Alopecia, Neurological Defects, and Endocrinopathy Syndrome Caused by Decreased Expression of RBM28, a Nucleolar Protein Associated with Ribosome Biogenesis

Slides:

Advertisements

Similar presentations

Myopodin, a Synaptopodin Homologue, Is Frequently Deleted in Invasive Prostate Cancers Fan Lin, Yan-Ping Yu, Jeff Woods, Kathleen Cieply, Bill Gooding,

Advertisements

Identification of a Novel Locus Associated with Congenital Recessive Ichthyosis on 12p11.2–q13 Mordechai Mizrachi-Koren, Dan Geiger, Margarita Indelman,

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

Cyclic Alopecia and Abnormal Epidermal Cornification in Zdhhc13-Deficient Mice Reveal the Importance of Palmitoylation in Hair and Skin Differentiation

Skin-Specific Expression of ank-393, a Novel Ankyrin-3 Splice Variant

Familial Pityriasis Rubra Pilaris Is Caused by Mutations in CARD14

A Nonsense Mutation in the Human Homolog of Drosophila rogdi Causes Kohlschutter– Tonz Syndrome Adi Mory, Efrat Dagan, Barbara Illi, Philippe Duquesnoy,

RIN2 Deficiency Results in Macrocephaly, Alopecia, Cutis Laxa, and Scoliosis: MACS Syndrome Lina Basel-Vanagaite, Ofer Sarig, Dov Hershkovitz, Dana Fuchs-Telem,

Human Skin is a Steroidogenic Tissue: Steroidogenic Enzymes and Cofactors Are Expressed in Epidermis, Normal Sebocytes, and an Immortalized Sebocyte Cell.

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

John E. Olerud, Diane S. Chiu, Marcia L. Usui

Volume 141, Issue 3, Pages (September 2011)

Hannah Mandel, Revital Shemer, Zvi U

Abraham Zlotogorski Journal of Investigative Dermatology

Olmsted Syndrome Caused by a Homozygous Recessive Mutation in TRPV3

Vitali Alexeev, Kyonggeun Yoon Journal of Investigative Dermatology

A Missense Mutation in CDH3, Encoding P-Cadherin, Causes Hypotrichosis with Juvenile Macular Dystrophy Margarita Indelman, Reuven Bergman, Danny Petronius,

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

Rose-Anne Romano, Barbara Birkaya, Satrajit Sinha

Protease-Activated Receptor-2 (PAR-2) Expression in Human Fibroblasts is Regulated by Growth Factors and Extracellular Matrix Barry L. Gruber, Mary J.

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

Olmsted Syndrome Caused by a Homozygous Recessive Mutation in TRPV3

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

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

Volume 141, Issue 3, Pages (September 2011)

A Mutation in SNAP29, Coding for a SNARE Protein Involved in Intracellular Trafficking, Causes a Novel Neurocutaneous Syndrome Characterized by Cerebral.

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

Volume 10, Issue 8, Pages (April 2000)

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

Refined Mapping of Naegeli–Franceschetti– Jadassohn Syndrome to a 6 cM Interval on Chromosome 17q11.2-q21 and Investigation of Candidate Genes Eli Sprecher,

Margarita Indelman, Reuven Bergman, Michal Ramon, Eli Sprecher

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

Semidominant Inheritance in Epidermolytic Ichthyosis

Clinical, Molecular, and Cellular Features of Non-Puerto Rican Hermansky–Pudlak Syndrome Patients of Hispanic Descent Carmelo Carmona-Rivera, Gretchen.

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

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.

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

Autosomal Recessive Hypotrichosis with Woolly Hair Caused by a Mutation in the Keratin 25 Gene Expressed in Hair Follicles Nikolay V. Zernov, Mikhail.

Christina A. Gurnett, Farhang Alaee, Lisa M. Kruse, David M

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

Abnormal development of glomerular endothelial and mesangial cells in mice with targeted disruption of the lama3 gene C.K. Abrass, A.K. Berfield, M.C.

M. Bamshad, T. Le, W. S. Watkins, M. E. Dixon, B. E. Kramer, A. D

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

Insulin-Like Growth Factor-Binding Protein 7 Regulates Keratinocyte Proliferation, Differentiation and Apoptosis Janna Nousbeck, Ofer Sarig, Nili Avidan,

An mtDNA Mutation in the Initiation Codon of the Cytochrome C Oxidase Subunit II Gene Results in Lower Levels of the Protein and a Mitochondrial Encephalomyopathy

Increased Expression of Wnt2 and SFRP4 in Tsk Mouse Skin: Role of Wnt Signaling in Altered Dermal Fibrillin Deposition and Systemic Sclerosis Julie Bayle,

Characterization of New Members of the Human Type II Keratin Gene Family and a General Evaluation of the Keratin Gene Domain on Chromosome 12q13.13 Michael.

