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

Slides:

Advertisements

Similar presentations

Volume 1, Issue 4, Pages (March 1998)

Advertisements

Identification of EpCAM as the Gene for Congenital Tufting Enteropathy

Homozygosity Mapping Reveals Mutations of GRXCR1 as a Cause of Autosomal- Recessive Nonsyndromic Hearing Impairment Margit Schraders, Kwanghyuk Lee, Jaap.

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

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

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

A Member of a Gene Family on Xp22

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

Homozygous Deletion of the Very Low Density Lipoprotein Receptor Gene Causes Autosomal Recessive Cerebellar Hypoplasia with Cerebral Gyral Simplification

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

Functional Null Mutations of MSRB3 Encoding Methionine Sulfoxide Reductase Are Associated with Human Deafness DFNB74 Zubair M. Ahmed, Rizwan Yousaf,

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.

Syndromic Short Stature in Patients with a Germline Mutation in the LIM Homeobox LHX4 Kalotina Machinis, Jacques Pantel, Irène Netchine, Juliane Léger,

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

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

Volume 54, Issue 3, Pages (September 1998)

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

A Novel Syndrome Combining Thyroid and Neurological Abnormalities Is Associated with Mutations in a Monocarboxylate Transporter Gene Alexandra M. Dumitrescu,

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,

Volume 1, Issue 4, Pages (March 1998)

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)

Thomas C. Hart, Yingze Zhang, Michael C. Gorry, P

Volume 2, Issue 2, Pages (August 2002)

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

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

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

Familial Syndromic Esophageal Atresia Maps to 2p23-p24

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

Julie M. Schultz, Shaheen N. Khan, Zubair M

Targeted Capture and Next-Generation Sequencing Identifies C9orf75, Encoding Taperin, as the Mutated Gene in Nonsyndromic Deafness DFNB79 Atteeq Ur Rehman,

Genetic studies into inherited and sporadic hemolytic uremic syndrome

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,

Sadaf Naz, Chantal M. Giguere, David C. Kohrman, Kristina L

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

Next-Generation Sequencing Identifies Mutations of SMPX, which Encodes the Small Muscle Protein, X-Linked, as a Cause of Progressive Hearing Impairment

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)

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

Identification of FOXP2 Truncation as a Novel Cause of Developmental Speech and Language Deficits Kay D. MacDermot, Elena Bonora, Nuala Sykes, Anne-Marie.

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

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 55, Issue 1, Pages (January 1999)

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

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

A Deleterious Mutation in SAMD9 Causes Normophosphatemic Familial Tumoral Calcinosis Orit Topaz, Margarita Indelman, Ilana Chefetz, Dan Geiger, Aryeh.

Atteeq U. Rehman, Regie Lyn P. Santos-Cortez, Robert J

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,

The sh339 and qmc554 alleles of gfi1b.

Volume 93, Issue 1, Pages (April 1998)

Mutations in CHEK2 Associated with Prostate Cancer Risk

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

Genomewide Association Analysis of Human Narcolepsy and a New Resistance Gene Minae Kawashima, Gen Tamiya, Akira Oka, Hirohiko Hohjoh, Takeo Juji, Takashi.

Birt-Hogg-Dubé Syndrome, a Genodermatosis Associated with Spontaneous Pneumothorax and Kidney Neoplasia, Maps to Chromosome 17p11.2 Laura S. Schmidt,

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

Regie Lyn P. Santos-Cortez, Rabia Faridi, Atteeq U

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

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.

Mutations in a Novel Isoform of TRIOBP That Encodes a Filamentous-Actin Binding Protein Are Responsible for DFNB28 Recessive Nonsyndromic Hearing Loss

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,

Presentation transcript:

Mutations in TRIOBP, Which Encodes a Putative Cytoskeletal-Organizing Protein, Are Associated with Nonsyndromic Recessive Deafness Saima Riazuddin, Shaheen N. Khan, Zubair M. Ahmed, Manju Ghosh, Kyle Caution, Sabiha Nazli, Madhulika Kabra, Ahmad U. Zafar, Kevin Chen, Sadaf Naz, Anthony Antonellis, William J. Pavan, Eric D. Green, Edward R. Wilcox, Penelope L. Friedman, Robert J. Morell, Sheikh Riazuddin, Thomas B. Friedman The American Journal of Human Genetics Volume 78, Issue 1, Pages 137-143 (January 2006) DOI: 10.1086/499164 Copyright © 2006 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigrees of 12 consanguineous families from Pakistan and India. Blackened symbols represent individuals with clinically documented congenital deafness. Genotype and haplotype data for families PKDF262 and DKB-01 are shown. For the chromosome 22q13 locus, the haplotype of affected individual IV:2 of family PKDF262 has a proximal breakpoint at D22S1180. Affected individual IV:1 of family DKB-01 has a distal breakpoint at D22S1181, which refines the smallest linkage interval to 702 kb. However, when TRIOBP mutation–containing families are removed, the minimal deafness-linkage interval is ∼10 cM, defined by two of the remaining families, PKSR19A and PKSR28A, with simulated LOD scores of 3.4 and 3.1, respectively (table 1). The American Journal of Human Genetics 2006 78, 137-143DOI: (10.1086/499164) Copyright © 2006 The American Society of Human Genetics Terms and Conditions

