ZNF687 Mutations in Severe Paget Disease of Bone Associated with Giant Cell Tumor Giuseppina Divisato, Daniela Formicola, Teresa Esposito, Daniela Merlotti,

Slides:

Advertisements

Similar presentations

Epidermolysis Bullosa: Novel and De Novo Premature Termination Codon and Deletion Mutations in the Plectin Gene Predict Late-Onset Muscular Dystrophy

Advertisements

STEVE S. SOMMER, M.D., Ph.D. Mayo Clinic Proceedings

Mutations in AGBL1 Cause Dominant Late-Onset Fuchs Corneal Dystrophy and Alter Protein-Protein Interaction with TCF4 S. Amer Riazuddin, Shivakumar Vasanth,

Manfred Fliegauf, Vanessa L

Mutations in the Transcription Factor Gene SOX18 Underlie Recessive and Dominant Forms of Hypotrichosis-Lymphedema-Telangiectasia Alexandre Irrthum,

Functional characterization of the atopy-associated gene PHF11

Whole-Gene Duplication of PCSK9 as a Novel Genetic Mechanism for Severe Familial Hypercholesterolemia Michael A. Iacocca, BSc, Jian Wang, MD, Samantha.

I. Silveira, I. Alonso, L. Guimarães, P. Mendonça, C. Santos, P

Federico Canzian, Patrizia Amati, H

Exome Sequencing and Functional Analysis Identifies BANF1 Mutation as the Cause of a Hereditary Progeroid Syndrome Xose S. Puente, Victor Quesada, Fernando G.

Mutations in PADI6 Cause Female Infertility Characterized by Early Embryonic Arrest Yao Xu, Yingli Shi, Jing Fu, Min Yu, Ruizhi Feng, Qing Sang, Bo Liang,

Germline Heterozygous Variants in SEC23B Are Associated with Cowden Syndrome and Enriched in Apparently Sporadic Thyroid Cancer Lamis Yehia, Farshad.

Mutations in the Histone Modifier PRDM6 Are Associated with Isolated Nonsyndromic Patent Ductus Arteriosus Na Li, Lakshman Subrahmanyan, Emily Smith,

Epidermolysis Bullosa: Novel and De Novo Premature Termination Codon and Deletion Mutations in the Plectin Gene Predict Late-Onset Muscular Dystrophy

Autosomal-Recessive Early-Onset Retinitis Pigmentosa Caused by a Mutation in PDE6G, the Gene Encoding the Gamma Subunit of Rod cGMP Phosphodiesterase

Rare Missense and Synonymous Variants in UBE1 Are Associated with X-Linked Infantile Spinal Muscular Atrophy Juliane Ramser, Mary Ellen Ahearn, Claus.

Peter Ianakiev, Michael W

GCM2-Activating Mutations in Familial Isolated Hyperparathyroidism

Haplotype-Sharing Analysis Implicates Chromosome 7q36 Harboring DPP6 in Familial Idiopathic Ventricular Fibrillation Marielle Alders, Tamara T. Koopmann,

Volume 8, Issue 2, Pages (February 2005)

Genotype/Phenotype Analysis of a Photoreceptor-Specific ATP-Binding Cassette Transporter Gene, ABCR, in Stargardt Disease Richard Alan Lewis, Noah F.

A Recurrent Missense Mutation in ZP3 Causes Empty Follicle Syndrome and Female Infertility Tailai Chen, Yuehong Bian, Xiaoman Liu, Shigang Zhao, Keliang.

A Mutation in the Fibroblast Growth Factor 14 Gene Is Associated with Autosomal Dominant Cerebral Ataxia John C. van Swieten, Esther Brusse, Bianca M.

Survival of Male Patients with Incontinentia Pigmenti Carrying a Lethal Mutation Can Be Explained by Somatic Mosaicism or Klinefelter Syndrome The.

Activation of a Cryptic Splice Site of PTEN and Loss of Heterozygosity in Benign Skin Lesions in Cowden Disease Stephen J. Meltzer, Manfred Wolter Journal.

PSMB8 Encoding the β5i Proteasome Subunit Is Mutated in Joint Contractures, Muscle Atrophy, Microcytic Anemia, and Panniculitis-Induced Lipodystrophy.

