Institut for Biomedicin

Lars Bolund

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

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

DOI

  • Brage Storstein Andresen, Aarhus Universitet, Center for Medical Molecular Biology
  • ,
  • Peter Bross
  • Szabolcs Udvari, Aarhus Universitet, University College Dublin
  • ,
  • Jean Kirk, Royal Hospital for Sick Children
  • ,
  • George Gray, Birmingham Women's and Children's NHS Foundation Trust
  • ,
  • Stanislav Kmoch, Charles University
  • ,
  • Nestor Chamoles, Fund. El Estud. Las Infermedades N.
  • ,
  • Inga Knudsen, Aarhus Universitet
  • ,
  • Vibeke Winter, Aarhus Universitet
  • ,
  • Bridget Wilcken, University of Sydney
  • ,
  • Ichiro Yokota, Yale University
  • ,
  • Kimberly Hart, University of California at San Francisco
  • ,
  • Seymour Packman, University of California at San Francisco
  • ,
  • Jean Paul Harpey, Sorbonne Université
  • ,
  • Jean Marie Saudubray, Universite Paris 5
  • ,
  • Daniel E. Hale, University of Texas at San Antonio
  • ,
  • Lars Bolund
  • Steen Kølvraa
  • ,
  • Niels Gregersen

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.

OriginalsprogEngelsk
TidsskriftHuman Molecular Genetics
Vol/bind6
Nummer5
Sider (fra-til)695-707
Antal sider13
ISSN0964-6906
DOI
StatusUdgivet - maj 1997

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