Figure 2 Audiograms of one congenitally deaf individual from each family. The carriers of a mutant allele have normal hearing. The American Journal of Human Genetics 2006 78, 137-143DOI: (10.1086/499164) Copyright © 2006 The American Society of Human Genetics Terms and Conditions

Figure 3 Genetic map of the 22q13 locus defined by proximal and distal meiotic breakpoints in families PKDF262 and DKB-01, respectively. The Marshfield map distance (Mfd) of polymorphic markers is shown (left) (see Center for Medical Genetics, Marshfield Medical Research Foundation Web site). The proximal breakpoint, D22S1180, and the distal breakpoint, D22S1181, are marked with an X on the chromosome. Linked markers are shown as blackened circles on the chromosome. In two affected individuals from at least six of the families, we evaluated the other 28 annotated genes in this interval for mutations but found none. TRIOBP is shown in bold italics. The American Journal of Human Genetics 2006 78, 137-143DOI: (10.1086/499164) Copyright © 2006 The American Society of Human Genetics Terms and Conditions

Figure 4 Structure and mutations of TRIOBP associated with deafness. A, Schematic representation of the genomic structure of isoforms of human TRIOBP and the locations of the mutations in exon 6 associated with deafness. Arrows represent the location of the primers used for RT-PCR. Red dots indicate the site of the mutations in exon 6 of TRIOBP. B, Protein structure of TRIOBP-6. There are five copies each of two different repeated motifs (dark blue and light blue rectangles) that have the amino acid sequences TPCA/I/TQR/WDNPRASSPNRT/ST/AQRDN/SPR and VCIGHRDAPRAS/TS/FPP. C, Mutations of TRIOBP segregating in six families. Electropherograms of amplimers from genomic DNA templates illustrate homozygosity for mutations found in all affected family members and homozygosity for the wild-type allele in an unaffected individual. All obligate carriers are heterozygous (not shown). All of the mutations described here are numbered beginning with +1 at the A base of the translation start codon (ATG) in exon 2 of TRIOBP-6. The stop codons due to nonsense mutations are underlined. The American Journal of Human Genetics 2006 78, 137-143DOI: (10.1086/499164) Copyright © 2006 The American Society of Human Genetics Terms and Conditions

Figure 5 Genomic structure of Triobp mouse isoforms and their expression in various tissues. A, Triobp splice variants. There are at least five different splice variants present in the mouse inner ear, including the previously reported short isoforms (Triobp-1 and Triobp-2). Locations of the primers used for RT-PCR expression profile are shown as arrowheads. B, Predicted protein products of different Triobp splice variants. Triobp-4 does not encode the PH domain and the coiled-coil regions. Triobp-1 encodes only the PH domain and the four coiled-coil domains. C, Expression profiles of Triobp-1, Triobp-3/5, and Triobp-4. PCR primers (table 2), shown as arrowheads in panel A, were designed to amplify each isoform from cDNA prepared from different mouse tissues. Left profile, Triobp-1 is widely expressed, whereas other isoforms have a more limited pattern of expression. Triobp-3 (arrow) is present in the brain, liver (faint band), kidney (faint band), retina (P15), and inner ear (P1–P5). Middle profile,Triobp-5 (arrowhead) is found in mouse embryo cDNA (E11.5), brain, kidney (faint band), retina, pancreas (faint band), and inner ear. Right profile, Triobp-4 seems to be expressed in kidney (faint band), retina, testis (faint band), and inner ear. These transcripts do not provide an exhaustive list of the isoforms of Triobp. A smaller, uncharacterized cDNA is present in many tissues (middle profile). There are 33 inner-ear RIKEN ESTs for Triobp (168–488 bp; not shown). PCR amplification of Actn1 cDNA encoding α-actinin was used as a control for the quality and quantity of RT-PCR templates. The American Journal of Human Genetics 2006 78, 137-143DOI: (10.1086/499164) Copyright © 2006 The American Society of Human Genetics Terms and Conditions