Identification of a Genetic Locus for Ichthyosis Vulgaris on Chromosome 10q22.3– q24.2 Ping Liu, Qingyu Yang, Xu Wang, Aiping Feng, Tao Yang, Rong Yang,

Imprinting at the SMPD1 Locus: Implications for Acid Sphingomyelinase–Deficient Niemann-Pick Disease Calogera M. Simonaro, Jae-Ho Park, Efrat Eliyahu,

RBPJ Mutations Identified in Two Families Affected by Adams-Oliver Syndrome Susan J. Hassed, Graham B. Wiley, Shaofeng Wang, Ji-Yun Lee, Shibo Li, Weihong.

A Dominantly Inherited 5′ UTR Variant Causing Methylation-Associated Silencing of BRCA1 as a Cause of Breast and Ovarian Cancer D.Gareth R. Evans, Elke.

A Nonsense Mutation in CRYBB1 Associated with Autosomal Dominant Cataract Linked to Human Chromosome 22q Donna S. Mackay, Olivera B. Boskovska, Harry.

Kimberly C. Sippel, Rebecca E. Fraioli, Gary D. Smith, Mary E

High Incidence of Later-Onset Fabry Disease Revealed by Newborn Screening* Marco Spada, Severo Pagliardini, Makiko Yasuda, Turgut Tukel, Geetha Thiagarajan,

The Origins of Hypertrophic Cardiomyopathy–Causing Mutations in Two South African Subpopulations: A Unique Profile of Both Independent and Founder Events

Mutation of Solute Carrier SLC16A12 Associates with a Syndrome Combining Juvenile Cataract with Microcornea and Renal Glucosuria Barbara Kloeckener-Gruissem,

ATM Mutations and Phenotypes in Ataxia-Telangiectasia Families in the British Isles: Expression of Mutant ATM and the Risk of Leukemia, Lymphoma, and.

A Missense Mutation in the Zinc-Finger Domain of the Human Hairless Gene Underlies Congenital Atrichia in a Family of Irish Travellers Wasim Ahmad, Alan.

A Heterozygous Truncating Mutation in RRM2B Causes Autosomal-Dominant Progressive External Ophthalmoplegia with Multiple mtDNA Deletions Henna Tyynismaa,

A Novel Point Mutation Affecting the Tyrosine Kinase Domain of the TRKA Gene in a Family with Congenital Insensitivity to Pain with Anhidrosis Shinichi.

Identification of a Kir3.4 Mutation in Congenital Long QT Syndrome

Christina A. Gurnett, Farhang Alaee, Lisa M. Kruse, David M

Autosomal-Dominant Woolly Hair Resulting from Disruption of Keratin 74 (KRT74), a Potential Determinant of Human Hair Texture Yutaka Shimomura, Muhammad.

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

Exome Sequencing Identifies Autosomal-Dominant SRP72 Mutations Associated with Familial Aplasia and Myelodysplasia Michael Kirwan, Amanda J. Walne, Vincent.

Exome Sequencing Identifies a DYNC1H1 Mutation in a Large Pedigree with Dominant Axonal Charcot-Marie-Tooth Disease Michael N. Weedon, Robert Hastings,

Characterization of a Germline Mosaicism in Families with Lowe Syndrome, and Identification of Seven Novel Mutations in the OCRL1 Gene Véronique Satre,

Next-Generation Sequencing Identifies Mutations of SMPX, which Encodes the Small Muscle Protein, X-Linked, as a Cause of Progressive Hearing Impairment

Lack of EVER2 Protein in Two Epidermodysplasia Verruciformis Patients with Skin Cancer Presenting Previously Unreported Homozygous Genetic Deletions in.

Mutations in FEZF1 Cause Kallmann Syndrome

Volume 58, Issue 2, Pages (August 2000)

X-Linked Dominant Scapuloperoneal Myopathy Is Due to a Mutation in the Gene Encoding Four-and-a-Half-LIM Protein 1 Catarina M. Quinzii, Tuan H. Vu, K.

A Unique Point Mutation in the PMP22 Gene Is Associated with Charcot-Marie-Tooth Disease and Deafness Margaret J. Kovach, Jing-Ping Lin, Simeon Boyadjiev,

Jittima Dhitavat, Leonard Dode, Natalie Leslie, Anavaj Sakuntabhai

Human RFT1 Deficiency Leads to a Disorder of N-Linked Glycosylation

Oligodontia Is Caused by Mutation in LTBP3, the Gene Encoding Latent TGF-β Binding Protein 3 Abdul Noor, Christian Windpassinger, Irina Vitcu, Marija.

