Imprinting-Mutation Mechanisms in Prader-Willi Syndrome

Slides:

Advertisements

Similar presentations

Lisa Edelmann, Raj K. Pandita, Bernice E. Morrow

Advertisements

Sporadic Imprinting Defects in Prader-Willi Syndrome and Angelman Syndrome: Implications for Imprint-Switch Models, Genetic Counseling, and Prenatal Diagnosis

Alternative Splicing of a Novel Glycophorin Allele GPHe(GL) Generates Two Protein Isoforms in the Human Erythrocyte Membrane by Cheng-Han Huang, Olga O.

Novel PMS2 Pseudogenes Can Conceal Recessive Mutations Causing a Distinctive Childhood Cancer Syndrome Michel De Vos, Bruce E. Hayward, Susan Picton,

A Pseudo-Full Mutation Identified in Fragile X Assay Reveals a Novel Base Change Abolishing an EcoRI Restriction Site Shujian Liang, Harold N. Bass,

Deficiency of the ADP-Forming Succinyl-CoA Synthase Activity Is Associated with Encephalomyopathy and Mitochondrial DNA Depletion Orly Elpeleg, Chaya.

Der(22) Syndrome and Velo-Cardio-Facial Syndrome/DiGeorge Syndrome Share a 1.5- Mb Region of Overlap on Chromosome 22q11 B. Funke, L. Edelmann, N. McCain,

Discordance between Genetic and Epigenetic Defects in Pseudohypoparathyroidism Type 1b Revealed by Inconsistent Loss of Maternal Imprinting at GNAS1

The DMPK Gene of Severely Affected Myotonic Dystrophy Patients Is Hypermethylated Proximal to the Largely Expanded CTG Repeat Peter Steinbach, Dieter.

A Member of a Gene Family on Xp22

Addition of H19 ‘Loss of Methylation Testing’ for Beckwith-Wiedemann Syndrome (BWS) Increases the Diagnostic Yield Jochen K. Lennerz, Robert J. Timmerman,

Cohen Syndrome Is Caused by Mutations in a Novel Gene, COH1, Encoding a Transmembrane Protein with a Presumed Role in Vesicle-Mediated Sorting and Intracellular.

Reciprocal and Nonreciprocal Recombination at the Glucocerebrosidase Gene Region: Implications for Complexity in Gaucher Disease Nahid Tayebi, Barbara.

A Novel Alu-Like Element Rearranged in the Dystrophin Gene Causes a Splicing Mutation in a Family with X-Linked Dilated Cardiomyopathy Alessandra Ferlini,

Chromosome Breakage in the Prader-Willi and Angelman Syndromes Involves Recombination between Large, Transcribed Repeats at Proximal and Distal Breakpoints

Reciprocal and Nonreciprocal Recombination at the Glucocerebrosidase Gene Region: Implications for Complexity in Gaucher Disease Nahid Tayebi, Barbara.

The SPCH1 Region on Human 7q31: Genomic Characterization of the Critical Interval and Localization of Translocations Associated with Speech and Language.

Molecular Characterization and Gene Content of Breakpoint Boundaries in Patients with Neurofibromatosis Type 1 with 17q11.2 Microdeletions Dieter E.

T. Ohta, K. Buiting, H. Kokkonen, S. McCandless, S. Heeger, H

Molecular Cytogenetic Evidence for a Common Breakpoint in the Largest Inverted Duplications of Chromosome 15 A.E. Wandstrat, J. Leana-Cox, L. Jenkins,

Shirley Rainier, Jing-Hua Chai, Debra Tokarz, Robert D

Mutations in a Novel Gene with Transmembrane Domains Underlie Usher Syndrome Type 3 Tarja Joensuu, Riikka Hämäläinen, Bo Yuan, Cheryl Johnson, Saara.