Mutations in the Gene Encoding Gap Junction Protein α12 (Connexin 46

Volume 58, Issue 2, Pages (August 2000)

Overexpression of Fetuin-A Counteracts Ectopic Mineralization in a Mouse Model of Pseudoxanthoma Elasticum (Abcc6−/−) Qiujie Jiang, Florian Dibra, Michael.

Mutations in the Gene Encoding Gap Junction Protein α12 (Connexin 46

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

A Novel Gene Expressed in Human Keratinocytes with Long-Term In Vitro Growth Potential is Required for Cell Growth Laure Aurelian, Cynthia C. Smith,

Normophosphatemic Familial Tumoral Calcinosis Is Caused by Deleterious Mutations in SAMD9, Encoding a TNF-α Responsive Protein Ilana Chefetz, Danny Ben.

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

Volume 6, Issue 3, Pages (September 2002)

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

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

ADAMTS10 Mutations in Autosomal Recessive Weill-Marchesani Syndrome

Volume 63, Issue 6, Pages (June 2003)

Mutations in NEXN, a Z-Disc Gene, Are Associated with Hypertrophic Cardiomyopathy Hu Wang, Zhaohui Li, Jizheng Wang, Kai Sun, Qiqiong Cui, Lei Song, Yubao.

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

Ciliary Abnormalities Due to Defects in the Retrograde Transport Protein DYNC2H1 in Short-Rib Polydactyly Syndrome Amy E. Merrill, Barry Merriman, Claire.

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

Hermansky-Pudlak Syndrome Type 3 in Ashkenazi Jews and Other Non–Puerto Rican Patients with Hypopigmentation and Platelet Storage-Pool Deficiency Marjan.

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,

Novel Mutations in the LAMB3 Gene Shared by Two Japanese Unrelated Families with Herlitz Junctional Epidermolysis Bullosa, and Their Application for Prenatal.

Targeting expression of a transgene to the airway surface epithelium using a ciliated cell-specific promoter Lawrence E Ostrowski, James R Hutchins,

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

Presentation transcript:

