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

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

Volume 14, Issue 5, Pages (March 2004)

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

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

A Missense Mutation in PRPF6 Causes Impairment of pre-mRNA Splicing and Autosomal-Dominant Retinitis Pigmentosa Goranka Tanackovic, Adriana Ransijn,

Eija Siintola, Meral Topcu, Nina Aula, Hannes Lohi, Berge A

Mutations in the Liver Glycogen Phosphorylase Gene (PYGL) Underlying Glycogenosis Type VI (Hers Disease) Barbara Burwinkel, Henk D. Bakker, Eliezer Herschkovitz,

Recessive Mutations in POLR3B, Encoding the Second Largest Subunit of Pol III, Cause a Rare Hypomyelinating Leukodystrophy Martine Tétreault, Karine.

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

A novel mutation of HFE explains the classical phenotype of genetic hemochromatosis in a C282Y heterozygote Daniel F. Wallace, James S. Dooley, Ann P.

A De Novo Mutation in the β-Tubulin Gene TUBB4A Results in the Leukoencephalopathy Hypomyelination with Atrophy of the Basal Ganglia and Cerebellum

A Defect in the TUSC3 Gene Is Associated with Autosomal Recessive Mental Retardation Masoud Garshasbi, Valeh Hadavi, Haleh Habibi, Kimia Kahrizi, Roxana.

Kimberly A. Aldinger, Stephen J. Mosca, Martine Tétreault, Jennifer C

Autosomal-Recessive Congenital Cerebellar Ataxia Is Caused by Mutations in Metabotropic Glutamate Receptor 1 Velina Guergueltcheva, Dimitar N. Azmanov,

Mutations of the SYCP3 Gene in Women with Recurrent Pregnancy Loss

A Homozygous Mutation in the Tight-Junction Protein JAM3 Causes Hemorrhagic Destruction of the Brain, Subependymal Calcification, and Congenital Cataracts

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

Mutations of POLR3A Encoding a Catalytic Subunit of RNA Polymerase Pol III Cause a Recessive Hypomyelinating Leukodystrophy Geneviève Bernard, Eliane.

Double Heterozygosity for a RET Substitution Interfering with Splicing and an EDNRB Missense Mutation in Hirschsprung Disease Alberto Auricchio, Paola.

Size Polymorphisms in the Human Ultrahigh Sulfur Hair Keratin-Associated Protein 4, KAP4, Gene Family Naoyuki Kariya, Yutaka Shimomura, Masaaki Ito

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

Identification and Rescue of Splice Defects Caused by Two Neighboring Deep-Intronic ABCA4 Mutations Underlying Stargardt Disease Silvia Albert, Alejandro.

Mutations in TRIOBP, Which Encodes a Putative Cytoskeletal-Organizing Protein, Are Associated with Nonsyndromic Recessive Deafness Saima Riazuddin, Shaheen.

Capillary Malformation–Arteriovenous Malformation, a New Clinical and Genetic Disorder Caused by RASA1 Mutations Iiro Eerola, Laurence M. Boon, John.

A Truncating Mutation of TRAPPC9 Is Associated with Autosomal-Recessive Intellectual Disability and Postnatal Microcephaly Ganeshwaran H. Mochida, Muhammad.

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

Propionic and Methylmalonic Acidemia: Antisense Therapeutics for Intronic Variations Causing Aberrantly Spliced Messenger RNA A. Rincón, C. Aguado, L.R.

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

De Novo and Inherited Mutations in COL4A2, Encoding the Type IV Collagen α2 Chain Cause Porencephaly Yuriko Yoneda, Kazuhiro Haginoya, Hiroshi Arai,

Identification of COL7A1 Alternative Splicing Inserting 9 Amino Acid Residues Into the Fibronectin Type III Linker Domain Daisuke Sawamura, Maki Goto,

Bi-allelic Mutations in EPRS, Encoding the Glutamyl-Prolyl-Aminoacyl-tRNA Synthetase, Cause a Hypomyelinating Leukodystrophy Marisa I. Mendes, Mariana.

