title: Mutations in the DBP-deficiency protein HSD17B4 cause ovarian dysgenesis, hearing loss, and ataxia of Perrault Syndrome.
abstract: 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.
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Pierce
authors.forename: Tom
authors.initials: T
authors.lastname: Walsh
authors.forename: Karen M
authors.initials: KM
authors.lastname: Chisholm
authors.forename: Ming K
authors.initials: MK
authors.lastname: Lee
authors.forename: Anne M
authors.initials: AM
authors.lastname: Thornton
authors.forename: Agata
authors.initials: A
authors.lastname: Fiumara
authors.forename: John M
authors.initials: JM
authors.lastname: Opitz
authors.forename: Ephrat
authors.initials: E
authors.lastname: Levy-Lahad
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Klevit
authors.forename: Mary-Claire
authors.initials: MC
authors.lastname: King
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000737:chemistry / Q000235:genetics*; D000595:Amino Acid Sequence; D001259:Ataxia / Q000150:complications* / Q000201:enzymology / Q000235:genetics; D001483:Base Sequence; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006059:Gonadal Dysgenesis / Q000150:complications* / Q000201:enzymology* / Q000235:genetics; D034381:Hearing Loss / Q000150:complications* / Q000201:enzymology / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D006836:Hydro-Lyases / Q000737:chemistry / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D010053:Ovary / Q000002:abnormalities*; D064029:Peroxisomal Multifunctional Protein-2; D017433:Protein Structure, Secondary; D013577:Syndrome
chemical_list: D050505:Mutant Proteins; D015067:17-Hydroxysteroid Dehydrogenases; D006836:Hydro-Lyases; D064029:Peroxisomal Multifunctional Protein-2; C104587:HSD17B4 protein, human