Volume 71, Issue 6, Pages (March 2007)

Early Onset of Severe Familial Amyotrophic Lateral Sclerosis with a SOD-1 Mutation: Potential Impact of CNTF as a Candidate Modifier Gene Ralf Giess,

Exome Sequencing Identifies CCDC8 Mutations in 3-M Syndrome, Suggesting that CCDC8 Contributes in a Pathway with CUL7 and OBSL1 to Control Human Growth

Mutations in CHEK2 Associated with Prostate Cancer Risk

A novel homozygous FBXO43 mutation associated with male infertility and teratozoospermia in a consanguineous Chinese family Ying Ma, Ph.D., Ning Xie,

Germline Mutations in CDH23, Encoding Cadherin-Related 23, Are Associated with Both Familial and Sporadic Pituitary Adenomas Qilin Zhang, Cheng Peng,

Mutations in NEXN, a Z-Disc Gene, Are Associated with Hypertrophic Cardiomyopathy Hu Wang, Zhaohui Li, Jizheng Wang, Kai Sun, Qiqiong Cui, Lei Song, Yubao.

Kazuhito Sugimura, Kent D

Mutations in POFUT1, Encoding Protein O-fucosyltransferase 1, Cause Generalized Dowling-Degos Disease Ming Li, Ruhong Cheng, Jianying Liang, Heng Yan,

Mutations in NOTCH1 Cause Adams-Oliver Syndrome

Epigenetic Allele Silencing Unveils Recessive RYR1 Mutations in Core Myopathies Haiyan Zhou, Martin Brockington, Heinz Jungbluth, David Monk, Philip Stanier,

Gain-of-Function Mutations in SCN11A Cause Familial Episodic Pain

Identification of a New Splice Form of the EDA1 Gene Permits Detection of Nearly All X- Linked Hypohidrotic Ectodermal Dysplasia Mutations Alex W. Monreal,

Volume 23, Issue 11, Pages (June 2018)

Glycyl tRNA Synthetase Mutations in Charcot-Marie-Tooth Disease Type 2D and Distal Spinal Muscular Atrophy Type V Anthony Antonellis, Rachel E. Ellsworth,

Presentation transcript:

ZNF687 Mutations in Severe Paget Disease of Bone Associated with Giant Cell Tumor Giuseppina Divisato, Daniela Formicola, Teresa Esposito, Daniela Merlotti, Laura Pazzaglia, Andrea Del Fattore, Ethel Siris, Philippe Orcel, Jacques P. Brown, Ranuccio Nuti, Pasquale Strazzullo, Maria Serena Benassi, M. Leonor Cancela, Laetitia Michou, Domenico Rendina, Luigi Gennari, Fernando Gianfrancesco The American Journal of Human Genetics Volume 98, Issue 2, Pages 275-286 (February 2016) DOI: 10.1016/j.ajhg.2015.12.016 Copyright © 2016 The Authors Terms and Conditions

Figure 1 Identification of the c.2810C>G Mutation in ZNF687 (A) The pedigree of family 1, including 14 affected members, four of whom developed GCT at pagetic skeletal sites. Circles indicate female family members, and squares indicate male family members; slashes indicate that the family member is deceased. Family members with the GCT/PDB phenotype are indicated by a white dot in solid symbols, those with PDB are indicated by solid symbols, and those without any clinical symptoms are indicated by open symbols. + or – signs indicate the presence or absence of the c.2810C>G mutation. This panel also includes the pedigree for a different family (family 2) with the same c.2810C>G mutation in ZNF687. The index individual with PDB (II-1) is indicated by an arrow. (B) The DNA sequence of a segment flanking c.2810C>G in ZNF687 from an unaffected family member (left) and a heterozygous GCT/PDB-affected individual (right). A single base substitution changes the non-mutant cytosine to guanine, leading to the substitution of proline (P) for arginine (R) at the 937 codon (indicated by a solid line). (C) A portion of the amino acid sequence of ZNF687 from diverse mammal species. (D) The ancestral haplotype with rare variants in SV2A-rs149735232 (t minor-allele frequency = 1.5%), SETDB1-rs138864506 (t minor-allele frequency = 0.1%), ZNF687-rs142842127 (a minor-allele frequency = 0.2%), and HRNR (ta deletion, frequency not available), all of which are genes surrounding the c.2810C>G mutation in ZNF687. For each variant, the position on chromosome 1 is indicated by arabic numerals. The American Journal of Human Genetics 2016 98, 275-286DOI: (10.1016/j.ajhg.2015.12.016) Copyright © 2016 The Authors Terms and Conditions

