Autosomal-Dominant Retinitis Pigmentosa Caused by a Mutation in SNRNP200, a Gene Required for Unwinding of U4/U6 snRNAs Chen Zhao, Deepti L. Bellur,

Slides:

Advertisements

Similar presentations

Identification of EpCAM as the Gene for Congenital Tufting Enteropathy

Advertisements

A Mutation in HOXA2 Is Responsible for Autosomal-Recessive Microtia in an Iranian Family Fatemeh Alasti, Abdorrahim Sadeghi, Mohammad Hossein Sanati,

Homozygous Mutations in ADAMTS10 and ADAMTS17 Cause Lenticular Myopia, Ectopia Lentis, Glaucoma, Spherophakia, and Short Stature Jose Morales, Latifa.

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

Familial Deafness, Congenital Heart Defects, and Posterior Embryotoxon Caused by Cysteine Substitution in the First Epidermal-Growth-Factor–Like Domain.

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

Mutations in TPRN Cause a Progressive Form of Autosomal-Recessive Nonsyndromic Hearing Loss Yun Li, Esther Pohl, Redouane Boulouiz, Margit Schraders,

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

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,

Daniel C. Koboldt, David E. Larson, Lori S. Sullivan, Sara J

Sequence Analysis and Homology Modeling Suggest That Primary Congenital Glaucoma on 2p21 Results from Mutations Disrupting Either the Hinge Region or.

Gail Billingsley, Sathiyavedu T. Santhiya, Andrew D

Rhonda Perriman, Manuel Ares Molecular Cell

Complement Factor H Gene Mutation Associated with Autosomal Recessive Atypical Hemolytic Uremic Syndrome Lihua Ying, Yitzhak Katz, Menachem Schlesinger,

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

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

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

Peter Ianakiev, Michael W

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

Genetic Heterogeneity in Erythrokeratodermia Variabilis: Novel Mutations in the Connexin Gene GJB4 (Cx30.3) and Genotype-Phenotype Correlations Gabriele.

Integrative Multi-omic Analysis of Human Platelet eQTLs Reveals Alternative Start Site in Mitofusin 2 Lukas M. Simon, Edward S. Chen, Leonard C. Edelstein,

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

Diabetes Mutations Delineate an Atypical POU Domain in HNF-1α

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

Pseudoexon Activation as a Novel Mechanism for Disease Resulting in Atypical Growth- Hormone Insensitivity Louise A. Metherell, Scott A. Akker, Patricia.

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,

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.

Nonsense mutation of EMX2 is potential causative for uterus didelphysis: first molecular explanation for isolated incomplete müllerian fusion Shan Liu,

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

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

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.

Gail Billingsley, Sathiyavedu T. Santhiya, Andrew D

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

Volume 50, Issue 3, Pages (May 2013)

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

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,

Sex-Linked period Genes in the Silkmoth, Antheraea pernyi

Evidence That the Penetrance of Mutations at the RP11 Locus Causing Dominant Retinitis Pigmentosa Is Influenced by a Gene Linked to the Homologous RP11.

Familial Hemophagocytic Lymphohistiocytosis Type 5 (FHL-5) Is Caused by Mutations in Munc18-2 and Impaired Binding to Syntaxin 11 Udo zur Stadt, Jan.

Hyperchlorhidrosis Caused by Homozygous Mutation in CA12, Encoding Carbonic Anhydrase XII Maya Feldshtein, Suliman Elkrinawi, Baruch Yerushalmi, Barak.

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.

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,

Maple Syrup Urine Disease: Identification and Carrier-Frequency Determination of a Novel Founder Mutation in the Ashkenazi Jewish Population Lisa Edelmann,

Mutations in LRP5 or FZD4 Underlie the Common Familial Exudative Vitreoretinopathy Locus on Chromosome 11q Carmel Toomes, Helen M. Bottomley, Richard.

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,

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

PKHD1, the Polycystic Kidney and Hepatic Disease 1 Gene, Encodes a Novel Large Protein Containing Multiple Immunoglobulin-Like Plexin-Transcription–Factor.

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,

Volume 71, Issue 6, Pages (March 2007)

Structure of the Siz/PIAS SUMO E3 Ligase Siz1 and Determinants Required for SUMO Modification of PCNA Ali A. Yunus, Christopher D. Lima Molecular Cell

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

A Gene for an Autosomal Dominant Scleroatrophic Syndrome Predisposing to Skin Cancer (Huriez Syndrome) Maps to Chromosome 4q23 Young-Ae Lee, Howard P.

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

Mutations in PTPRQ Are a Cause of Autosomal-Recessive Nonsyndromic Hearing Impairment DFNB84 and Associated with Vestibular Dysfunction Margit Schraders,

Identification and Functional Consequences of a New Mutation (E155G) in the Gene for GCAP1 That Causes Autosomal Dominant Cone Dystrophy Susan E. Wilkie,

Volume 23, Issue 3, Pages (August 2006)

Volume 14, Issue 6, Pages (June 2004)

Next-Generation Sequencing of a 40 Mb Linkage Interval Reveals TSPAN12 Mutations in Patients with Familial Exudative Vitreoretinopathy Konstantinos Nikopoulos,

Comparative Genomic Analysis Identifies an ADP-Ribosylation Factor–like Gene as the Cause of Bardet-Biedl Syndrome (BBS3) Annie P. Chiang, Darryl Nishimura,

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

Mutation of CERKL, a Novel Human Ceramide Kinase Gene, Causes Autosomal Recessive Retinitis Pigmentosa (RP26) Miquel Tuson, Gemma Marfany, Roser Gonzàlez-Duarte

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

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:

