Dominant Mutation of CCDC78 in a Unique Congenital Myopathy with Prominent Internal Nuclei and Atypical Cores Karen Majczenko, Ann E. Davidson, Sandra.

Slides:

Advertisements

Similar presentations

ABCB6 Mutations Cause Ocular Coloboma

Advertisements

Epidermolysis Bullosa: Novel and De Novo Premature Termination Codon and Deletion Mutations in the Plectin Gene Predict Late-Onset Muscular Dystrophy

Identification of EpCAM as the Gene for Congenital Tufting Enteropathy

Mutations in CDC14A, Encoding a Protein Phosphatase Involved in Hair Cell Ciliogenesis, Cause Autosomal-Recessive Severe to Profound Deafness Sedigheh.

Familial Pityriasis Rubra Pilaris Is Caused by Mutations in CARD14

Insulin Receptor Splicing Alteration in Myotonic Dystrophy Type 2

Volume 11, Issue 8, Pages (May 2015)

Transient Bullous Dermolysis of the Newborn Associated with Compound Heterozygosity for Recessive and Dominant COL7A1 Mutations Nadja Hammami-Hauasli,

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,

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

Zebrafish as a Model System to Study Skin Biology and Pathology

Disruptive SCYL1 Mutations Underlie a Syndrome Characterized by Recurrent Episodes of Liver Failure, Peripheral Neuropathy, Cerebellar Atrophy, and Ataxia

Undifferentiated Small Round Cell Sarcomas with Rare EWS Gene Fusions

A Truncating Mutation of CEP135 Causes Primary Microcephaly and Disturbed Centrosomal Function Muhammad Sajid Hussain, Shahid Mahmood Baig, Sascha Neumann,

Targeted High-Throughput Sequencing Identifies Mutations in atlastin-1 as a Cause of Hereditary Sensory Neuropathy Type I Christian Guelly, Peng-Peng.

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

Depletion of primary cilia in articular chondrocytes results in reduced Gli3 repressor to activator ratio, increased Hedgehog signaling, and symptoms.

A Novel Alu-Like Element Rearranged in the Dystrophin Gene Causes a Splicing Mutation in a Family with X-Linked Dilated Cardiomyopathy Alessandra Ferlini,

Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy Daniel P.S. Osborn, Heather.

Genomic Amplification of the Human Plakophilin 1 Gene and Detection of a New Mutation in Ectodermal Dysplasia/Skin Fragility Syndrome Neil V. Whittock,

A Nonsense Mutation in DHTKD1 Causes Charcot-Marie-Tooth Disease Type 2 in a Large Chinese Pedigree Wang-yang Xu, Ming-min Gu, Lian-hua Sun, Wen-ting.

Knockdown of Myosin Va Isoforms by RNAi as a Tool to Block Melanosome Transport in Primary Human Melanocytes Mireille Van Gele, Barbara Geusens, Anne-Marie.

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

Exome Sequencing Reveals Mutations in TRPV3 as a Cause of Olmsted Syndrome Zhimiao Lin, Quan Chen, Mingyang Lee, Xu Cao, Jie Zhang, Donglai Ma, Long Chen,

Autosomal-Dominant Microtia Linked to Five Tandem Copies of a Copy-Number- Variable Region at Chromosome 4p16 Irina Balikova, Kevin Martens, Cindy Melotte,

Exome Sequencing and Functional Analysis Identifies BANF1 Mutation as the Cause of a Hereditary Progeroid Syndrome Xose S. Puente, Victor Quesada, Fernando G.

Aoi Nakano, Hajime Nakano, Sal LaForgia, Leena Pulkkinen, Jouni Uitto

Anna M. G. Pasmooij, Hendri H. Pas, Franciska C. L

Zebrafish: A Model System to Study Heritable Skin Diseases

Marie-Thérèse Leccia Journal of Investigative Dermatology

Epidermolysis Bullosa: Novel and De Novo Premature Termination Codon and Deletion Mutations in the Plectin Gene Predict Late-Onset Muscular Dystrophy

Analysis of Rare APC Variants at the mRNA Level

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

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

Anna M. G. Pasmooij, Hendri H. Pas, Franciska C. L

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

Novel SLC39A4 Mutations in Acrodermatitis Enteropathica

Novel Homozygous and Compound Heterozygous COL17A1 Mutations Associated with Junctional Epidermolysis Bullosa Michaela Floeth, Heike Schäcke, Nadja Hammami-Hauasli,

Short Stature, Onychodysplasia, Facial Dysmorphism, and Hypotrichosis Syndrome Is Caused by a POC1A Mutation Ofer Sarig, Sagi Nahum, Debora Rapaport,

Mutations in the ZNF41 Gene Are Associated with Cognitive Deficits: Identification of a New Candidate for X-Linked Mental Retardation Sarah A. Shoichet,

Renata C. Gallagher, Birgit Pils, Mohammed Albalwi, Uta Francke

Rapid Actin-Based Plasticity in Dendritic Spines

ABCB6 Mutations Cause Ocular Coloboma

Local Arrangement of Fibronectin by Myofibroblasts Governs Peripheral Nuclear Positioning in Muscle Cells William Roman, João P. Martins, Edgar R. Gomes

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.

