Mutational spectrum of D-bifunctional protein deficiency and structure-based genotype-phenotype analysis

Am J Hum Genet. 2006 Jan;78(1):112-24. doi: 10.1086/498880. Epub 2005 Nov 15.


D-bifunctional protein (DBP) deficiency is an autosomal recessive inborn error of peroxisomal fatty acid oxidation. The clinical presentation of DBP deficiency is usually very severe, but a few patients with a relatively mild presentation have been identified. In this article, we report the mutational spectrum of DBP deficiency on the basis of molecular analysis in 110 patients. We identified 61 different mutations by DBP cDNA analysis, 48 of which have not been reported previously. The predicted effects of the different disease-causing amino acid changes on protein structure were determined using the crystal structures of the (3R)-hydroxyacyl-coenzyme A (CoA) dehydrogenase unit of rat DBP and the 2-enoyl-CoA hydratase 2 unit and liganded sterol carrier protein 2-like unit of human DBP. The effects ranged from the replacement of catalytic amino acid residues or residues in direct contact with the substrate or cofactor to disturbances of protein folding or dimerization of the subunits. To study whether there is a genotype-phenotype correlation for DBP deficiency, these structure-based analyses were combined with extensive biochemical analyses of patient material (cultured skin fibroblasts and plasma) and available clinical information on the patients. We found that the effect of the mutations identified in patients with a relatively mild clinical and biochemical presentation was less detrimental to the protein structure than the effect of mutations identified in those with a very severe presentation. These results suggest that the amount of residual DBP activity correlates with the severity of the phenotype. From our data, we conclude that, on the basis of the predicted effect of the mutations on protein structure, a genotype-phenotype correlation exists for DBP deficiency.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 17-Hydroxysteroid Dehydrogenases / deficiency*
  • 17-Hydroxysteroid Dehydrogenases / genetics*
  • Amino Acid Sequence
  • Base Sequence
  • Coenzyme A Ligases / metabolism
  • DNA Mutational Analysis
  • DNA Primers
  • Dimerization
  • Enoyl-CoA Hydratase / deficiency*
  • Enoyl-CoA Hydratase / genetics*
  • Fatty Acids / metabolism
  • Fibroblasts / metabolism
  • Fluorescent Antibody Technique
  • Genotype
  • Humans
  • Hydro-Lyases
  • Immunoblotting
  • Models, Molecular*
  • Molecular Sequence Data
  • Multienzyme Complexes / deficiency*
  • Multienzyme Complexes / genetics*
  • Mutation / genetics*
  • Peroxisomal Multifunctional Protein-2
  • Phenotype*
  • Protein Folding
  • Sequence Analysis, DNA


  • DNA Primers
  • Fatty Acids
  • Multienzyme Complexes
  • 17-Hydroxysteroid Dehydrogenases
  • Hydro-Lyases
  • Peroxisomal Multifunctional Protein-2
  • HSD17B4 protein, human
  • Enoyl-CoA Hydratase
  • Coenzyme A Ligases
  • long-chain-fatty-acid-CoA ligase