RGD Reference Report - Mutational spectrum of D-bifunctional protein deficiency and structure-based genotype-phenotype analysis. - Rat Genome Database

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

Authors: Ferdinandusse, S  Ylianttila, MS  Gloerich, J  Koski, MK  Oostheim, W  Waterham, HR  Hiltunen, JK  Wanders, RJ  Glumoff, T 
Citation: Ferdinandusse S, etal., Am J Hum Genet. 2006 Jan;78(1):112-24. Epub 2005 Nov 15.
RGD ID: 10411884
Pubmed: PMID:16385454   (View Abstract at PubMed)
PMCID: PMC1380208   (View Article at PubMed Central)
DOI: DOI:10.1086/498880   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
HSD17B4HumanD-bifunctional protein deficiency severityIAGP DNA:mutations:multiple (human)RGD 
Hsd17b4RatD-bifunctional protein deficiency severityISOHSD17B4 (Homo sapiens)DNA:mutations:multiple (human)RGD 
Hsd17b4MouseD-bifunctional protein deficiency severityISOHSD17B4 (Homo sapiens)DNA:mutations:multiple (human)RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
HSD17B4HumanDeath in infancy severityIAGP DNA:mutations:multipleRGD 
Objects Annotated

Genes (Rattus norvegicus)
Hsd17b4  (hydroxysteroid (17-beta) dehydrogenase 4)

Genes (Mus musculus)
Hsd17b4  (hydroxysteroid (17-beta) dehydrogenase 4)

Genes (Homo sapiens)
HSD17B4  (hydroxysteroid 17-beta dehydrogenase 4)


Additional Information