A Recurrent RNA-Splicing Mutation in the SEDL Gene Causes X-Linked Spondyloepiphyseal Dysplasia Tarda George E. Tiller, Vickie L. Hannig, Damon Dozier,

Slides:

Advertisements

Similar presentations

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

Advertisements

Alternative Splicing of a Novel Glycophorin Allele GPHe(GL) Generates Two Protein Isoforms in the Human Erythrocyte Membrane by Cheng-Han Huang, Olga O.

Betaine, Dimethyl Sulfoxide, and 7-Deaza-dGTP, a Powerful Mixture for Amplification of GC-Rich DNA Sequences Marco Musso, Renata Bocciardi, Sara Parodi,

Yanggu Shi, Sharon F. Terry, Patrick F. Terry, Lionel G

Splicing defects in the CFTR gene: Minigene analysis of two mutations, G>C and A>G Gwendal Dujardin, Diane Commandeur, Catherine Le Jossic-Corcos,

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

Mutations in the Liver Glycogen Phosphorylase Gene (PYGL) Underlying Glycogenosis Type VI (Hers Disease) Barbara Burwinkel, Henk D. Bakker, Eliezer Herschkovitz,

Combination of a Novel Frameshift Mutation (1929delCA) and a Recurrent Nonsense Mutation (W610X) of the LAMB3 Gene in a Japanese Patient with Herlitz.

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

A novel mutation of HFE explains the classical phenotype of genetic hemochromatosis in a C282Y heterozygote Daniel F. Wallace, James S. Dooley, Ann P.

Thomas W. Prior, Scott J. Bridgeman

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

Toward a Survey of Somatic Mutation of the NF1 Gene in Benign Neurofibromas of Patients with Neurofibromatosis Type 1 Ingrid Eisenbarth, Kim Beyer, Winfrid.

A Comparative Study of Fibrous Dysplasia and Osteofibrous Dysplasia with Regard to GSα Mutation at the Arg201 Codon Akio Sakamoto, Yoshinao Oda, Yukihide.

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

Kimberly A. Aldinger, Stephen J. Mosca, Martine Tétreault, Jennifer C

T. Ohta, K. Buiting, H. Kokkonen, S. McCandless, S. Heeger, H

Autosomal-Recessive Congenital Cerebellar Ataxia Is Caused by Mutations in Metabotropic Glutamate Receptor 1 Velina Guergueltcheva, Dimitar N. Azmanov,

Volume 54, Issue 3, Pages (September 1998)

Investigation of the human stem cell factor KIT ligand gene, KITLG, in women with 46,XX spontaneous premature ovarian failure Emily S. Hui, B.A., Ekemini.

Analysis of an exon 1 polymorphism of the B2 bradykinin receptor gene and its transcript in normal subjects and patients with C1 inhibitor deficiency

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

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

A Synonymous Mutation in the CFTR Gene Causes Aberrant Splicing in an Italian Patient Affected by a Mild Form of Cystic Fibrosis Valeria Faa′, Alessandra.

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

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)

Survival of Male Patients with Incontinentia Pigmenti Carrying a Lethal Mutation Can Be Explained by Somatic Mosaicism or Klinefelter Syndrome The.

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

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

Volume 2, Issue 2, Pages (August 1998)

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.

Michaela Floeth, Leena Bruckner-Tuderman

The role of sequence variations within the genes encoding collagen II, IX and XI in non- syndromic, early-onset osteoarthritis E. Jakkula, M.D., M. Melkoniemi,

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

A Novel Point Mutation Affecting the Tyrosine Kinase Domain of the TRKA Gene in a Family with Congenital Insensitivity to Pain with Anhidrosis Shinichi.

A Recurrent Expansion of a Maternal Allele with 36 CAG Repeats Causes Huntington Disease in Two Sisters Franco Laccone, Wilhelm Christian The American.

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

Novel Polymorphism in the FMR1 Gene Resulting in a “Pseudodeletion” of FMR1 in a Commonly Used Fragile X Assay Thomas M. Daly, Arash Rafii, Rick A. Martin,

Null Alleles of the COL5A1 Gene of Type V Collagen Are a Cause of the Classical Forms of Ehlers-Danlos Syndrome (Types I and II) Ulrike Schwarze, Mary.

Volume 54, Issue 1, Pages (July 1998)

Dominique J. Verlaan, Adrian M. Siegel, Guy A. Rouleau

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.

