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

Is there correlation between genotype and phenotype?

Brage Storstein Andresen, Peter Bross, Szabolcs Udvari, Jean Kirk, George Gray, Stanislav Kmoch, Nestor Chamoles, Inga Knudsen, Vibeke Winter, Bridget Wilcken, Ichiro Yokota, Kimberly Hart, Seymour Packman, Jean Paul Harpey, Jean Marie Saudubray, Daniel Hale, Lars Bolund, Steen Kølvraa, Niels Gregersen

Research output: Contribution to journalArticle

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Abstract

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most commonly recognized defect of mitochondrial β-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.

Original languageEnglish (US)
Pages (from-to)695-707
Number of pages13
JournalHuman Molecular Genetics
Volume6
Issue number5
DOIs
StatePublished - Jan 1 1997

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Genetic Association Studies
Mutation
Acyl-CoA Dehydrogenase
Chaperonins
Missense Mutation
Enzymes
Medium chain acyl CoA dehydrogenase deficiency
Physiological Stress
Protein Stability
Nonsense Codon
Disease Susceptibility
Genotype
Escherichia coli
Phenotype

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Andresen, Brage Storstein ; Bross, Peter ; Udvari, Szabolcs ; Kirk, Jean ; Gray, George ; Kmoch, Stanislav ; Chamoles, Nestor ; Knudsen, Inga ; Winter, Vibeke ; Wilcken, Bridget ; Yokota, Ichiro ; Hart, Kimberly ; Packman, Seymour ; Harpey, Jean Paul ; Saudubray, Jean Marie ; Hale, Daniel ; Bolund, Lars ; Kølvraa, Steen ; Gregersen, Niels. / The molecular basis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in compound heterozygous patients : Is there correlation between genotype and phenotype?. In: Human Molecular Genetics. 1997 ; Vol. 6, No. 5. pp. 695-707.
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abstract = "Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most commonly recognized defect of mitochondrial β-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.",
author = "Andresen, {Brage Storstein} and Peter Bross and Szabolcs Udvari and Jean Kirk and George Gray and Stanislav Kmoch and Nestor Chamoles and Inga Knudsen and Vibeke Winter and Bridget Wilcken and Ichiro Yokota and Kimberly Hart and Seymour Packman and Harpey, {Jean Paul} and Saudubray, {Jean Marie} and Daniel Hale and Lars Bolund and Steen K{\o}lvraa and Niels 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, D, 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, vol. 6, no. 5, pp. 695-707. https://doi.org/10.1093/hmg/6.5.695

The molecular basis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in compound heterozygous patients : Is there correlation between genotype and phenotype? / Andresen, Brage Storstein; Bross, Peter; Udvari, Szabolcs; Kirk, Jean; Gray, George; Kmoch, Stanislav; Chamoles, Nestor; Knudsen, Inga; Winter, Vibeke; Wilcken, Bridget; Yokota, Ichiro; Hart, Kimberly; Packman, Seymour; Harpey, Jean Paul; Saudubray, Jean Marie; Hale, Daniel; Bolund, Lars; Kølvraa, Steen; Gregersen, Niels.

In: Human Molecular Genetics, Vol. 6, No. 5, 01.01.1997, p. 695-707.

Research output: Contribution to journalArticle

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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, Brage Storstein

AU - Bross, Peter

AU - Udvari, Szabolcs

AU - Kirk, Jean

AU - Gray, George

AU - Kmoch, Stanislav

AU - Chamoles, Nestor

AU - Knudsen, Inga

AU - Winter, Vibeke

AU - Wilcken, Bridget

AU - Yokota, Ichiro

AU - Hart, Kimberly

AU - Packman, Seymour

AU - Harpey, Jean Paul

AU - Saudubray, Jean Marie

AU - Hale, Daniel

AU - Bolund, Lars

AU - Kølvraa, Steen

AU - Gregersen, Niels

PY - 1997/1/1

Y1 - 1997/1/1

N2 - Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most commonly recognized defect of mitochondrial β-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 β-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.

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