Alternative titles; symbols
HGNC Approved Gene Symbol: HSD17B4
SNOMEDCT: 238068007;
Cytogenetic location: 5q23.1 Genomic coordinates (GRCh38) : 5:119,452,497-119,542,332 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q23.1 | D-bifunctional protein deficiency | 261515 | Autosomal recessive | 3 |
| Perrault syndrome 1 | 233400 | Autosomal recessive | 3 |
The HSD17B4 gene encodes an enzyme involved in peroxisomal fatty acid beta-oxidation. It was first identified as a 17-beta-estradiol dehydrogenase (Leenders et al., 1996; van Grunsven et al., 1998).
Multifunctional protein-2 (MFP2), also called D-bifunctional protein, catalyzes the second (hydration) and third (dehydrogenation) reactions of the peroxisomal beta-oxidation of fatty acids and fatty acid derivatives (summary by Ferdinandusse et al., 2006). The 2 enzymatic activities of MFP2, enoyl-CoA hydratase and D-3-hydroxyacyl-CoA dehydrogenase, are essential for the oxidation of a wide range of peroxisomal substrates (very long-chain acyl-CoAs, branched-chain acyl-CoAs including pristanoyl-CoA, and bile acid precursors) (summary by Lines et al., 2014).
See also the L-bifunctional peroxisomal protein (EHHADH; 607037). The D- and L-bifunctional proteins have different substrate specificities. The D-bifunctional protein catalyzes the formation of 3-ketoacyl-CoA intermediates from both straight-chain and 2-methyl-branched-chain fatty acids and also acts in shortening cholesterol for bile acid formation. In contrast, the L-specific bifunctional protein does not have the latter 2 activities (Jiang et al., 1997).
Adamski et al. (1995) cloned a fourth type of 17-beta-hydroxysteroid dehydrogenase, HSD17B4, from a human liver cDNA library. The HSD17B4 gene encodes a 736-amino acid polypeptide with a predicted molecular mass of approximately 80 kD and less than 25% identity with the 3 previously characterized 17-HSDs (HSD17B1, 109684; HSD17B2, 109685; and HSD17B3, 605573). Northern blot analysis revealed that HSD17B4 is expressed in many tissues as an approximately 3.0-kb mRNA transcript, with highest expression in liver, heart, prostate, and testis. Adamski et al. (1995) overexpressed the gene in mammalian cells and found that HSD17B4 displays specific unidirectional oxidative 17-HSD activity.
Jiang et al. (1996) purified and characterized a medium-chain enoyl-CoA hydratase from human liver. By immunohistochemistry, they confirmed the presence of the enzyme in peroxisomes of cultured human skin fibroblasts. Jiang et al. (1997) determined the DNA and peptide sequences of medium-chain enoyl-CoA hydratase and found that it was identical to that of human 17-beta-hydroxysteroid dehydrogenase IV. The native enzyme is a 77-kD polypeptide.
By analysis of the porcine enzyme, Leenders et al. (1996) determined that the N-terminal region (residues 1-323) encodes the 17-steroid dehydrogenase activity, whereas the central region (residues 324-596) catalyzes the hydratase activity. The C-terminal portion facilitates the transfer of 7-dehydrocholesterol and phosphatidylcholine between membranes in vitro. The authors emphasized the unique ability of a single protein to catalyze different reactions.
Leenders et al. (1998) found that the HSD17B4 gene contains 24 exons and spans more than 100 kb.
By fluorescence in situ hybridization, Leenders et al. (1996) mapped the HSD17B4 gene to human chromosome 5q2. Novikov et al. (1997) mapped the HSD17B4 gene to chromosome 5q2.3 by FISH.
Due to the presence of 25-methyl and 24-hydroxyl groups, 4 stereoisomers of varanoyl-CoA are possible. By assaying subcellular fractions of human liver, Novikov et al. (1997) found that peroxisomal MFP2 catalyzed dehydrogenation of 24R,25R-varanoyl-CoA. By a hydratation reaction, MFP2 also catalyzed formation of 24R,25R-varanoyl-CoA.
Green et al. (1999) investigated HSD17B1, -2, -3, and -4 gene expression and HSD17B estrogenic activity in human anterior pituitary adenomas. HSD17B mRNA expression was studied by RT-PCR in 42 pituitary tumors and 3 normal pituitaries, HSD17B activity was studied in 11 tumors, and HSD17B1 was immunolocalized in vitro in 6 tumors. HSD17B1 gene expression was detected in 34 of 42 (81%) adenomas in all tumor subtypes; HSD17B2 mRNA was detected in 18 of 42 (43%) adenomas but not in prolactinomas; HSD17B3 mRNA was detected in 12 of 42 (29%) adenomas but not in corticotropinomas; and HSD17B4 was expressed in 20 of 42 (48%) adenomas by all adenoma subtypes. All 4 HSD17B isoforms were variably expressed in human anterior pituitary adenomas, which also showed HSD17B enzyme activity, suggesting that HSD17B may play an important role in regulating the local cellular levels of estradiol.