Autosomal-Dominant Retinitis Pigmentosa Caused by a Mutation in SNRNP200, a Gene Required for Unwinding of U4/U6 snRNAs Chen Zhao, Deepti L. Bellur, Shasha Lu, Feng Zhao, Michael A. Grassi, Sara J. Bowne, Lori S. Sullivan, Stephen P. Daiger, Li Jia Chen, Chi Pui Pang, Kanxing Zhao, Jonathan P. Staley, Catharina Larsson The American Journal of Human Genetics Volume 85, Issue 5, Pages 617-627 (November 2009) DOI: 10.1016/j.ajhg.2009.09.020 Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 1 Schematic Representation of RP33 Mapping and Analyzed Genes A physical map of the RP33 region in chromosomal region 2cen-q12.17 is shown in the middle, critical microsatellite markers are indicated above, and physical distances (in Mb) are shown below. The adRP-affected family was reportedly linked to the region with maximum LOD score at D2S2222,7 as indicated at the top (gray bar). RP33 is flanked by D2S2159 and D2S1343, on the basis of unaffected recombinants (black bar), and is flanked by D2S329 and D2S2229, on the basis of affected recombinants (green bar).7 Candidate genes within the 9.4 Mb RP33 region are shown below the physical map. The American Journal of Human Genetics 2009 85, 617-627DOI: (10.1016/j.ajhg.2009.09.020) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 2 Identification of Missense Mutation c.3260C>T in Exon 25 of the SNRNP200 Gene Segregating Completely with the Affected Phenotype in a Four-Generation adRP Family (A) Pedigree of the kindred in which the RP33 locus was initially assigned.7 The genotypes C/T (heterozygous mutation) and C/C (wild-type) are given below the pedigree symbols. (B) Sequencing chromatograms from affected (top) and unaffected (bottom) family members, showing the c.3260C>T substitution in exon 25 of SNRNP200 and corresponding wild-type sequence. (C) Confirmation of the c.3260C>T mutation by pyrosequencing. Genotypes are highlighted by blue color, as C/T in the presence of mutation and as C/C in wild-type sequence. (D) Fundus photography of the right eye of affected individual IV:5. Notably, bone-spicule-like pigmentary deposits (denoted by arrows) were found in the peripheral retina, whereas the posterior retina is less affected (denoted by white box). The American Journal of Human Genetics 2009 85, 617-627DOI: (10.1016/j.ajhg.2009.09.020) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 3 Analysis of the SNRNP200 Gene and the c.3260C>T (p.S1087L) Mutation (A) The SNRNP200 gene, including 45 exons, is illustrated at the top, and the mutated exon 25 is highlighted in red. The encoded hBrr2 protein includes 2136 amino acids and contains two DExD/H box ATPase domains (green) and two Sec63 domains (red). The p.S1087L mutation resides in the first Sec63 domain. (B) Ubiquitous expression of human SNRNP200 and murine Snrnp200 demonstrated by PCR of cDNA samples. The expected product of 285 bp for human (top panel) and 491 bp for mouse (third panel) was found in all tested tissues. Human GAPDH and murine Gapdh transcripts were analyzed in parallel as a positive control (second and bottom panels). (C) Sequence alignment of hBrr2 from human (Hs), cow (Bt), horse (Ec), dog (Cf), mouse (Mm), rat (Rn), fruit fly (Dm), worm (Ce), and budding yeast (Sc). Conserved residues are shaded, the position of the mutated human S1087 residue in the RP33 family is boxed, and the R1107 mutation36 is indicated by a line. The American Journal of Human Genetics 2009 85, 617-627DOI: (10.1016/j.ajhg.2009.09.020) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 4 Two adRP Mutations in Budding Yeast Brr2p Impair Unwinding of U4/U6 snRNAs (A) The mutant yeast strains brr2-N1104L, brr2-N1104S, and brr2-R1107L were assayed for growth relative to wild-type. Strains were grown to log phase, serially diluted, spotted onto rich media, and grown at 30°C (1 day) or 15°C (7 days). (B) Triple snRNPs purified from wild-type BRR2 (lanes 1–6), mutant brr2-N1104L (lanes 7–12), or mutant brr2-R1107L (lanes 13–18) were assayed for their ability to unwind U4/U6 snRNAs in the presence of ATP at 20°C. Quenched samples were cold-phenol extracted, RNA was resolved by native gel electrophoresis, and the U4 and U6 snRNAs were detected by RNA blotting analysis. For comparison, lane 19 shows a sample from brr2-R1107L that was hot-phenol extracted. (C) Quantification of U4/U6 unwinding at 20°C by triple snRNPs purified from BRR2 (black closed diamonds), the RP33 mutant brr2-N1104L (blue closed triangles), and the other adRP mutant brr2-R1107L (orange closed circles). Data from (B) and data not shown were quantified and plotted. Error bars represent the standard deviation from three or more experiments. (D) The SNRNP200 adRP mutations reside in a “ratchet” helix of the Sec63 domain of Brr2p implicated in promoting the directionality and processivity of unwinding. A close-up of the “ratchet” helix of the corresponding domain in Hel308 (pdb 2P6R35) (red) is shown with the “ratchet” helix at the top. Residues of the ratchet helix that face and/or interact with nucleic acid (cyan) are highlighted (yellow). T596 corresponds to N1104 in yeast and to the RP33 residue S1087 in humans. W599 corresponds to R1107 in yeast and to the adRP residue R1090 in humans.36 R592 corresponds to F1100 in yeast and to Y1083 in humans. The American Journal of Human Genetics 2009 85, 617-627DOI: (10.1016/j.ajhg.2009.09.020) Copyright © 2009 The American Society of Human Genetics Terms and Conditions