A Heterozygous Truncating Mutation in RRM2B Causes Autosomal-Dominant Progressive External Ophthalmoplegia with Multiple mtDNA Deletions Henna Tyynismaa,

Deletion of the Cytoplasmatic Domain of BP180/Collagen XVII Causes a Phenotype with Predominant Features of Epidermolysis Bullosa Simplex Marcel Huber,

The Chemokine SDF1a Coordinates Tissue Migration through the Spatially Restricted Activation of Cxcr7 and Cxcr4b Guillaume Valentin, Petra Haas, Darren.

Mutation in Exon 1f of PLEC, Leading to Disruption of Plectin Isoform 1f, Causes Autosomal-Recessive Limb-Girdle Muscular Dystrophy Hulya Gundesli, Beril.

Exome Sequencing Identifies Autosomal-Dominant SRP72 Mutations Associated with Familial Aplasia and Myelodysplasia Michael Kirwan, Amanda J. Walne, Vincent.

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

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

Volume 18, Issue 1, Pages (January 2010)

The abcc6a Gene Expression Is Required for Normal Zebrafish Development Qiaoli Li, Sara Sadowski, Michael Frank, Chunli Chai, Andras Váradi, Shiu-Ying.

Ushio Takeda, Atsushi Utani, Jinghai Wu, Hiroshi Shinkai

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

Compound Heterozygosity for Novel Splice Site Mutations in the BPAG2/COL17A1 Gene Underlies Generalized Atrophic Benign Epidermolysis Bullosa Leena Pulkkinen,

Intronic ITGA3 Mutation Impacts Splicing Regulation and Causes Interstitial Lung Disease, Nephrotic Syndrome, and Epidermolysis Bullosa Yinghong He,

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 Second Leaky Splice-Site Mutation in the Spastin Gene

Biljana Ilkovski, Sandra T. Cooper, Kristen Nowak, Monique M

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

Mutations in POFUT1, Encoding Protein O-fucosyltransferase 1, Cause Generalized Dowling-Degos Disease Ming Li, Ruhong Cheng, Jianying Liang, Heng Yan,

Gene Augmentation and Readthrough Rescue Channelopathy in an iPSC-RPE Model of Congenital Blindness Pawan K. Shahi, Dalton Hermans, Divya Sinha, Simran.

A Mutation in LIPN, Encoding Epidermal Lipase N, Causes a Late-Onset Form of Autosomal-Recessive Congenital Ichthyosis Shirli Israeli, Ziyad Khamaysi,

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

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,

Volume 26, Issue 4, Pages (April 2018)

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

Presentation transcript:

Dominant Mutation of CCDC78 in a Unique Congenital Myopathy with Prominent Internal Nuclei and Atypical Cores Karen Majczenko, Ann E. Davidson, Sandra Camelo-Piragua, Pankaj B. Agrawal, Richard A. Manfready, Xingli Li, Sucheta Joshi, Jishu Xu, Weiping Peng, Alan H. Beggs, Jun Z. Li, Margit Burmeister, James J. Dowling The American Journal of Human Genetics Volume 91, Issue 2, Pages 365-371 (August 2012) DOI: 10.1016/j.ajhg.2012.06.012 Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 1 Histopathological Features of a Unique Centronuclear Myopathy with Cores (A) and (B) Hematoxylin and eosin staining highlights mild variation in fiber size (B is a higher magnification). A significant number of fibers have central nuclei (30%). (C) Trichrome shows fibers with irregular central staining (∗). (D) Toluidine blue highlights the marked (>90%) type 1 (dark blue) predominance. (E) and (F) Succinate dehydrogenase (SDH) (E) and combined SDH and cytochrome oxidase (F) reveal type 1 fibers with areas of central pallor. (G) and (H) Positive abnormal immunoreactivity for actin (G) and desmin (H). (I)–(L) Electron microscopy (EM) shows fibers with disorganized sarcomeric architecture (I–L), Z-band streaming (K), and a relative absence of mitochondria within the lesions, with increased accumulation of mitochondria at the periphery (L). Scale bars for EM = 2 μm. The American Journal of Human Genetics 2012 91, 365-371DOI: (10.1016/j.ajhg.2012.06.012) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 2 CCDC78 Mutation in a Family with Autosomal-Dominant Centronuclear Myopathy (A) Pedigree of a family with autosomal-dominant centronuclear myopathy with cores. The index case is indicated with an arrow. Ten individuals (indicated by ∗), including five affected individuals, were clinically evaluated and were part of the linkage analysis. (B) SNP linkage plot showing LOD scores for chromosome 16. (C) Chromatograph from whole-exome sequencing of the index case indicating a heterozygous C>T change at c.68-1 of CCDC78. The sequence is in reverse orientation and is thus a G>A change in the canonical splice-acceptor sequence for intron 1. (D) RT-PCR from lymphoblastoid-cell-derived RNA with the use of CCDC78 exon 1–3-spanning primers. RNA from affected individuals (PT) reveals the presence of a higher molecular weight band (∗∗) that is barely detectable in RNA from unaffected relatives (CTL). (E) Sequencing of the upper (∗∗, top chromatogram) and lower (∗, bottom chromatogram) bands revealed that the upper band contains the entire sequence of intron 1. The reference sequence is listed (in black) below each chromatogram, and confirms that the upper band has intron 1 sequence contiguous with exon 2 sequence. The mutation is detected in the upper band of patient samples only (arrow). (F) Schematic of the exon-intron structure of the first three exons of CCDC78. Control individuals have normal processing of these exons, while affected individuals with the CCDC78 mutation have RNA products that do not remove intron 1. The American Journal of Human Genetics 2012 91, 365-371DOI: (10.1016/j.ajhg.2012.06.012) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 3 Immunolocalization of CCDC78 in Normal and Patient Skeletal Muscle Immunofluorescent analysis of anti-CCDC78 (red) and anti-RyR1 (green) on control (upper panels) and patient (lower panels) skeletal-muscle cryosections. Upper panels (row A): CCDC78 is found localized to the sarcolemmal membrane (arrowheads) and the perinuclear region (∗∗), as well as in a latticework-type pattern within the sarcoplasm (arrow). Costaining with RyR1 reveals that the latticework pattern corresponds to the triad (arrow), which is the intersection of the terminal sarcoplasmic reticulum and the T-tubule. Lower panels (row B): Immunostaining on patient muscle reveals aggregates of both CCDC78 and RyR1 within the sarcoplasm (arrows). The American Journal of Human Genetics 2012 91, 365-371DOI: (10.1016/j.ajhg.2012.06.012) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 4 Morpholino-Mediated Alteration of ccdc78 Intron 1 Splicing Results in Morphological, Behavioral, and Structural Abnormalities (A) RT-PCR on RNA from 3 dpf zebrafish injected with either control morpholino (CTL) or increasing concentrations of ccdc78 morpholino (in mM). RT-PCR with primers from exons 1–3 of ccdc78 demonstrate that the morpholino inhibits proper splicing of intron 1/exon 2. The most prominent change is the presence of a higher molecular band that was confirmed to contain exons 1–3 and all of intron 1 (arrow). RT-PCR with actin primers was done for verification of RNA integrity. (B) ccdc78 morphants are morphologically abnormal, having bent backs and foreshortened tails. (C) ccdc78 morphants had abnormal motor behavior. Depicted is a graph of the touch-evoked escape response (see also Movies S1 and S2). A total of 73.1% ± 3.9% of ccdc78 morphants (as opposed to 10.3% ± 3.5% of control morphants) had an abnormal touch-evoked escape response (n = 9 independently injected clutches, and a minimum of 20 embryos were assessed per clutch). MO, morpholino. (D) Immunostaining was performed on isolated myofibers from 3 dpf control (CTL) and ccdc78 morphants. Left panels show anti-CCDC78 staining. CTL morpholino (MO) myofibers had a staining pattern similar to that seen in human skeletal muscle, with localization to the membrane and the perinuclear region (nuclei in blue), as well as more faintly to the triad. ccdc78 MO myofibers had aberrantly aggregated clusters of CCDC78 (arrowheads). Right panels show anti-RyR1 staining. CTL MO myofibers had a normal pattern of staining, whereas ccdc78 MO myofibers had disorganized areas of RyR1 staining that included small aggregates (arrow). (E) Electron-microscopic analysis of 3 dpf morphant zebrafish. As compared to control muscle fibers (CTL MO, left panel), muscle from ccdc78 morphants had dilated terminal sarcoplasmic reticulum (boxes, middle panel). In addition, whirls of redundant membranes (arrow) and areas of dilated and swollen sarcoplasmic reticulum (∗∗) were frequently seen throughout the skeletal muscle of ccdc78 morphants and were never observed in controls (n = 3 embryos examined). Scale bar for left and center panels: 500 nm. Scale bar for right panel: 2 μm. The American Journal of Human Genetics 2012 91, 365-371DOI: (10.1016/j.ajhg.2012.06.012) Copyright © 2012 The American Society of Human Genetics Terms and Conditions