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

Slides:

Advertisements

Similar presentations

Biallelic Mutations in TMTC3, Encoding a Transmembrane and TPR-Containing Protein, Lead to Cobblestone Lissencephaly Julie Jerber, Maha S. Zaki, Jumana.

Advertisements

Hair Keratin Associated Proteins: Characterization of a Second High Sulfur KAP Gene Domain on Human Chromosome 211 Michael A. Rogers, Hermelita Winter,

The H Syndrome Is Caused by Mutations in the Nucleoside Transporter hENT3 Vered Molho-Pessach, Israela Lerer, Dvorah Abeliovich, Ziad Agha, Abdulasalam.

Grouping of Multiple-Lentigines/LEOPARD and Noonan Syndromes on the PTPN11 Gene Maria Cristina Digilio, Emanuela Conti, Anna Sarkozy, Rita Mingarelli,

Mutation Spectrum of the Survival of Motor Neuron 1 and Functional Analysis of Variants in Chinese Spinal Muscular Atrophy Yu-jin Qu, Jin-li Bai, Yan-yan.

A Mutation in the Vesicle-Trafficking Protein VAPB Causes Late-Onset Spinal Muscular Atrophy and Amyotrophic Lateral Sclerosis Agnes L. Nishimura, Miguel.

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

Total-Genome Analysis of BRCA1/2-Related Invasive Carcinomas of the Breast Identifies Tumor Stroma as Potential Landscaper for Neoplastic Initiation

The Diversity Present in 5140 Human Mitochondrial Genomes

From Prescription to Transcription: Genome Sequence as Drug Target

A Clinical Grade Sequencing-Based Assay for CEBPA Mutation Testing

MET Mutation Associated with Responsiveness to Crizotinib

Biallelic Mutations in TMTC3, Encoding a Transmembrane and TPR-Containing Protein, Lead to Cobblestone Lissencephaly Julie Jerber, Maha S. Zaki, Jumana.

Qing Cheng, Cheng Cheng, Kristine R. Crews, Raul C

Volume 54, Issue 3, Pages (September 1998)

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

Autosomal Dominant Familial Calcium Pyrophosphate Dihydrate Deposition Disease Is Caused by Mutation in the Transmembrane Protein ANKH Charlene J. Williams,

Harry R. Hill, Nancy H. Augustine, Robert J. Pryor, Gudrun H

Pharmacogenomic variability and anaesthesia

Structure of the 5′ Portion of the Human Plakoglobin Gene

Syed Hussain Askree, Lawrence N

Volume 23, Issue 1, Pages 9-22 (January 2013)

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

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

A Shared Surface of TBP Directs RNA Polymerase II and III Transcription via Association with Different TFIIB Family Members Xuemei Zhao, Laura Schramm,

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.

Mental Retardation and Abnormal Skeletal Development (Dyggve-Melchior-Clausen Dysplasia) Due to Mutations in a Novel, Evolutionarily Conserved Gene Daniel.

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

Gajja S. Salomons, Silvy J. M. van Dooren, Nanda M. Verhoeven, Kim M

A Presenilin-1 Truncating Mutation Is Present in Two Cases with Autopsy-Confirmed Early-Onset Alzheimer Disease Carolyn Tysoe, Joanne Whittaker, John.

Mutations of MYO6 Are Associated with Recessive Deafness, DFNB37

A Mutation Hot Spot for Nonspecific X-Linked Mental Retardation in the MECP2 Gene Causes the PPM-X Syndrome Sabine M. Klauck, Susan Lindsay, Kim S. Beyer,

Splitting p63 The American Journal of Human Genetics

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

Germline Epigenetic Silencing of the Tumor Suppressor Gene PTPRJ in Early-Onset Familial Colorectal Cancer Ramprasath Venkatachalam Gastroenterology

CC2D2A, Encoding A Coiled-Coil and C2 Domain Protein, Causes Autosomal- Recessive Mental Retardation with Retinitis Pigmentosa Abdul Noor, Christian Windpassinger,

Mutations of the Ephrin-B1 Gene Cause Craniofrontonasal Syndrome

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.

A Distinct DNA-Methylation Boundary in the 5′- Upstream Sequence of the FMR1 Promoter Binds Nuclear Proteins and Is Lost in Fragile X Syndrome Anja Naumann,

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

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,

X-Linked Mental Retardation and Autism Are Associated with a Mutation in the NLGN4 Gene, a Member of the Neuroligin Family Frédéric Laumonnier, Frédérique.

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

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.

Novel Truncating Mutations in the Polyglutamine Tract Binding Protein 1 Gene (PQBP1) Cause Renpenning Syndrome and X-Linked Mental Retardation in Another.

Characterization and Mutation Analysis of Human LEFTY A and LEFTY B, Homologues of Murine Genes Implicated in Left-Right Axis Development K. Kosaki,

Mutation Analysis of the Entire PKD1 Gene: Genetic and Diagnostic Implications Sandro Rossetti, Lana Strmecki, Vicki Gamble, Sarah Burton, Vicky Sneddon,

Autosomal-Dominant Striatal Degeneration Is Caused by a Mutation in the Phosphodiesterase 8B Gene Silke Appenzeller, Anja Schirmacher, Hartmut Halfter,

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,

Transcriptional Control of SLC26A4 Is Involved in Pendred Syndrome and Nonsyndromic Enlargement of Vestibular Aqueduct (DFNB4) Tao Yang, Hilmar Vidarsson,

Mental Retardation and Abnormal Skeletal Development (Dyggve-Melchior-Clausen Dysplasia) Due to Mutations in a Novel, Evolutionarily Conserved Gene Daniel.