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

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

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

Evaluating the Effect of Unclassified Variants Identified in MMR Genes Using Phenotypic Features, Bioinformatics Prediction, and RNA Assays Lucia Pérez-Cabornero,

Volume 10, Issue 7, Pages (February 2015)

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

Germline Nonsense Mutation and Somatic Inactivation of SMARCA4/BRG1 in a Family with Rhabdoid Tumor Predisposition Syndrome Reinhard Schneppenheim, Michael.

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

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.

A De Novo Mutation in the β-Tubulin Gene TUBB4A Results in the Leukoencephalopathy Hypomyelination with Atrophy of the Basal Ganglia and Cerebellum

Biallelic SUN5 Mutations Cause Autosomal-Recessive Acephalic Spermatozoa Syndrome Fuxi Zhu, Fengsong Wang, Xiaoyu Yang, Jingjing Zhang, Huan Wu, Zhou.

Identification of Mutations in TRAPPC9, which Encodes the NIK- and IKK-β-Binding Protein, in Nonsyndromic Autosomal-Recessive Mental Retardation Asif.

Heterozygous Mutations in OAS1 Cause Infantile-Onset Pulmonary Alveolar Proteinosis with Hypogammaglobulinemia Kazutoshi Cho, Masafumi Yamada, Kazunaga.

Periklis Makrythanasis, Mitsuhiro Kato, Maha S

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.

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

A Defect in the TUSC3 Gene Is Associated with Autosomal Recessive Mental Retardation Masoud Garshasbi, Valeh Hadavi, Haleh Habibi, Kimia Kahrizi, Roxana.

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

Wook Lew Journal of Investigative Dermatology

The Gene Mutated in Variant Late-Infantile Neuronal Ceroid Lipofuscinosis (CLN6) and in nclf Mutant Mice Encodes a Novel Predicted Transmembrane Protein

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

De Novo Mutations in GNAO1, Encoding a Gαo Subunit of Heterotrimeric G Proteins, Cause Epileptic Encephalopathy Kazuyuki Nakamura, Hirofumi Kodera, Tenpei.

Activation of MET by Gene Amplification or by Splice Mutations Deleting the Juxtamembrane Domain in Primary Resected Lung Cancers Ryoichi Onozato, MD,

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

Cerebral Cavernomas in a Family with Multiple Cutaneous and Uterine Leiomyomas Associated with a New Mutation in the Fumarate Hydratase Gene Elena Campione,

Mutations in CHEK2 Associated with Prostate Cancer Risk

Two Exon-Skipping Mutations as the Molecular Basis of Succinic Semialdehyde Dehydrogenase Deficiency (4-Hydroxybutyric Aciduria) Ken L. Chambliss, Debra.

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

Alexandre Irrthum, Marika J

Marshall Syndrome Associated with a Splicing Defect at the COL11A1 Locus Andrew J. Griffith, Leslie K. Sprunger, D. Alexa Sirko-Osadsa, George E. Tiller,

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,

Mutations in the Fatty Acid 2-Hydroxylase Gene Are Associated with Leukodystrophy with Spastic Paraparesis and Dystonia Simon Edvardson, Hiroko Hama,

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

Loss of LKB1 Kinase Activity in Peutz-Jeghers Syndrome, and Evidence for Allelic and Locus Heterogeneity Hamid Mehenni, Corinne Gehrig, Jun-ichi Nezu,

A Truncating Mutation of TRAPPC9 Is Associated with Autosomal-Recessive Intellectual Disability and Postnatal Microcephaly Ganeshwaran H. Mochida, Muhammad.

Exome Sequencing Reveals a Homozygous SYT14 Mutation in Adult-Onset, Autosomal-Recessive Spinocerebellar Ataxia with Psychomotor Retardation Hiroshi.