A Gene Mutated in Nephronophthisis and Retinitis Pigmentosa Encodes a Novel Protein, Nephroretinin, Conserved in Evolution Edgar Otto, Julia Hoefele,

Barbara R. Migeon, Catherine H. Lee, Ashis K

Myotonic Dystrophy Type 2: Human Founder Haplotype and Evolutionary Conservation of the Repeat Tract Christina L. Liquori, Yoshio Ikeda, Marcy Weatherspoon,

S. Hussain Askree, Shika Dharamrup, Lawrence N. Hjelm, Bradford Coffee

Structure of the GM2A Gene: Identification of an Exon 2 Nonsense Mutation and a Naturally Occurring Transcript with an In-Frame Deletion of Exon 2 Biao.

Volume 65, Issue 6, Pages (June 2004)

A Novel STX16 Deletion in Autosomal Dominant Pseudohypoparathyroidism Type Ib Redefines the Boundaries of a cis-Acting Imprinting Control Element of GNAS

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

Syed Hussain Askree, Lawrence N

Mutations in the ZNF41 Gene Are Associated with Cognitive Deficits: Identification of a New Candidate for X-Linked Mental Retardation Sarah A. Shoichet,

Detection and Discrimination between Deletional and Non-Deletional Prader-Willi and Angelman Syndromes by Methylation-Specific PCR and Quantitative Melting.

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

Renata C. Gallagher, Birgit Pils, Mohammed Albalwi, Uta Francke

John D. Rioux, Valerie A. Stone, Mark J

A Multi-Exonic BRCA1 Deletion Identified in Multiple Families through Single Nucleotide Polymorphism Haplotype Pair Analysis and Gene Amplification with.

Airong Li, Sonia Davila, Laszlo Furu, Qi Qian, Xin Tian, Patrick S

Disruption of Contactin 4 (CNTN4) Results in Developmental Delay and Other Features of 3p Deletion Syndrome Thomas Fernandez, Thomas Morgan, Nicole Davis,

Small Evolutionarily Conserved RNA, Resembling C/D Box Small Nucleolar RNA, Is Transcribed from PWCR1, a Novel Imprinted Gene in the Prader-Willi Deletion.

A Physical Map, Including a BAC/PAC Clone Contig, of the Williams-Beuren Syndrome– Deletion Region at 7q11.23 Risa Peoples, Yvonne Franke, Yu-Ker Wang,

A Mutation in the Variable Repeat Region of the Aggrecan Gene (AGC1) Causes a Form of Spondyloepiphyseal Dysplasia Associated with Severe, Premature.

Novel PMS2 Pseudogenes Can Conceal Recessive Mutations Causing a Distinctive Childhood Cancer Syndrome Michel De Vos, Bruce E. Hayward, Susan Picton,

Deletion of PREPL, a Gene Encoding a Putative Serine Oligopeptidase, in Patients with Hypotonia-Cystinuria Syndrome Jaak Jaeken, Kevin Martens, Inge.

Volume 58, Issue 2, Pages (August 2000)

Analysis of GNAS1 and Overlapping Transcripts Identifies the Parental Origin of Mutations in Patients with Sporadic Albright Hereditary Osteodystrophy.

Meiotic Microdeletion Breakpoints in the BRCA1 Gene Are Significantly Associated with Symmetric DNA-Sequence Elements Beatrice Schmucker, Michael Krawczak

Imprinting of Human GRB10 and Its Mutations in Two Patients with Russell-Silver Syndrome Hiroshi Yoshihashi, Katsuhiro Maeyama, Rika Kosaki, Tsutomu.

Assessing the Functional Characteristics of Synonymous and Nonsynonymous Mutation Candidates by Use of Large DNA Constructs A.M. Eeds, D. Mortlock, R.

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,

Volume 57, Issue 3, Pages (March 2000)

Constitutional Mutations of the hSNF5/INI1 Gene Predispose to a Variety of Cancers Nicolas Sévenet, Eammon Sheridan, Daniel Amram, Pascale Schneider,

Der(22) Syndrome and Velo-Cardio-Facial Syndrome/DiGeorge Syndrome Share a 1.5- Mb Region of Overlap on Chromosome 22q11 B. Funke, L. Edelmann, N. McCain,

2012 William Allan Award: Adventures in Cytogenetics1

Identification of TSIX, Encoding an RNA Antisense to Human XIST, Reveals Differences from its Murine Counterpart: Implications for X Inactivation Barbara.

