DVL1 Frameshift Mutations Clustering in the Penultimate Exon Cause Autosomal- Dominant Robinow Syndrome Janson White, Juliana F. Mazzeu, Alexander Hoischen,

Slides:

Advertisements

Similar presentations

Mutations in MED12 Cause X-Linked Ohdo Syndrome Anneke T. Vulto-van Silfhout, Bert B.A. de Vries, Bregje W.M. van Bon, Alexander Hoischen, Martina Ruiterkamp-Versteeg,

Advertisements

Ilse Feenstra, Lisenka E. L. M. Vissers, Ronald J. E

A Novel Mutation and Large Size Polymorphism Affecting the V2 Domain of Keratin 1 in an African-American Family with Severe, Diffuse Palmoplantar Keratoderma.

by Wen-feng Xu, Zhi-wei Xie, Dominic W. Chung, and Earl W. Davie

Biallelic Loss of Proprioception-Related PIEZO2 Causes Muscular Atrophy with Perinatal Respiratory Distress, Arthrogryposis, and Scoliosis Andrea Delle.

P. M. Kelley, D. J. Harris, B. C. Comer, J. W. Askew, T. Fowler, S. D

Tracy Dixon-Salazar, Jennifer L. Silhavy, Sarah E. Marsh, Carrie M

A Clinical Grade Sequencing-Based Assay for CEBPA Mutation Testing

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,

Mutations in the Human Sterol Δ7-Reductase Gene at 11q12-13 Cause Smith-Lemli- Opitz Syndrome Christopher A. Wassif, Cheryl Maslen, Stivelia Kachilele-Linjewile,

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.

Structural and Functional Mutations of the Perlecan Gene Cause Schwartz-Jampel Syndrome, with Myotonic Myopathy and Chondrodysplasia Eri Arikawa-Hirasawa,

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

Gail Billingsley, Sathiyavedu T. Santhiya, Andrew D

Volume 54, Issue 3, Pages (September 1998)

Pathogenicity Evaluation of BRCA1 and BRCA2 Unclassified Variants Identified in Portuguese Breast/Ovarian Cancer Families Catarina Santos, Ana Peixoto,

Progress in Molecular Genetics of Heritable Skin Diseases: The Paradigms of Epidermolysis Bullosa and Pseudoxanthoma Elasticum Jouni Uitto, Leena Pulkkinen,

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,

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

Analysis of Rare APC Variants at the mRNA Level

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

Splice Site and Deletion Mutations in Keratin (KRT1 and KRT10) Genes: Unusual Phenotypic Alterations in Scandinavian Patients with Epidermolytic Hyperkeratosis

Terminal Osseous Dysplasia Is Caused by a Single Recurrent Mutation in the FLNA Gene Yu Sun, Rowida Almomani, Emmelien Aten, Jacopo Celli, Jaap van der.

A Human Homologue of the Drosophila melanogaster diaphanous Gene Is Disrupted in a Patient with Premature Ovarian Failure: Evidence for Conserved Function.

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 Homozygous Nonsense Mutation in Type XVII Collagen Gene (COL17A1) Uncovers an Alternatively Spliced mRNA Accounting for an Unusually Mild Form of Non-Herlitz.

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

Christian Gilissen, Heleen H

Loss-of-Function Mutations in Euchromatin Histone Methyl Transferase 1 (EHMT1) Cause the 9q34 Subtelomeric Deletion Syndrome Tjitske Kleefstra, Han G.

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

Cantú Syndrome Is Caused by Mutations in ABCC9

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,

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

Mutations in MED12 Cause X-Linked Ohdo Syndrome

Haploinsufficiency of HDAC4 Causes Brachydactyly Mental Retardation Syndrome, with Brachydactyly Type E, Developmental Delays, and Behavioral Problems

Gail Billingsley, Sathiyavedu T. Santhiya, Andrew D

Yavuz Bayram, Janson J. White, Nursel Elcioglu, Megan T

Dominant Mutations in KAT6A Cause Intellectual Disability with Recognizable Syndromic Features Emma Tham, Anna Lindstrand, Avni Santani, Helena Malmgren,

Mutations in DVL1 Cause an Osteosclerotic Form of Robinow Syndrome

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

Biallelic Mutations in PATL2 Cause Female Infertility Characterized by Oocyte Maturation Arrest Biaobang Chen, Zhihua Zhang, Xiaoxi Sun, Yanping Kuang,

DVL3 Alleles Resulting in a −1 Frameshift of the Last Exon Mediate Autosomal- Dominant Robinow Syndrome Janson J. White, Juliana F. Mazzeu, Alexander.

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.

Opitz G/BBB Syndrome in Xp22: Mutations in the MID1 Gene Cluster in the Carboxy- Terminal Domain Karin Gaudenz, Erich Roessler, Nandita Quaderi, Brunella.

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

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.

