Molecular basis of d-bifunctional protein deficiency

doi:10.1016/S0303-7207(00)00388-9

Molecular and Cellular Endocrinology

Volume 171, Issues 1–2, 22 January 2001, Pages 61-70

https://doi.org/10.1016/S0303-7207(00)00388-9 Get rights and content

Abstract

Peroxisomal disorders appear with a frequency of 1:5000 in newborns. They are caused either by peroxisomal assembly defects or by deficiencies of single peroxisomal enzymes. The phenotypes vary widely: affected humans may die very early in life within a few days to several months as a result of the impairment in essential peroxisomal functions as, for example, in Zellweger syndrome, or they may show only minor disabilities as is in acatalasemia. The deficiency of d-bifunctional protein, an enzyme involved in peroxisomal β-oxidation of certain fatty acids and the synthesis of bile acids, causes a very severe, Zellweger-like phenotype. A number of different mutations in the gene coding for the enzyme were found in humans causing the total or partial loss of its enzymatic function. This paper gives a review of cases and their molecular basis.

Section snippets

d-Bifunctional protein/17β-hydroxysteroid dehydrogenase type 4/multifunctional protein 2

The d-bifunctional protein (d-BP) was first discovered in the pig as 17β-hydroxysteroid dehydrogenase type 4 (HSD4) (Adamski et al., 1992) due to its ability to oxidize 17β-estradiol and Δ5-androstene-3β/17β-diol at position 17 of the steroid backbone. The rat 17β-HSD4 ortholog was described as a protein that is induced by the peroxisome proliferation activator clofibrate (Corton et al., 1996). cDNAs of the enzyme were also cloned from man (Adamski et al., 1995), mouse (Normand et al., 1995),

Synonyms

Due to its multifunctionality and its discovery in connection with different metabolic pathways several names are in use for this enzyme: bifunctional protein (BP) or d-bifunctional protein (d-BP), multifunctional protein 2 (MFP-2) or multifunctional enzyme 2 (MFE-2), 17β-hydroxysteroid dehydrogenase type 4 (17β-HSD4), d-3-hydroxyacyl-CoA dehydratase/d-3-hydroxyacyl-CoA dehydrogenase, 2-enoyl-CoA hydratase-2/(R)-3-hydroxyacyl-CoA dehydrogenase (reviewed in de Launoit and Adamski (1999)).

d-Bifunctional protein deficiency

d-Bifunctional protein deficiency belongs to the large group of peroxisomal disorders that are inherited in man. These disorders are subdivided into two categories: (1) peroxisome biogenesis or assembly disorders in which peroxisomes are not formed, and (2) the defect or deficiency of single peroxisomal proteins. Four phenotypes are associated with the assembly disorders: Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and rhizomelic

Point mutation G16S

The first explanation of the d-BP deficiency was given by van Grunsven et al. (1998). A patient with a homozygous point mutation in the SDR domain was reported. The base exchange 46G → A led to the expression of a full length protein with the amino acid exchange G16S in the cofactor binding region (Table 3 and Fig. 3). In the patient elevated plasma levels of VLCFA, pristanic acid and bile acid intermediates were found. Peroxisomes were present in the patient's fibroblasts although in reduced

Call for mutants

The authors would like to maintain a comprehensive data base on d-BP mutants. Should we have missed any observation we would greatly appreciate a notification about that.

Acknowledgements

The work was supported by a grant of the Deutsche Forschungsgemeinschaft to JA.