D-Bifunctional Protein Deficiency
In 2 Japanese patients with D-bifunctional protein deficiency (261515), Suzuki et al. (1997) identified 2 different homozygous mutations in the HSD17B4 gene (601860.0001; 601860.0002). The patients had previously been diagnosed with L-bifunctional protein deficiency by complementation analysis (Suzuki et al., 1994).
In an infant with a defect in peroxisomal beta-oxidation, van Grunsven et al. (1998) demonstrated D-bifunctional protein deficiency caused by a homozygous mutation in the HSD17B4 gene (601860.0003).
In a patient with D-bifunctional protein deficiency originally reported by Watkins et al. (1989), van Grunsven et al. (1999) identified a homozygous 2-bp deletion in the HSD17B4 gene (601860.0007). The patient was originally thought to have L-bifunctional protein deficiency based on immunoblot analysis of postmortem liver tissue. However, reanalysis showed accumulation of both very long chain fatty acids and bile acid intermediates, which was hard to reconcile with an isolated deficiency of the L-bifunctional protein. The results suggested that most, if not all, patients whose peroxisomal disorder had been diagnosed as L-bifunctional protein deficiency were in fact cases of D-bifunctional protein deficiency.
Nakano et al. (2001) reported a patient with D-bifunctional protein deficiency who was compound heterozygous for 2 mutations in the HSD17B4 gene (601860.0001 and 601860.0005).
Ferdinandusse et al. (2002) reinvestigated the patient of Goldfischer et al. (1986), who was the only patient ever reported with a presumed deficiency of peroxisomal 3-ketoacyl-CoA thiolase (604054). Molecular analysis identified a homozygous deletion in the HSD17B4 gene (601860.0006), confirming a diagnosis of D-bifunctional protein deficiency.
Ferdinandusse et al. (2006) reported the mutational spectrum of DBP deficiency on the basis of molecular analysis in 110 patients. They identified 61 different mutations by DBP cDNA analysis, 48 of which had not been previously reported. The predicted effects of the different disease-causing amino acid changes in protein structure were determined using the crystal structures. 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. They 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 suggested that the amount of residual DBP activity correlates with the severity of the phenotype. Thus the data indicated that on the basis of the predicted effect of mutations on protein structure, a genotype-phenotype correlation exists for DBP deficiency.
Ferdinandusse et al. (2006) found that the missense mutation G16S (601860.0003) is by far the most common mutation causing DBP deficiency (type III), which had in their study an allele frequency of approximately 24% and was detected in 28 of the 110 patients. The second most common mutation causing DBP deficiency (type II) was the missense mutation N457Y (601860.0004), which had an allele frequency of approximately 11% and was found in 13 patients. Of 5 patients for whom homozygosity was checked, 2 turned out to be heterozygotes at the genomic level.
In DBP type I-deficient patients, Ferdinandusse et al. (2006) found only deletions, insertions, and nonsense mutations. All deletions resulted in a truncated protein, except for 3 large in-frame deletions. Two patients with DBP type-II deficiency had in-frame deletions in the hydratase unit. All other DBP type II-deficient patients had missense mutations in the coding region of the DBP hydratase unit. DBP type III deficiency was predominantly caused by missense mutations and, in 2 cases, by a 1-amino acid deletion in the coding region of the dehydrogenase unit.
Perrault Syndrome 1
Pierce et al. (2010) performed whole-exome sequencing of genomic DNA from a woman with Perrault syndrome-1 (PRLTS1; 233400), which is characterized by ovarian dysgenesis and sensorineural deafness, originally described by McCarthy and Opitz (1985) and identified 2 rare variants in the HSD17B4 gene (601860.0008 and 601860.0009). Sequencing revealed that both the proband and her affected sister were compound heterozygous for the missense (Y217C) and nonsense (Y568X) mutations, and that their unaffected mother was heterozygous for the missense mutation. Pierce et al. (2010) noted that Perrault syndrome and DBP deficiency overlap clinically, and suggested that mutations in HSD17B4 leading to DBP deficiency that is mild enough to allow survival to the age of puberty are likely to cause ovarian dysgenesis in females in addition to the known neurologic defects. The authors predicted that because the affected sisters were likely to express only protein with the Y217C mutation, they would have so-called type III DBP deficiency, with a defect in dehydrogenase activity.