Mutations in CHEK2 Associated with Prostate Cancer Risk

The Tumor-Necrosis-Factor Receptor–Associated Periodic Syndrome: New Mutations in TNFRSF1A, Ancestral Origins, Genotype-Phenotype Studies, and Evidence.

C. E. Browne, N. R. Dennis, E. Maher, F. L. Long, J. C. Nicholson, J

C. Denier, S. Goutagny, P. Labauge, V. Krivosic, M Arnoult, A

Polymorphic X-Chromosome Inactivation of the Human TIMP1 Gene

Addition of H19 ‘Loss of Methylation Testing’ for Beckwith-Wiedemann Syndrome (BWS) Increases the Diagnostic Yield Jochen K. Lennerz, Robert J. Timmerman,

Kit-Sing Au, Adelaide A. Hebert, E. Steve Roach, Hope Northrup

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

Cohen Syndrome Is Caused by Mutations in a Novel Gene, COH1, Encoding a Transmembrane Protein with a Presumed Role in Vesicle-Mediated Sorting and Intracellular.

Loss-of-Function Mutations in a Human Gene Related to Chlamydomonas reinhardtii Dynein IC78 Result in Primary Ciliary Dyskinesia Gaëlle Pennarun, Estelle.

Exon Skipping in IVD RNA Processing in Isovaleric Acidemia Caused by Point Mutations in the Coding Region of the IVD Gene Jerry Vockley, Peter K. Rogan,

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

Identification of Novel pro-α2(IX) Collagen Gene Mutations in Two Families with Distinctive Oligo-Epiphyseal Forms of Multiple Epiphyseal Dysplasia Paul.

Sequence Homology between 4qter and 10qter Loci Facilitates the Instability of Subtelomeric KpnI Repeat Units Implicated in Facioscapulohumeral Muscular.

K. Miura, M. Obama, K. Yun, H. Masuzaki, Y. Ikeda, S. Yoshimura, T

Presentation transcript:

