| Mutations in the DBP-deficiency protein HSD17B4 cause ovarian dysgenesis, hearing loss, and ataxia of Perrault Syndrome. | |
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MedLine Citation:
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PMID: 20673864 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Sarah B Pierce; Tom Walsh; Karen M Chisholm; Ming K Lee; Anne M Thornton; Agata Fiumara; John M Opitz; Ephrat Levy-Lahad; Rachel E Klevit; Mary-Claire King |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-07-30 |
Journal Detail:
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Title: American journal of human genetics Volume: 87 ISSN: 1537-6605 ISO Abbreviation: Am. J. Hum. Genet. Publication Date: 2010 Aug |
Date Detail:
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Created Date: 2010-08-10 Completed Date: 2010-09-01 Revised Date: 2011-07-25 |
Medline Journal Info:
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Nlm Unique ID: 0370475 Medline TA: Am J Hum Genet Country: United States |
Other Details:
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Languages: eng Pagination: 282-8 Citation Subset: IM |
Affiliation:
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Department of Medicine, University of Washington, Seattle, WA 98195, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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17-Hydroxysteroid Dehydrogenases
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chemistry,
genetics* Amino Acid Sequence Ataxia / complications*, enzymology, genetics Base Sequence DNA Mutational Analysis Exons / genetics Female Gene Expression Regulation, Enzymologic Gonadal Dysgenesis / complications*, enzymology*, genetics Hearing Loss / complications*, enzymology, genetics Heterozygote Humans Hydro-Lyases / chemistry, genetics* Male Molecular Sequence Data Mutant Proteins / chemistry, genetics Mutation / genetics* Ovary / abnormalities* Protein Structure, Secondary Syndrome |
| Grant Support | |
ID/Acronym/Agency:
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R01DC005641/DC/NIDCD NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Mutant Proteins; EC 1.1.-/17-Hydroxysteroid Dehydrogenases; EC 4.2.1.-/Hydro-Lyases; EC 4.2.1.107/HSD17B4 protein, human |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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