Figure 2 Identification of the c.725G>T Mutation in ZNF687 (A) The pedigree of family 3. The index individual is indicated by an arrow. Individuals with PDB are indicated by black symbols, and individuals without PDB are shown as unfilled symbols. Circles represent females, squares represent males, and slashes indicate deceased subjects. (B) The DNA sequence of a segment flanking c.725G>T in ZNF687 from an unaffected family member (left) and a heterozygous PDB-affected individual (right). A single base substitution changes the non-mutant guanine to thymine, leading to the substitution of serine (S) for isoleucine (I) at the 242 codon (indicated by a solid line). (C) The evolutive conservation of the 242 serine from rodents to humans. (D) The number of the affected skeletal sites (left) and the age of disease onset (right) across PDB-affected individuals with ZNF687 mutations, PDB-affected individuals with SQSTM1 mutations, and PDB-affected individuals without mutations in either gene. Genotype-phenotype correlations were tested by ANOVA with Bonferroni correction and reported as mean ratio ± SEM (not mutated, n = 615; mutated in SQSTM1, n = 78; mutated in ZNF687, n = 20). ∗p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.001. The American Journal of Human Genetics 2016 98, 275-286DOI: (10.1016/j.ajhg.2015.12.016) Copyright © 2016 The Authors Terms and Conditions

Figure 3 Expression and Functional Characterization of ZNF687 (A and B) Expression analysis of ZNF687 during human osteoclastogenesis (A) and human osteoblastogenesis (B). The data shown are representative of three independent experiments and were analyzed by Student’s t test. (C and D) The scheme of caudal fin regeneration in zebrafish (Danio rerio) (C) and the expression of ZNF687a and ZNF687b (zebrafish orthologs) during this process (D). (E) ZNF687a and ZNF687b expression during Danio rerio development. (F) Bioinformatic prediction of the NLS in ZNF687 between amino acids 938 and 955 enhanced as a consequence of the substitution of arginine at the 937 position. (G) The expression of ZNF687 in nuclear- and cytoplasmic-extracts in lymphoblastic cell lines derived from affected individuals with the p.Pro937Arg change (PDB-affected individuals 1–4) in comparison to expression in those derived from healthy subjects (control individuals 1 and 2). ZNF687 antibody detected one band of about 135 kDa in the cytoplasm and two bands of about 100 and 135 kDa in the nucleus. Cytoplasm and nuclear extracts contained only minimal or no contamination (data not shown). (H) The quantifications of cytoplasmic and nuclear fractions. (I–K) The increased number of nuclei and the increased cellular area of osteoclasts derived from PDB subjects carrying the c.2810C>G mutation compared to the controls. ∗p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.001. The American Journal of Human Genetics 2016 98, 275-286DOI: (10.1016/j.ajhg.2015.12.016) Copyright © 2016 The Authors Terms and Conditions

Figure 4 Upregulation of ZNF687 in Peripheral Blood of PDB-Affected Subjects and in Tumor Tissues of GCT/PDB-Affected Individuals (A) The expression of ZNF687 in peripheral blood from healthy subjects, PDB-affected individuals without SQSTM1 or ZNF687 mutations, PDB-affected individuals with an SQSTM1 mutation, and PDB-affected individuals with a ZNF687 mutation. ∗ = p < 0.05; ∗∗ = p < 0.01; ∗∗∗ = p < 0.001. (B) NFkB binding sites on the ZNF687 promoter region. (C) The expression profile of ZNF687 in frozen tumor tissues from five GCT/PDB-affected individuals in comparison to the expression in tissue from healthy bone marrow. (D and E) ZNF687 expression on a tumor biopsy of a GCT/PDB-affected individual (D) in comparison to the tumor section derived from the same individual (E) without primary antibody (negative control). (F) A hypothetical model of ZNF687 involvement in the PDB molecular pathway. The American Journal of Human Genetics 2016 98, 275-286DOI: (10.1016/j.ajhg.2015.12.016) Copyright © 2016 The Authors Terms and Conditions