Genome-Edited Triple-Recessive Mutation Alters Seed Dormancy in Wheat

Presentation transcript:

Mutations in POLR3A and POLR3B Encoding RNA Polymerase III Subunits Cause an Autosomal-Recessive Hypomyelinating Leukoencephalopathy Hirotomo Saitsu, Hitoshi Osaka, Masayuki Sasaki, Jun-ichi Takanashi, Keisuke Hamada, Akio Yamashita, Hidehiro Shibayama, Masaaki Shiina, Yukiko Kondo, Kiyomi Nishiyama, Yoshinori Tsurusaki, Noriko Miyake, Hiroshi Doi, Kazuhiro Ogata, Ken Inoue, Naomichi Matsumoto The American Journal of Human Genetics Volume 89, Issue 5, Pages 644-651 (November 2011) DOI: 10.1016/j.ajhg.2011.10.003 Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 1 Mutations in POLR3B and POLR3A (A) Pedigrees of four kindreds with HCAHC are shown. We identified four mutations in POLR3B encoding RPC2 in three individuals from two unrelated families and two mutations in POLR3A encoding RPC1 in one family. The segregation of each mutation is shown. (B) Schematic representation of RPC2 (upper) and RPC1 (lower) proteins with Pfam domains (from Ensembl). Locations of each amino-acid-altering mutation are depicted with electropherograms. All of the missense mutations occurred at evolutionally conserved amino acids. Homologous sequences were aligned with the CLUSTALW website. (C–F) 3D representations of RPC1 and RPC2 mutations. Mutated amino acids in RPC1 and RPC2 are shown along with their equivalent positions in the homologous RPB1 and RPB2 subunits of RNA Polymerase II (amino acid and its position in parenthesis). The structure and positions of mutations are illustrated by PyMOL with the crystal structure (PDB accession number 3GTP). RPB3, RPB9, and RPB11 subunits, which are specific to RNA Polymerase II, have been omitted from the figure. RPB1 is shown in green, RPB2 in sky blue, RPB5 in yellow, RPB6 in dark blue, RPB8 in pink, RPB10 in orange, RPB12 in purple, DNA in brown, and RNA in red. Amino acids that interact with mutated amino acids are also shown. The American Journal of Human Genetics 2011 89, 644-651DOI: (10.1016/j.ajhg.2011.10.003) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 2 Effects of Splice-Site and Nonsense Mutations in POLR3B (A) Schematic representation of the genomic structure of POLR3B from exon 16 to 19. Exons, introns, and primers are shown by boxes, dashed lines, and arrows, respectively. The mutation in intron 17 is depicted as a red dot. (B) RT-PCR analysis of individuals 1 and 2 with c.1857-2A>C and a normal control. Two PCR products were detected from the individual's cDNA: the upper band is the wild-type (WT) transcript, and the lower band is the mutant. Only a single wild-type amplicon was detected in the control. (C) Sequence of WT and mutant amplicons clearly showed exon 18 skipping in the mutant allele. (D) Analysis of the c.1648C>T mutation. Sequence of PCR products amplified with genomic (upper), cDNA from untreated cells (middle), and cDNA from CHX treated cells (lower) as a template. Although untreated cells show extremely low levels of c.1648C>T mutant allele expression, cells treated to inhibit NMD show significantly increased levels of mutant allele expression. The American Journal of Human Genetics 2011 89, 644-651DOI: (10.1016/j.ajhg.2011.10.003) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 3 Brain MRI of Individuals with POLR3B and POLR3A Mutations (A, C, E, and G) T2-weighted axial images through the basal ganglia. High-intensity areas in the white matter were observed in all individuals. (B, D, F, and H) T1-weighted midline sagittal images. All the individuals showed hypoplastic corpus callosum (arrowheads) and atrophy of cerebellum (arrows). The American Journal of Human Genetics 2011 89, 644-651DOI: (10.1016/j.ajhg.2011.10.003) Copyright © 2011 The American Society of Human Genetics Terms and Conditions