Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: Mutations in the DBP-deficiency protein HSD17B4 cause ovarian dysgenesis, hearing loss, and ataxia of Perrault Syndrome. Pierce SB et al. (2010) Perrault syndrome is a recessive disorder characterized by ovarian dysgenesis in females, sensorineural deafness in both males and females, and in some patients, neurological manifestations. No genes for Perrault syndrome have heretofore been identified. A small family of mixed European ancestry includes two sisters with well-characterized Perrault syndrome. Whole-exome sequencing of genomic DNA from one of these sisters revealed exactly one gene with two rare functional variants: HSD17B4, which encodes 17beta-hydroxysteroid dehydrogenase type 4 (HSD17B4), also known as D-bifunctional protein (DBP). HSD17B4/DBP is a multifunctional peroxisomal enzyme involved in fatty acid beta-oxidation and steroid metabolism. Both sisters are compound heterozygotes for HSD17B4 c.650A>G (p.Y217C) (maternal allele) and HSB17B4 c.1704T>A (p.Y568X) (paternal allele). The missense mutation is predicted by structural analysis to destabilize the HSD17B4 dehydrogenase domain. The nonsense mutation leads to very low levels of HSD17B4 transcript. Expression of mutant HSD17B4 protein in a compound heterozygote was severely reduced. Mutations in HSD17B4 are known to cause DBP deficiency, an autosomal-recessive disorder of peroxisomal fatty acid beta-oxidation that is generally fatal within the first two years of life. No females with DBP deficiency surviving past puberty have been reported, and ovarian dysgenesis has not previously been associated with this illness. Six other families with Perrault syndrome have wild-type sequences of HSD17B4. These results indicate that Perrault syndrome and DBP deficiency overlap clinically; that Perrault syndrome is genetically heterogeneous; that DBP deficiency may be underdiagnosed; and that whole-exome sequencing can reveal critical genes in small, nonconsanguineous families.//////////////////

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: A homozygous missense variant in HSD17B4 identified in a consanguineous Chinese Han family with type II Perrault syndrome. Chen K et al. (2017) Perrault syndrome is a rare multisystem disorder that manifests with sensorineural hearing loss in both sexes, primary ovarian insufficiency in females and neurological features. The syndrome is heterogeneous both genetically and phenotypically. We reported a consanguineous family (two affected sisters) with Perrault syndrome. The proband had the characteristics of Perrault syndrome: ovarian dysgenesis, bilateral hearing loss and obvious neurological signs. Target genetic sequencing and triplet repeat primed PCR (TP-PCR) plus capillary electrophoresis was conducted to detect causative mutations in the proband. The detected variant was further confirmed in the proband and tested in other family members by Sanger sequencing. Both the proband and her sister were found homozygous for the novel variant HSD17B4 c.298G > T (p.A100S) with their parents heterozygous. Detected by western blot, the protein expression of HSD17B4 mutant was much lower than that of the wild type in SH-SY5Y cells transfected by HSD17B4 wild type or mutant plasmid, which indicated the pathogenicity of the HSD17B4 mutation. Our findings supported that HSD17B4 was one of the genes contributing to Perrault syndrome with the likely pathogenic variant c.298G > T (p.A100S). Special manifestations of cerebellar impairment were found in cases caused by HSD17B4 mutations. Besides, attention should be paid to distinguish Perrault syndrome from D-bifunctional protein deficiency and hereditary ataxia.//////////////////

Species: mouse
Mutation name:
type: null mutation
fertility: fertile
Comment: Inactivation of the 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. Baes M et al. (2000) According to current views, peroxisomal beta-oxidation is organized as two parallel pathways: the classical pathway that is responsible for the degradation of straight chain fatty acids and a more recently identified pathway that degrades branched chain fatty acids and bile acid intermediates. Multifunctional protein-2 (MFP-2), also called d-bifunctional protein, catalyzes the second (hydration) and third (dehydrogenation) reactions of the latter pathway. In order to further clarify the physiological role of this enzyme in the degradation of fatty carboxylates, MFP-2 knockout mice were generated. MFP-2 deficiency caused a severe growth retardation during the first weeks of life, resulting in the premature death of one-third of the MFP-2(-/-) mice. Furthermore, MFP-2-deficient mice accumulated VLCFA in brain and liver phospholipids, immature C(27) bile acids in bile, and, after supplementation with phytol, pristanic and phytanic acid in liver triacylglycerols. These changes correlated with a severe impairment of peroxisomal beta-oxidation of very long straight chain fatty acids (C(24)), 2-methyl-branched chain fatty acids, and the bile acid intermediate trihydroxycoprostanic acid in fibroblast cultures or liver homogenates derived from the MFP-2 knockout mice. In contrast, peroxisomal beta-oxidation of long straight chain fatty acids (C(16)) was enhanced in liver tissue from MFP-2(-/-) mice, due to the up-regulation of the enzymes of the classical peroxisomal beta-oxidation pathway. The present data indicate that MFP-2 is not only essential for the degradation of 2-methyl-branched fatty acids and the bile acid intermediates di- and trihydroxycoprostanic acid but also for the breakdown of very long chain fatty acids.//////////////////