sequence Deletion, Temperature",
author = "Andresen, {B S} and P Bross and S Udvari and J Kirk and G Gray and S Kmoch and N Chamoles and I Knudsen and V Winter and B Wilcken and I Yokota and K Hart and S Packman and Harpey, {J P} and Saudubray, {J M} and Hale, {D E} and L Bolund and S K{\o}lvraa and N Gregersen",
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Andresen, BS, Bross, P, Udvari, S, Kirk, J, Gray, G, Kmoch, S, Chamoles, N, Knudsen, I, Winter, V, Wilcken, B, Yokota, I, Hart, K, Packman, S, Harpey, JP, Saudubray, JM, Hale, DE, Bolund, L, Kølvraa, S & Gregersen, N 1997, 'The molecular basis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in compound heterozygous patients: is there correlation between genotype and phenotype?', Human Molecular Genetics, bind 6, nr. 5, s. 695-707.

The molecular basis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in compound heterozygous patients : is there correlation between genotype and phenotype? / Andresen, B S; Bross, P; Udvari, S; Kirk, J; Gray, G; Kmoch, S; Chamoles, N; Knudsen, I; Winter, V; Wilcken, B; Yokota, I; Hart, K; Packman, S; Harpey, J P; Saudubray, J M; Hale, D E; Bolund, L; Kølvraa, S; Gregersen, N.

I: Human Molecular Genetics, Bind 6, Nr. 5, 1997, s. 695-707.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - The molecular basis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in compound heterozygous patients

T2 - is there correlation between genotype and phenotype?

AU - Andresen, B S

AU - Bross, P

AU - Udvari, S

AU - Kirk, J

AU - Gray, G

AU - Kmoch, S

AU - Chamoles, N

AU - Knudsen, I

AU - Winter, V

AU - Wilcken, B

AU - Yokota, I

AU - Hart, K

AU - Packman, S

AU - Harpey, J P

AU - Saudubray, J M

AU - Hale, D E

AU - Bolund, L

AU - Kølvraa, S

AU - Gregersen, N

PY - 1997

Y1 - 1997

N2 - Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most commonly recognized defect of mitochondrial beta-oxidation. It is potentially fatal, but shows a wide clinical spectrum. The aim of the present study was to investigate whether any correlation exists between MCAD genotype and disease phenotype. We determined the prevalence of the 14 known and seven previously unknown non-G985 mutations in 52 families with MCAD deficiency not caused by homozygosity for the prevalent G985 mutation. This showed that none of the non-G985 mutations are prevalent, and led to the identification of both disease-causing mutations in 14 families in whom both mutations had not previously been reported. We then evaluated the severity of the mutations identified in these 14 families. Using expression of mutant MCAD in Escherichia coli with or without co-overexpression of the molecular chaperonins GroESL we showed that five of the missense mutations affect the folding and/or stability of the protein, and that the residual enzyme activity of some of them could be modulated to a different extent depending on the amounts of available chaperonins. Thus, some of the missense mutations may result in relatively high levels of residual enzyme activity, whereas the mutations leading to premature stop codons will result in no residual enzyme activity. By correlating the observed types of mutations identified to the clinical/biochemical data in the 14 patients in whom we identified both disease-causing mutations, we show that a genotype/phenotype correlation in MCAD deficiency is not straightforward. Different mutations may contribute with different susceptibilities for disease precipitation, when the patient is subjected to metabolic stress, but other genetic and environmental factors may play an equally important role.

AB - Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most commonly recognized defect of mitochondrial beta-oxidation. It is potentially fatal, but shows a wide clinical spectrum. The aim of the present study was to investigate whether any correlation exists between MCAD genotype and disease phenotype. We determined the prevalence of the 14 known and seven previously unknown non-G985 mutations in 52 families with MCAD deficiency not caused by homozygosity for the prevalent G985 mutation. This showed that none of the non-G985 mutations are prevalent, and led to the identification of both disease-causing mutations in 14 families in whom both mutations had not previously been reported. We then evaluated the severity of the mutations identified in these 14 families. Using expression of mutant MCAD in Escherichia coli with or without co-overexpression of the molecular chaperonins GroESL we showed that five of the missense mutations affect the folding and/or stability of the protein, and that the residual enzyme activity of some of them could be modulated to a different extent depending on the amounts of available chaperonins. Thus, some of the missense mutations may result in relatively high levels of residual enzyme activity, whereas the mutations leading to premature stop codons will result in no residual enzyme activity. By correlating the observed types of mutations identified to the clinical/biochemical data in the 14 patients in whom we identified both disease-causing mutations, we show that a genotype/phenotype correlation in MCAD deficiency is not straightforward. Different mutations may contribute with different susceptibilities for disease precipitation, when the patient is subjected to metabolic stress, but other genetic and environmental factors may play an equally important role.

KW - Acyl-CoA Dehydrogenase

KW - Acyl-CoA Dehydrogenases

KW - Adolescent

KW - Alleles

KW - Blotting, Western

KW - Chaperonin 10

KW - Chaperonin 60

KW - Child

KW - Child, Preschool

KW - Enzyme Activation

KW - Escherichia coli

KW - Exons

KW - Female

KW - Heterozygote

KW - Humans

KW - Infant

KW - Infant, Newborn

KW - Male

KW - Mutation

KW - Pedigree

KW - Phenotype

KW - Polymerase Chain Reaction

KW - Recombinant Proteins

KW - Restriction Mapping

KW - Sequence Analysis, DNA

KW - Sequence Deletion

KW - Temperature

M3 - Journal article

C2 - 9158144

VL - 6

SP - 695

EP - 707

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 5

ER -