Alopecia, Neurological Defects, and Endocrinopathy Syndrome Caused by Decreased Expression of RBM28, a Nucleolar Protein Associated with Ribosome Biogenesis Janna Nousbeck, Ronen Spiegel, Akemi Ishida-Yamamoto, Margarita Indelman, Ayelet Shani-Adir, Noam Adir, Ehud Lipkin, Sivan Bercovici, Dan Geiger, Maurice A. van Steensel, Peter M. Steijlen, Reuven Bergman, Albrecht Bindereif, Mordechai Choder, Stavit Shalev, Eli Sprecher The American Journal of Human Genetics Volume 82, Issue 5, Pages 1114-1121 (May 2008) DOI: 10.1016/j.ajhg.2008.03.014 Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 1 Clinical Features of ANE Syndrome Patients display varying patterns of alopecia including (A) alopecia universalis, (B) hypotrichosis, (C) near-normal scalp hair associated with absence of body and (D) axillary hair; additional features include (E) gynecomastia, (F) flexural reticulate hyperpigmentation and (G) hypodontia and tooth malplacement; (H) cerebral MRI (T1 weighted after gadolinium injection) shows normal hypothalamus, hypoplastic thin anterior pituitary gland at the bottom of the sella turcica (thick arrow), and ectopic posterior pituitary hyperintense signal located at a proximal level of the pituitary stalk (thin arrow); (I) a skin biopsy obtained from patient scalp reveals absence of mature hair follicles, and instead, presence of dermal cysts (Cy) as well as elongated vertically oriented epithelial structures associated with sebaceous glands, corresponding to rudimentary hair follicles (Rhf). The American Journal of Human Genetics 2008 82, 1114-1121DOI: (10.1016/j.ajhg.2008.03.014) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 2 Genetic Mapping of ANE Syndrome (A) Multipoint LOD score analysis in ANE syndrome. The LOD scores are plotted against the physical distances separating the markers assessed. (B) Haplotype analysis of the ANE family with polymorphic markers on chromosome 7q31.32-7q32 reveals a homozygous haplotype shared by all patients (boxed in red). The American Journal of Human Genetics 2008 82, 1114-1121DOI: (10.1016/j.ajhg.2008.03.014) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 3 Mutation Analysis (A) Sequence analysis of RBM28 reveals a homozygous T→C transition at cDNA position 1052 of the RBM28 gene (red arrow, upper panel). The wild-type sequence is given for comparison (lower panel). (B) PCR-RFLP analysis confirms segregation of the mutation in the family. PCR amplification was performed as described in the text. Mutation c.T1052C creates a recognition site for BSAJI. Thus, affected patients display two 127 bp and 132 bp fragments (appearing as one band) and healthy individuals show a 257 bp fragment only, whereas all fragments are found in heterozygous carriers of the mutation. The American Journal of Human Genetics 2008 82, 1114-1121DOI: (10.1016/j.ajhg.2008.03.014) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 4 Tissue Expression of RBM28 RBM28 gene expression was assessed with Clontech tissue blot cDNA array. The tissue used in each lane is as follows: lane 1, trachea; lane 2, thymus; lane 3, thyroid; lane 4, testes; lane 5, spleen; lane 6, muscle; lane 7, small intestine; lane 8, prostate; lane 9, heart; lane 10, ovary; lane 11, cervix; lane 12, bladder; lane 13, colon; lane 14, brain; lane 15, lungs; lane 16, liver; lane 17, kidney; lane 18, esophagus; lane 19, adipose tissue; and lane 20, placenta. Expression of RBM28 was compared to that of ACTB. The American Journal of Human Genetics 2008 82, 1114-1121DOI: (10.1016/j.ajhg.2008.03.014) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 5 Consequences of p.L351P Mutation in RBM28 (A) ClustalW analysis of the RBM28 protein region encompassing the mutation site demonstrates that L351 (boxed in red) is conserved across species. (B) The sequence of the N-terminal part of RBM28 was modeled with the Phyre homology recognition engine server with the crystal structure of the N-terminal region of the yeast RNA splicing factor Prp2426 (PDB code 2GHP). Four hundred and twenty residues could be modeled in this fashion with an extremely high degree of confidence (E = 10−24). The Prp24 structure includes three RNA recognition motifs (RRM), consisting of a four-stranded β sheet flanked by two α helices. Wild-type L351 (white ellipse, left panel) is located on the C-terminal end of helix 1 of RRM3 and is expected to destabilize the protein α-helix 1 when mutated to proline (white ellipse, right panel). (C) Protein was extracted from fibroblast cell cultures established from two ANE patients (P1 and P2) and a control healthy individual (C) and immunoblotted against anti-RBM28 antibodies. Membranes were reblotted with anti-β-actin antibodies to control for protein loading. (D) Cultured fibroblasts obtained from a patient (lower panel) and a control individual (upper panel) were stained with an anti-RBM28 antibody (green) and propidium iodide (red) and were examined with confocal microscopy. Merged images are presented. Note increased focal expression of RBM28 in the nucleus of control cells and markedly decreased expression of the protein in patient cells. (E) Skin-biopsy sections obtained from a patient (right panel) and a control individual (left panel) were stained with antibodies directed against RBM28. Immunostaining is markedly decreased in the skin of the patient as compared with control skin (original magnification, 400×). The American Journal of Human Genetics 2008 82, 1114-1121DOI: (10.1016/j.ajhg.2008.03.014) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 6 Ultrastructural Abnormalities Associated with RBM28 Deficiency (A) Transmission electron microscopy (TEM) of cultured fibroblasts in a patient (right panels) and a healthy control individual (left panels) revealed dilated cisterns of the rough endoplasmic reticulum (RER, upper panels) and decreased number of free ribosomes (red circles, lower panels) in the patient cells. The rectangles in the upper panels correspond to the magnified electron micrographs shown in the lower panels. (B) Free cytoplasmic ribosomes were counted at a TEM magnification of 40000× in control and patient fibroblasts in six independent samples (>1500 ribosomes counted in each group). Results are given as number of free ribosomes per μm2 ± SE. Statistical differences were assessed with a paired Student's t test. The American Journal of Human Genetics 2008 82, 1114-1121DOI: (10.1016/j.ajhg.2008.03.014) Copyright © 2008 The American Society of Human Genetics Terms and Conditions