Human Molecular Genetics, Vol 6, 695-707, Copyright © 1997 by Oxford University Press
BS 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, JP Harpey, JM Saudubray, DE Hale, L Bolund, S Kolvraa and N Gregersen
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.
ARTICLES
The molecular basis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in compound heterozygous patients: is there correlation between genotype and phenotype?
Center for Medical Molecular Biology, Aarhus University Hospital and Faculty of Health Science, Denmark. brage@biobase.dk
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