Presentation is loading. Please wait.

Presentation is loading. Please wait.

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

Published byBrianna Wright Modified over 5 years ago

Similar presentations

Presentation on theme: "Mutations in the DBP-Deficiency Protein HSD17B4 Cause Ovarian Dysgenesis, Hearing Loss, and Ataxia of Perrault Syndrome  Sarah B. Pierce, Tom Walsh, Karen."— Presentation transcript:

1 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 (August 2010) DOI: /j.ajhg Copyright © 2010 The American Society of Human Genetics Terms and Conditions

2 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  , DOI: ( /j.ajhg ) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

3 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 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 The lower panels indicate sequence from an unrelated control, who is heterozygous at c.1687 and wild-type at c.650 and c 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  , DOI: ( /j.ajhg ) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

4 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  , DOI: ( /j.ajhg ) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

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

Similar presentations

Mutations in LARS2, Encoding Mitochondrial Leucyl-tRNA Synthetase, Lead to Premature Ovarian Failure and Hearing Loss in Perrault Syndrome Sarah B. Pierce,

Mutations in LARS2, Encoding Mitochondrial Leucyl-tRNA Synthetase, Lead to Premature Ovarian Failure and Hearing Loss in Perrault Syndrome Sarah B. Pierce,
Identification of EpCAM as the Gene for Congenital Tufting Enteropathy

Identification of EpCAM as the Gene for Congenital Tufting Enteropathy
C.-H. Huang, G.-J. Cheng, M.E. Reid, Y. Chen 

C.-H. Huang, G.-J. Cheng, M.E. Reid, Y. Chen 
Deficiency of the ADP-Forming Succinyl-CoA Synthase Activity Is Associated with Encephalomyopathy and Mitochondrial DNA Depletion  Orly Elpeleg, Chaya.

Deficiency of the ADP-Forming Succinyl-CoA Synthase Activity Is Associated with Encephalomyopathy and Mitochondrial DNA Depletion  Orly Elpeleg, Chaya.
Genomic Duplication and Overexpression of TJP2/ZO-2 Leads to Altered Expression of Apoptosis Genes in Progressive Nonsyndromic Hearing Loss DFNA51  Tom.

Genomic Duplication and Overexpression of TJP2/ZO-2 Leads to Altered Expression of Apoptosis Genes in Progressive Nonsyndromic Hearing Loss DFNA51  Tom.
A Missense Mutation in PRPF6 Causes Impairment of pre-mRNA Splicing and Autosomal-Dominant Retinitis Pigmentosa  Goranka Tanackovic, Adriana Ransijn,

A Missense Mutation in PRPF6 Causes Impairment of pre-mRNA Splicing and Autosomal-Dominant Retinitis Pigmentosa  Goranka Tanackovic, Adriana Ransijn,
A Clinical Grade Sequencing-Based Assay for CEBPA Mutation Testing

A Clinical Grade Sequencing-Based Assay for CEBPA Mutation Testing
Eija Siintola, Meral Topcu, Nina Aula, Hannes Lohi, Berge A

Eija Siintola, Meral Topcu, Nina Aula, Hannes Lohi, Berge A
Mutational Spectrum of d-Bifunctional Protein Deficiency and Structure-Based Genotype-Phenotype Analysis  Sacha Ferdinandusse, Mari S. Ylianttila, Jolein.

Mutational Spectrum of d-Bifunctional Protein Deficiency and Structure-Based Genotype-Phenotype Analysis  Sacha Ferdinandusse, Mari S. Ylianttila, Jolein.
Rose-Anne Romano, Barbara Birkaya, Satrajit Sinha 

Rose-Anne Romano, Barbara Birkaya, Satrajit Sinha 
Mutations in CYC1, Encoding Cytochrome c1 Subunit of Respiratory Chain Complex III, Cause Insulin-Responsive Hyperglycemia  Pauline Gaignard, Minal Menezes,

Mutations in CYC1, Encoding Cytochrome c1 Subunit of Respiratory Chain Complex III, Cause Insulin-Responsive Hyperglycemia  Pauline Gaignard, Minal Menezes,
A Defect in the TUSC3 Gene Is Associated with Autosomal Recessive Mental Retardation  Masoud Garshasbi, Valeh Hadavi, Haleh Habibi, Kimia Kahrizi, Roxana.

A Defect in the TUSC3 Gene Is Associated with Autosomal Recessive Mental Retardation  Masoud Garshasbi, Valeh Hadavi, Haleh Habibi, Kimia Kahrizi, Roxana.
Exome Sequencing and Functional Analysis Identifies BANF1 Mutation as the Cause of a Hereditary Progeroid Syndrome  Xose S. Puente, Victor Quesada, Fernando G.

Exome Sequencing and Functional Analysis Identifies BANF1 Mutation as the Cause of a Hereditary Progeroid Syndrome  Xose S. Puente, Victor Quesada, Fernando G.
Gail Billingsley, Sathiyavedu T. Santhiya, Andrew D

Gail Billingsley, Sathiyavedu T. Santhiya, Andrew D
Multiple Mutations ofMYO1A, a Cochlear-Expressed Gene, in Sensorineural Hearing Loss  Francesca Donaudy, Antonella Ferrara, Laura Esposito, Ronna Hertzano,

Multiple Mutations ofMYO1A, a Cochlear-Expressed Gene, in Sensorineural Hearing Loss  Francesca Donaudy, Antonella Ferrara, Laura Esposito, Ronna Hertzano,
Mutations in a Novel Gene with Transmembrane Domains Underlie Usher Syndrome Type 3  Tarja Joensuu, Riikka Hämäläinen, Bo Yuan, Cheryl Johnson, Saara.

Mutations in a Novel Gene with Transmembrane Domains Underlie Usher Syndrome Type 3  Tarja Joensuu, Riikka Hämäläinen, Bo Yuan, Cheryl Johnson, Saara.
Double Heterozygosity for a RET Substitution Interfering with Splicing and an EDNRB Missense Mutation in Hirschsprung Disease  Alberto Auricchio, Paola.

Double Heterozygosity for a RET Substitution Interfering with Splicing and an EDNRB Missense Mutation in Hirschsprung Disease  Alberto Auricchio, Paola.
Analysis of Rare APC Variants at the mRNA Level

Analysis of Rare APC Variants at the mRNA Level
Rare Missense and Synonymous Variants in UBE1 Are Associated with X-Linked Infantile Spinal Muscular Atrophy  Juliane Ramser, Mary Ellen Ahearn, Claus.

Rare Missense and Synonymous Variants in UBE1 Are Associated with X-Linked Infantile Spinal Muscular Atrophy  Juliane Ramser, Mary Ellen Ahearn, Claus.
Germline Mutations of the Paired–Like Homeobox 2B (PHOX2B) Gene in Neuroblastoma  Delphine Trochet, Franck Bourdeaut, Isabelle Janoueix-Lerosey, Anne.

Germline Mutations of the Paired–Like Homeobox 2B (PHOX2B) Gene in Neuroblastoma  Delphine Trochet, Franck Bourdeaut, Isabelle Janoueix-Lerosey, Anne.

Similar presentations

Ads by Google