Tracy Dixon-Salazar, Jennifer L. Silhavy, Sarah E. Marsh, Carrie M

De Novo Nonsense Mutations in KAT6A, a Lysine Acetyl-Transferase Gene, Cause a Syndrome Including Microcephaly and Global Developmental Delay Valerie A.

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

Neil V. Whittock, Frances J. Smith, W.H. Irwin McLean

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

Janson J. White, Juliana F

Mutation of the Ca2+ Channel β Subunit Gene Cchb4 Is Associated with Ataxia and Seizures in the Lethargic (lh) Mouse Daniel L Burgess, Julie M Jones,

Asaf Ta-Shma, Tahir N. Khan, Asaf Vivante, Jason R

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.

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,

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

Sabrina Sacconi, Richard J. L. F. Lemmers, Judit Balog, Patrick J

Presentation transcript:

DVL1 Frameshift Mutations Clustering in the Penultimate Exon Cause Autosomal- Dominant Robinow Syndrome Janson White, Juliana F. Mazzeu, Alexander Hoischen, Shalini N. Jhangiani, Tomasz Gambin, Michele Calijorne Alcino, Samantha Penney, Jorge M. Saraiva, Hanne Hove, Flemming Skovby, Hülya Kayserili, Elicia Estrella, Anneke T. Vulto-van Silfhout, Marloes Steehouwer, Donna M. Muzny, V. Reid Sutton, Richard A. Gibbs, James R. Lupski, Han G. Brunner, Bregje W.M. van Bon, Claudia M.B. Carvalho The American Journal of Human Genetics Volume 96, Issue 4, Pages 612-622 (April 2015) DOI: 10.1016/j.ajhg.2015.02.015 Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 1 Clinical Presentation of the Individuals with DRS in This Study Subjects (clockwise from the top left) BAB5264, 016462, 016516, 016517, and 017604 have DRS due to mutations in DLV1 and show characteristic facial features of frontal bossing with a high, broad forehead, hypertelorism, a broad nasal tip, and low-set ears. The American Journal of Human Genetics 2015 96, 612-622DOI: (10.1016/j.ajhg.2015.02.015) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 2 DVL1 Variants Identified in This Study (A) Position of known functional domains and their distribution within the DVL1 transcript. The N-terminal DIX domain is most likely involved in regulating canonical Wnt signaling, leading to β-catenin stability;22 the PDZ domain is required for DVL1-mediated microtubule stabilization23 and for regulation of signal transduction. The C-terminal DEP domain is predicted to be important for protein interaction and most likely has a role in signal transduction; it can be found in other proteins involved in G protein signaling.24 The approximate locations of variants identified for each affected individual all cluster within exon 14 and display the same PTC within exon 15. (B) Sanger sequencing of allele-specific PCR-product clones confirmed the presence of frameshift mutations in each affected individual and revealed a C insertion in subject BAB4073. Electropherograms displaying the cloning results of both alleles for six affected individuals are shown. Electropherograms for individual 016462, who carries the recurrent deletion c.1505_1517, are displayed in Figure S3. Underlined bases are deleted in the mutant allele, and the highlighted pink base (for subject BAB4073) in the mutant allele represents an insertion that did not exist in the reference allele. (C) Predicted amino acid sequence with a change in the reading frame for part of exon 14 and exon 15. All variants in affected individuals have an identical PTC within exon 15. Identical amino acids are highlighted in yellow. Asterisks indicate termination codons. The American Journal of Human Genetics 2015 96, 612-622DOI: (10.1016/j.ajhg.2015.02.015) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 3 mRNA Expression of Mutant Alleles (A) Schematic representation of the DVL1 coding region. Green ovals display approximate locations of TaqMan probes Hs00182896_m1 and Hs00737028_m1. Arrows show approximate locations of primers 5′-TGCTACTACGTCTTCGGGGA-3′ (exon 13 fwd) and 5′-TGTGATCCGATTCACTGCCA-3′ (exon 15 rev), which were used to amplify cDNA of mRNA extracted from subjects’ and parents’ leukocytes. (B) Pedigrees of subjects BAB4073 and BAB5264 and available parents for RNA isolation. Agarose gel shows a 343-bp RT-PCR band, which was amplified with primers 5′-TGCTACTACGTCTTCGGGGA-3′ (exon 13 fwd) and 5′-TGTGATCCGATTCACTGCCA-3′ (exon 15 rev); below, electropherograms display sequencing results of amplified cDNA. Affected individuals harbor frameshift mutations identical to the genomic mutations identified. The variants are present in the cDNA of affected individuals but are not present in unaffected parents. (C) Levels of DVL1 expression in leukocytes were measured by qPCR with TaqMan probes Hs00182896_m1 and Hs00737028_m1. For evaluating relative expression of DVL1, the ΔΔCT method was used with TBP as the endogenous control and one unaffected parent per family as the relative control. This experiment was replicated once and showed similar results. The American Journal of Human Genetics 2015 96, 612-622DOI: (10.1016/j.ajhg.2015.02.015) Copyright © 2015 The American Society of Human Genetics Terms and Conditions