In 2 brothers of European descent with Perrault syndrome, McMillan et al. (2012) identified compound heterozygous mutations in the HSD17B4 gene (A34V, 601860.0010 and I516T, 601860.0011). Each mutation affected a different domain, dehydrogenase and hydratase, respectively. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family.
In 3 Italian sibs with Perrault syndrome, Lines et al. (2014) identified compound heterozygous missense mutations in the HSD17B4 gene (P513L, 601860.0012 and R543P, 601860.0013), both affecting the hydratase domain. The mutations were found by whole-exome sequencing.
Baes et al. (2000) obtained Mfp2 -/- mice at the expected mendelian ratio. At birth, Mfp2 -/- mice were indistinguishable from wildtype or Mfp2 +/- littermates, but Mfp2 -/- pups failed to thrive, and about one-third died within the first 12 days of life. At weaning, surviving Mfp2 -/- pups resumed weight gain. Adult Mfp2 -/-females were fertile, but Mfp2 -/- males were subfertile. Mfp2 -/- mice accumulated very long chain fatty acids in brain and liver phospholipids, as well as immature C27 bile acids in bile. Dietary supplementation with phytol, a tetramethyl-branched fatty alcohol, revealed accumulation of branched chain fatty acids in Mfp2 -/- mice, concomitant with severe weight loss and development of cataracts and ataxia. Oxidation of long chain fatty acids was enhanced in liver of Mfp2 -/- mice, suggesting compensatory increased Mfp1 (EHHADH; 607037) activity. Mature C24 bile acids were found in adult Mfp2 -/- mice, suggesting bile acid formation by alternative pathways. Baes et al. (2000) concluded that MFP2 degrades 2-methyl-branched fatty acids, bile acid intermediates, and very long chain fatty acids.
In a Japanese patient with D-bifunctional protein deficiency (261515), Suzuki et al. (1997) identified a 52-bp deletion in the HSD17B4 gene, resulting in a 17-amino acid deletion and premature termination. Studies of postmortem liver tissue confirmed absence of the activity and immunoreactivity of D-bifunctional protein. The patient was previously thought to have L-bifunctional protein deficiency (Suzuki et al., 1994).
In a Japanese patient with D-bifunctional protein deficiency (261515), Suzuki et al. (1997) identified a 237-bp deletion in the HSD17B4 gene, resulting in a 79-amino acid deletion. Studies of postmortem liver tissue confirmed absence of the activity and immunoreactivity of D-bifunctional protein. The patient was previously thought to have L-bifunctional protein deficiency (Suzuki et al., 1994).
In an infant with a D-bifunctional protein deficiency (261515), van Grunsven et al. (1998) identified a 46G-A transition in the HSD17B4 gene, resulting in a gly16-to-ser (G16S) substitution within an important loop of the Rossman fold forming the NAD(+)-binding site. Biochemical analysis showed that the 3-hydroxyacyl-CoA dehydrogenase activity of the D-bifunctional protein was completely inactive, whereas the enoyl-CoA hydratase component was active. Their findings showed that the D-bifunctional protein plays an essential role in the peroxisomal beta-oxidation pathway that cannot be compensated for by the L-specific bifunctional protein. Both parents were heterozygous for the mutation.
Van Grunsven et al. (1999) demonstrated the G16S mutation in 9 additional patients previously thought to have deficiency of L-bifunctional protein on the basis of complementation studies. The findings confirmed D-bifunctional protein deficiency in these cases.
In 2 unrelated patients with D-bifunctional protein deficiency (261515), van Grunsven et al. (1999) identified a homozygous 1369A-T transversion in the HSD17B4 gene, resulting in an asn457-to-tyr (N457Y) substitution. Both patients had an isolated defect of the enoyl-CoA hydratase domain of the D-bifunctional protein. Both patients had abnormalities of peroxisomal beta-oxidation with elevated very long chain fatty acids and branch chain fatty acids, but normal levels of bile acid intermediates. Both patients were born of consanguineous parents. Sequence analysis of the D-bifunctional protein cDNA of 15 control subjects of Caucasian origin did not identify the N457Y mutation. Expression of the N457Y mutation in Saccharomyces cerevisiae confirmed that it is the disease-causing mutation. Immunoblot analysis of patient fibroblast homogenates showed that the protein levels of full-length D-bifunctional protein were strongly reduced, while the enoyl-CoA hydratase component produced after processing within the peroxisome was undetectable, indicating that the mutation leads to an unstable protein.
