Mutations in the DBP-Deficiency Protein HSD17B4 Cause Ovarian Dysgenesis, Hearing Loss, and Ataxia of Perrault Syndrome Sarah B. Pierce, Tom Walsh, Karen.

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Mutations in the DBP-Deficiency Protein HSD17B4 Cause Ovarian Dysgenesis, Hearing Loss, and Ataxia of Perrault Syndrome 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 The American Journal of Human Genetics Volume 87, Issue 2, Pages 282-288 (August 2010) DOI: 10.1016/j.ajhg.2010.07.007 Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 1 Coumpound Heterozygosity for HSD17B4 Mutations in Family 4 (A) Pedigree of Perrault syndrome family 4. (B) Validation by Sanger sequencing of HSD17B4 mutations identified in individual 4-01 by whole-exome sequencing. Genomic DNA was sequenced after amplification with primers flanking exon 9 (5′- TGGAAAGGTGTGTCTGATAC-3′, 5′- CAAATGTAGAACTAAGTAAAAAC-3′) and exon 20 (5′- TTGAAAGACAAAGAATTGGC-3′, 5′-TGAAAACACCAGACAAGCTG-3′). Arrows indicate heterozygosity for chr5:118,824,914A>G, HSD17B4 c.650A>G (p.Y217C), in the upper panel, and for chr5:118,862,851T>A, HSB17B4 c.1704T>A (p.Y568X), in the lower panel. (C) Schematic of the HSD17B4 protein. (D) Diagram of the four steps of peroxisomal β-oxidation (left) and the enzymes by which they are catalyzed (right), using oxidation of very long chain fatty acids (VLCFA) as an example. (E) Protein sequence alignment of HSD17B4 orthologs, showing the region surrounding the mutated Y217 (indicated in red). The project was approved by the Human Subjects Division of the University of Washington, and informed consent was obtained from all of the subjects. The American Journal of Human Genetics 2010 87, 282-288DOI: (10.1016/j.ajhg.2010.07.007) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 2 Expression of HSD17B4 Mutant Transcripts and Protein (A) Expression of the two mutant transcripts of HSD17B4. Gene-specific cDNA for HSD17B4 was prepared from lymphoblast RNA of patient 4-02 and an unrelated control. cDNA was generated from total RNA with a primer located in exon 23 (5′- CCAGAACCACTTTTCAGGTCAATAGTCCAC-3′), amplified with primer pairs spanning exons 7–12 (5′-GGGTTCATTCCAAGTGACAC-3′, 5′-TCCTGATGTTGCTGTAGACG-3′) and exons 17–22, (5′- GCCATACCTAATAGACCTCC-3′, 5′- CAGCATTTACTTTCTTCACC-3′), and Sanger sequenced. The upper panels indicate sequence from patient 4-02, whose genomic DNA is heterozygous at nucleotide positions c.650, c.1687 (rs11205), and c.1704. The cDNA sequence harboring the GGT haplotype, which carries the missense allele G at c.650, the G allele at c.1687, and the wild-type allele T at c.1704 is more highly expressed than the sequence harboring the AAA haplotype, which carries the wild-type allele A at c.650, the A allele at c.1687, and the nonsense allele A at c.1704. The lower panels indicate sequence from an unrelated control, who is heterozygous at c.1687 and wild-type at c.650 and c.1704. The two alleles of the SNP at c.1687 appear equally expressed in the lymphoblast cDNA of the control. (B) Lymphoblast cell lysates (50 μg) of patients (4-02 and 4-03) and controls (C1–C4) and Huh7 lysates (10 μg) were analyzed by immunoblotting using primary antibodies rabbit anti-HSD17B4 (Sigma) and mouse anti-β-actin (Sigma) and IRDye-conjugated secondary antibodies (LI-COR Biosciences). Full-length HSD17B4 (79 kD) and the processed dehydrogenase domain (35 kD) are indicated. The American Journal of Human Genetics 2010 87, 282-288DOI: (10.1016/j.ajhg.2010.07.007) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 3 Structure of the HSD17B4 Dehydrogenase Domain A ribbon representation of the HSD17B4 dehydrogenase domain in complex with NAD (PDB 1GZ6), showing the region surrounding the mutated residue Y217. The A and B chains of the homodimer are colored green and blue, respectively. NAD is represented as sticks within the binding site. As explained in the text, substitution of cysteine for tyrosine at position 217 is predicted to abrogate the cation-π orbital interaction of Y217 and R258 and thus the critical charged interaction of R258 with D303, leading to destabilization of the dehydrogenase domain and loss of specific activity of the enzyme. The American Journal of Human Genetics 2010 87, 282-288DOI: (10.1016/j.ajhg.2010.07.007) Copyright © 2010 The American Society of Human Genetics Terms and Conditions