Figure 1 Pedigree and genetic findings

Spectrum of Mutations in the RPGR Gene That Are Identified in 20% of Families with X- Linked Retinitis Pigmentosa Monika Buraczynska, Weiping Wu, Ricardo.

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

Mutations in POLR3A and POLR3B Encoding RNA Polymerase III Subunits Cause an Autosomal-Recessive Hypomyelinating Leukoencephalopathy Hirotomo Saitsu,

Mutations in the Gene Encoding Capillary Morphogenesis Protein 2 Cause Juvenile Hyaline Fibromatosis and Infantile Systemic Hyalinosis Sandra Hanks,

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

Volume 53, Issue 5, Pages (May 1998)

Pleiotropic Effects of Trait-Associated Genetic Variation on DNA Methylation: Utility for Refining GWAS Loci Eilis Hannon, Mike Weedon, Nicholas Bray,

Mutations in CHEK2 Associated with Prostate Cancer Risk

Mutations in PRPS1, Which Encodes the Phosphoribosyl Pyrophosphate Synthetase Enzyme Critical for Nucleotide Biosynthesis, Cause Hereditary Peripheral.

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

Methylation status of IGFBPL1 in human breast cancer.

Gene Mutations in the Succinate Dehydrogenase Subunit SDHB Cause Susceptibility to Familial Pheochromocytoma and to Familial Paraganglioma Dewi Astuti,

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

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

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

Qing Cheng, Cheng Cheng, Kristine R. Crews, Raul C

Presentation transcript:

Rare Missense and Synonymous Variants in UBE1 Are Associated with X-Linked Infantile Spinal Muscular Atrophy Juliane Ramser, Mary Ellen Ahearn, Claus Lenski, Kemal O. Yariz, Heide Hellebrand, Michael von Rhein, Robin D. Clark, Rita K. Schmutzler, Peter Lichtner, Eric P. Hoffman, Alfons Meindl, Lisa Baumbach-Reardon The American Journal of Human Genetics Volume 82, Issue 1, Pages 188-193 (January 2008) DOI: 10.1016/j.ajhg.2007.09.009 Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigree of XL-SMA Family #2 As described by Kobayashi et al.6 Affected males are indicated by black boxes, obligate carriers with a dotted circle. The index patient is marked with an arrow. The synonymous C→T substitution (c.1731 C→T, p.Asn577Asn) was shown by direct sequencing approaches to segregate with disease in the family. The American Journal of Human Genetics 2008 82, 188-193DOI: (10.1016/j.ajhg.2007.09.009) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 2 Sequence Alterations Detected in Exon 15 of the UBE1 Gene (A) The synonymous c.1731 C→T substitution. Top, wild-type sequence with the “C” highlighted in blue; center, heterozygote status in an obligate carrier; bottom, C→T substitution in a patient with the “T” highlighted in gray. (B) The c.1617 G→T substitution, p.Met539Ile in family #5. Top, wild-type sequence; center, heterozygote status of an obligate carrier; bottom, G→T substitution in a patient. The American Journal of Human Genetics 2008 82, 188-193DOI: (10.1016/j.ajhg.2007.09.009) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 3 Genomic Structure of the UBE1 Gene and Amino Acid Conservation of Exon 15 in Several Species (A) Yellow boxes represent the 26 exons of UBE1 with an alternative exon 1a. The gene structure was obtained from publicly available databases (UCSC Genome Bioinformatics). Translation start in exon 2 is indicated with a black arrow. Five exonic CpG islands were detected by using in silico CpG island prediction tools (MethPrimer). (B) Position of CpG island and the methylated CpG dinucleotides in exon 15 are represented by green boxes. In index patients of three XL-SMA families, one C methylation less is observed resulting from the C→T exchange (red box). For bisulphite genomic sequencing, genomic DNA was isolated from cell lines or whole blood by means of the DNA Extraction Mini Kit (QIAGEN). The bisulfite modification reaction was performed with the EZ DNA Methylation Kit (HISS Diagnostics), and the bisulfite-treated DNA was amplified with primer pair (1f, 5′-GGT GAA TGT ATA AAT AAG TGA GT-3′; 1r, 5′-ACA CCC CTC TTA ATA TAT ACA C-3′) and subsequently sequenced with Big Dye kits (Perkin Elmer). The positions of the three detected mutations in exon 15 are marked with red stars. (C) Exon 15 represents parts of the transcript that codes for a highly conserved protein domain that form interactions with gigaxonin. Amino acid exchanges in the different species are highlighted in blue. The American Journal of Human Genetics 2008 82, 188-193DOI: (10.1016/j.ajhg.2007.09.009) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 4 Model for Suggested Transcription Regulatory Element in Exon 15 of UBE1 (A) In the wild-type, the CpG island in exon 15 is fully methylated (symbolized by four green cylinders), which prevents the binding of proteins (red diamond) that block a specific transcription enhancer element, thus allowing a putative enhancer to stimulate the transcription. (B) In the XL-SMA patient harboring the synonymous C→T exchange, the CpG island in exon 15 is only partly methylated (symbolized by a white cylinder among three green cylinders), thus allowing the proteins to bind and as a consequence the transcription enhancer is blocked. The American Journal of Human Genetics 2008 82, 188-193DOI: (10.1016/j.ajhg.2007.09.009) Copyright © 2008 The American Society of Human Genetics Terms and Conditions