Imprinting-Mutation Mechanisms in Prader-Willi Syndrome T. Ohta, T.A. Gray, P.K. Rogan, K. Buiting, J.M. Gabriel, S. Saitoh, B. Muralidhar, B. Bilienska, M. Krajewska-Walasek, D.J. Driscoll, B. Horsthemke, M.G. Butler, R.D. Nicholls The American Journal of Human Genetics Volume 64, Issue 2, Pages 397-413 (February 1999) DOI: 10.1086/302233 Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 1 PWS domain in proximal chromosome 15q11-q13. The positions of genes and genetic markers (circles), transcription from paternal (“PAT”) or maternal (“MAT”) alleles, common cytogenetic deletion breakpoints (zigzag lines), and regions involved in PWS, AS, and the IC are illustrated. A plus sign (+) indicates presence of expression, and a minus sign (−) indicates no expression. The American Journal of Human Genetics 1999 64, 397-413DOI: (10.1086/302233) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 2 Clinical photographs of PWS patients. a, PWS-14. This patient has the smallest known PWS deletion (7.5 kb). b and c, PWS-29. d and e, PWS-B. f, PWS-G. These three patients with an IM have no 15q11-q13 IC microdeletion or detectable mutation. Note the small hands typical of PWS. g and h, PWS-P sibs. These sibs have a large IC deletion. The American Journal of Human Genetics 1999 64, 397-413DOI: (10.1086/302233) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 3 DNA methylation identifies PWS IMs. DNA was digested with XbaI/NotI, Southern blotted, and probed with the 0.6NE fragment of the SNRPN 5′ CpG island. The upper 4.3-kb band represents the methylated allele, which is usually of maternal origin, and the lower 0.9-kb band represents the unmethylated allele, which is of paternal origin. a, PWS-14. The SNRPN probe is deleted from the paternal allele (lane 1 is overloaded). b, PWS-B. Only the methylated band is present, but the patient is not deleted at this locus (lane 4), indicating that the paternal chromosome has a maternal imprint. del = deletion, and N = normal. The American Journal of Human Genetics 1999 64, 397-413DOI: (10.1086/302233) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 4 Microdeletion of 7.5 kb in patient PWS-14. a, Distal breakpoint. SNRPN exons 1–3 cDNA as probe detected the distal breakpoint in EcoRI-digested DNA. b, Proximal breakpoint. The 393SS probe detected the proximal breakpoint in XbaI-digested DNA. c, Map of the IC microdeletion. The deletion is shown as a blackened bar. Arrows indicate breakpoint fragments. E = exon. The American Journal of Human Genetics 1999 64, 397-413DOI: (10.1086/302233) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 5 Summary map of PWS microdeletions, with SRO. The extent of each deletion is shown by a blackened bar, with new cases in boldface (PWS-B, PWS-G, and PWS-29 are nondeleted); records for families PWS-O, PWS-U, and PWS-S and for the AS SRO are published elsewhere (Buiting et al. 1995; Saitoh et al. 1996). A point mutation in family AS-C2 occurs in the splice donor site of an IC transcript (Dittrich et al. 1996). The microdeletions in families with PWS or AS affect the maternal-to-paternal (“mat→pat”) or the paternal-to-maternal (“pat→mat”) switch in the male or female germ line, respectively. Exons of the IC transcript and SNRPN (upper blackened boxes) and of the probes (lower blackened boxes or horizontal lines [for L48.6I and L48.3I]) are shown. The American Journal of Human Genetics 1999 64, 397-413DOI: (10.1086/302233) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 6 Silencing of paternal-only gene expression in PWS IMs. Paternally expressed genes and transcripts across a 1.0–1.5-Mb domain (ZNF127, SNRPN, PAR-5, IPW, and PAR-1) are not expressed in (a) PWS-14, a patient with PWS who has a 7.5-kb microdeletion, or in (b) PWS-B, a patient with PWS who does not have an IC mutation. RT-PCR expression analysis of lymphoblast cell lines of the patients and controls are shown. RT-PCR analysis of the control GAPDH (a) and FBN (b) genes shows expression in all the RT+ samples. The American Journal of Human Genetics 1999 64, 397-413DOI: (10.1086/302233) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 7 A paternal-specific DHS in the PWS SRO. a, Nuclei from lymphoblastoid cell lines with a maternally derived (AS-139) or paternally derived (PWS-109) 15q11-q13 deletion were treated with varying concentrations of DNase I. The resulting genomic DNAs were cut with BamHI (“B”), Southern blotted, and probed with an EcoRI (“E”)/BamHI fragment from intron 1 of SNRPN. In AS-139, a major subfragment was generated in nuclei exposed to 50 and 250 U DNase I/ml, indicating the presence of a DHS ∼3.1 kb upstream of the distal BamHI site. No specific DHSs were seen in PWS-109. b, Schematic diagram depicting the relative positions of the PWS SRO (blackened bar), the probe fragment (hatched bar), the SNRPN exon 1 transcription start (thin arrow), and the major DHS (thick arrow). The American Journal of Human Genetics 1999 64, 397-413DOI: (10.1086/302233) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 8 Phylogenetic footprints within the PWS SRO. The transcription start site for human SNRPN and mouse Snrpn genes are indicated by arrows, and mouse and human promoter sequences are aligned 5′ of these start sites (determined by use of the Clustal algorithm, with modifications to maximize parsimony). Six putative evolutionarily conserved footprints, which are likely to represent TF binding sites, are identified (blackened boxes [top] and boxed sequences [bottom]). One or more of these TF binding sites are also candidates for the IC imprint-switch element. The American Journal of Human Genetics 1999 64, 397-413DOI: (10.1086/302233) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 9 Microsatellite haplotype analysis of the family of PWS-B. Haplotypes were generated by use of the marker loci shown. One normal sib has the same paternal haplotype (boxed) as patient PWS-B, and this haplotype was derived from the paternal grandmother. The American Journal of Human Genetics 1999 64, 397-413DOI: (10.1086/302233) Copyright © 1999 The American Society of Human Genetics Terms and Conditions