In a male patient with D-bifunctional protein deficiency (261515), Nakano et al. (2001) identified compound heterozygosity for 2 mutations in the HSD17B4 gene: a 317G-C transversion, resulting in an arg106-to-pro (R106P) substitution, and a 52-bp deletion (601860.0001). The mutations were associated with complete loss of function of the protein.
In a patient with D-bifunctional protein deficiency (261515), Ferdinandusse et al. (2002) identified a homozygous 138-bp deletion in the HSD17B4 gene extending from basepair 145 in exon 3 through the first 63 basepairs of intron 3 of the DBP gene. This deletion resulted in skipping of exon 3. The patient had originally been reported by Goldfischer et al. (1986) and Schram et al. (1987) as the only patient ever reported to have peroxisomal 3-ketoacyl-CoA thiolase (604054) deficiency. However, reanalysis showed normal thiolase and absence of the D-bifunctional protein in brain tissue.
In a patient with D-bifunctional protein deficiency (261515) originally reported by Watkins et al. (1989), van Grunsven et al. (1999) identified a homozygous 2-bp deletion (422delAG) in the HSD17B4 gene, resulting in a premature stop codon at position 490 and a shortened protein of 163 amino acids. The patient was originally thought to have L-bifunctional protein deficiency.
In 2 sisters with Perrault syndrome (PRLTS1; 233400), previously described by McCarthy and Opitz (1985) and Fiumara et al. (2004), Pierce et al. (2010) identified compound heterozygosity for a 605A-G transition in exon 9 of the HSD17B4 gene, resulting in a tyr217-to-cys (Y217C) substitution in a very highly conserved region of the protein, and a 1704T-A transversion in exon 20, resulting in a tyr568-to-ter (Y568X; 601860.0009) substitution. Their unaffected mother was found to be heterozygous for the Y217C mutation, and neither mutation was detected in 1,092 control individuals. Expression analysis using lymphoblast cDNA showed that Y568X transcript was expressed at very low levels relative to the Y217C transcript, suggesting that Y568X undergoes nonsense-mediated decay, whereas Y217C is more stably expressed.
For discussion of the tyr568-to-ter (Y568X) mutation in the HSD17B4 gene that was found in compound heterozygous state in 2 sisters with Perrault syndrome (PRLTS1; 233400) by Pierce et al. (2010), see 601860.0008.
In 2 teenaged brothers of European descent with Perrault syndrome (PRLTS1; 233400), McMillan et al. (2012) identified compound heterozygous mutations in the HSD17B4 gene: a c.101C-T transition, resulting in an ala34-to-val (A34V) substitution in the dehydrogenase domain, and a c.1547T-C transition, resulting in an ile516-to-thr (I516T; 601860.0011) substitution in the hydratase domain. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. McMillan et al. (2012) postulated that the relatively mild phenotype was due to the fact that only 1 of the functional HSD17B4 domains was affected on each allele. There was reduced but detectable DBP hydratase and dehydrogenase activity, with some reduction of pristanic acid beta-oxidation in patient fibroblasts. The 45-kD DBP fragment was not detected by immunoblot analysis; however, peroxisomes and plasma very long-chain and branched fatty acids were normal.
For discussion of the ile516-to-thr (I516T) mutation in the HSD17B4 gene that was found in compound heterozygous state in 2 brothers with Perrault syndrome (PRLTS1; 233400) by McMillan et al. (2012), see 601860.0010.
In 3 Italian sibs, including 2 sisters, with Perrault syndrome (PRLTS1; 233400), Lines et al. (2014) identified compound heterozygous mutations in the HSD17B4 gene: a c.1537C-A transversion, resulting in a pro513-to-leu (P513L) substitution, and a c.1628G-C transversion, resulting in an arg543-to-pro (R543P; 601860.0013) substitution. The mutations, which were found by whole-exome sequencing, occurred at highly conserved residues within the active site of the hydratase domain and segregated with the disorder in the family. They were filtered against the dbSNP, 1000 Genomes Project, and Exome Variant Server databases, as well as 130 local control exomes. Immunoblot analysis of patient cells showed markedly reduced DBP enoyl-CoA hydratase activity, as well as absence of the 45-kD posttranslational fragment containing the hydratase domain. Laboratory studies of all patients showed increased serum total bile acids, but phytanic and very long-chain fatty acids were normal. Patient fibroblasts showed decreased beta-oxidation of pristanic acid. Peroxisome morphology was normal.
For discussion of the arg543-to-pro (R543P) mutation in the HSD17B4 gene that was found in compound heterozygous state in sibs with Perrault syndrome (PRLTS1; 233400) by Lines et al. (2014), see 601860.0012.
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