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Peroxisomal D-bifunctional protein (DBP) deficiency is an autosomal recessive disorder historically described as a Zellweger-like syndrome comprising neonatal seizures, retinopathy, hearing loss, dysmorphic features, and other complications. The HSD17B4 gene encodes DBP which is essential for oxidation of peroxisomal substrates. We describe 4 patients - 2 unrelated female girls and 2 monozygotic twin sisters - with DBP deficiency and phenotypic diversity.
Patient 1 presented neonatally with hypotonia and seizures, and later on developed global developmental delay and regression, sensorineural hearing loss, nystagmus and cortical blindness. The brain MRI demonstrated bilateral peri-sylvian polymicrogyria. Whole exome sequencing revealed 2 mutations in the HSD17B4 gene (c.752G>A, p.(Arg251Gln); c.868 + 1delG).
Patient 2 presented with hypotonia, motor delay, and sensorineural hearing loss in infancy, considerable developmental regression during her fourth year, nystagmus, and peripheral neuropathy. Brain MRI demonstrated cerebellar atrophy and abnormal basal ganglia and white matter signal, which appeared after the age of two years. Whole exome sequencing revealed 2 mutations in the HSD17B4 gene (c.14 T>G, p.(Leu5Arg); c.752G>A, p.(Arg251Gln)).
Patients 3 and 4, two female monozygotic twins, presented with hypotonia, developmental delay, and macrocephaly from birth, and later on also sensorineural hearing loss, infantile spasms and hypsarrhythmia, and adrenal insufficiency. Brain MRI demonstrated delayed myelination, and an assay of peroxisomal beta oxidation suggested DBP deficiency. Sequencing of the HSD17B4 gene revealed the same 2 mutations as in patient 1.
We describe 4 patients with variable and diverse clinical picture of DBP deficiency and particularly emphasize the clinical, biochemical, and neuroimaging characteristics. Interestingly, the clinical phenotype varied even between patients with the exact two mutations in the HSD17B4 gene. In addition, in two of the three patients in whom levels of VLCFA including phytanic acid were measured, the levels were within normal limits. This is expanding further the clinical spectrum of this disorder, which should be considered in the differential diagnosis of every patient with hypotonia and developmental delay especially if accompanied by polymicrogyria, seizures, sensorineural hearing loss, or adrenal insufficiency regardless of their VLCFA profile.
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Molecular basis of d-bifunctional protein deficiency

Abstract

Section snippets

d-Bifunctional protein/17β-hydroxysteroid dehydrogenase type 4/multifunctional protein 2

Synonyms

d-Bifunctional protein deficiency

Point mutation G16S

Call for mutants

Acknowledgements

Am. J. Hum. Genet.

Brain. Res.

Exp. Eye Res.

Mol. Cell. Endocrinol.

Genomics

J. Biol. Chem.

J. Steroid Biochem. Mol. Biol.

J. Steroid Biochem. Mol. Biol.

Biochim. Biophys. Acta

J. Biol. Chem.

Am. J. Hum. Genet.

J. Lipid Res.

FEBS Lett.

J. Lipid Res.

Purification and properties of oestradiol 17 beta-dehydrogenase extracted from cytoplasmic vesicles of porcine endometrial cells

Biochem. J.

Molecular cloning of a novel widely expressed human 80 kDa 17 beta-hydroxysteroid dehydrogenase IV

Biochem. J.

New 17 beta-hydroxysteroid dehydrogenases. Molecular and cell biology of the type IV porcine and human enzymes

Ann. New York Acad. Sci.

Inactivation of peroxisomal multifunctional protein-2 in mice impedes the degradation of not only 2-methyl branched fatty acids and bile acid intermediates but also of very long chain fatty acids

J. Biol. Chem.

Differential regulation by a peroxisome proliferator of the different multifunctional proteins in guinea pig: cDNA cloning of the guinea pig d-specific multifunctional protein 2

Biochem. J.

Rat 17 beta-hydroxysteroid dehydrogenase type IV is a novel peroxisome proliferator-inducible gene

Mol. Pharmacol.

Further characterization of the peroxisomal 3-hydroxyacyl-CoA dehydrogenases from rat liver. Relationship between the different dehydrogenases and evidence that fatty acids and the C27 bile acids di- and tri-hydroxycoprostanic acids are metabolized by separate multifunctional proteins

Eur. J. Biochem.

Evidence that multifunctional protein 2, and not multifunctional protein 1, is involved in the peroxisomal beta-oxidation of pristanic acid

Biochem. J.

Identification of a human PTS1 receptor docking protein directly required for peroxisomal protein import

Proc. Natl. Acad. Sci. USA

Genetic heterogeneity in patients with a disorder of peroxisomal beta-oxidation: a complementation study based on pristanic acid beta-oxidation suggesting different enzyme defects

J. Inherit. Metab. Dis.