Imprinting of Human GRB10 and Its Mutations in Two Patients with Russell-Silver Syndrome Hiroshi Yoshihashi, Katsuhiro Maeyama, Rika Kosaki, Tsutomu.

SLC7A9 mutations in all three cystinuria subtypes

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.

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

Mutation Analysis of the Entire PKD1 Gene: Genetic and Diagnostic Implications Sandro Rossetti, Lana Strmecki, Vicki Gamble, Sarah Burton, Vicky Sneddon,

Wook Lew Journal of Investigative Dermatology

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

The 97 kDa Linear IgA Bullous Dermatosis Antigen is not Expressed in a Patient with Generalized Atrophic Benign Epidermolysis Bullosa with a Novel Homozygous.

Anthony M. Raizis, Martin M. Ferguson, David T. Nicholls, Derek W

Early Onset of Severe Familial Amyotrophic Lateral Sclerosis with a SOD-1 Mutation: Potential Impact of CNTF as a Candidate Modifier Gene Ralf Giess,

A Second Leaky Splice-Site Mutation in the Spastin Gene

Mutations in CHEK2 Associated with Prostate Cancer Risk

Identification and Characterization of a Mutation, in the Human UDP-Galactose-4- Epimerase Gene, Associated with Generalized Epimerase-Deficiency Galactosemia

Contiguous Deletion of the X-Linked Adrenoleukodystrophy Gene (ABCD1) and DXS1357E: A Novel Neonatal Phenotype Similar to Peroxisomal Biogenesis Disorders

Polymorphic X-Chromosome Inactivation of the Human TIMP1 Gene

Kit-Sing Au, Adelaide A. Hebert, E. Steve Roach, Hope Northrup

Richard J. Wenstrup, Jane B. Florer, Marcia C

Loss-of-Function Mutations in a Human Gene Related to Chlamydomonas reinhardtii Dynein IC78 Result in Primary Ciliary Dyskinesia Gaëlle Pennarun, Estelle.

Marshall Syndrome Associated with a Splicing Defect at the COL11A1 Locus Andrew J. Griffith, Leslie K. Sprunger, D. Alexa Sirko-Osadsa, George E. Tiller,

Familial Porphyria Cutanea Tarda: Characterization of Seven Novel Uroporphyrinogen Decarboxylase Mutations and Frequency of Common Hemochromatosis Alleles

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,

Identification of Novel pro-α2(IX) Collagen Gene Mutations in Two Families with Distinctive Oligo-Epiphyseal Forms of Multiple Epiphyseal Dysplasia Paul.

Presentation transcript:

A Recurrent RNA-Splicing Mutation in the SEDL Gene Causes X-Linked Spondyloepiphyseal Dysplasia Tarda George E. Tiller, Vickie L. Hannig, Damon Dozier, Laura Carrel, Karrie C. Trevarthen, William R. Wilcox, Stefan Mundlos, Jonathan L. Haines, Agi K. Gedeon, Jozef Gecz The American Journal of Human Genetics Volume 68, Issue 6, Pages 1398-1407 (June 2001) DOI: 10.1086/320594 Copyright © 2001 The American Society of Human Genetics Terms and Conditions

Figure 1 Abbreviated pedigree of a North American family with SEDL. Plus signs (+) indicate genotyped individuals; arrow indicates proband (V:1); question marks (?) indicate questionable clinical status. The American Journal of Human Genetics 2001 68, 1398-1407DOI: (10.1086/320594) Copyright © 2001 The American Society of Human Genetics Terms and Conditions

Figure 2 Radiographs of the lateral spine (left) and pelvis (right) of a 31-year-old man (IV:8 in fig. 1) with SEDL. Note platyspondyly and superior and inferior humping of vertebrae, as well as irregular hip-joint surfaces and short femoral necks. The American Journal of Human Genetics 2001 68, 1398-1407DOI: (10.1086/320594) Copyright © 2001 The American Society of Human Genetics Terms and Conditions

Figure 3 Articular cartilage ultrastructure from the femoral head of a 50-year-old man with SEDL (IV:15 in fig. 1) and a 50-year-old patient with idiopathic osteoarthritis. a, SEDL chondrocyte with dilated rER. Arrows indicate rER, and n indicates nucleus (original magnification, 8,140×). b, Chondrocyte from a 50-year-old man with osteoarthritis (original magnification, 8,140×). Note normal nuclear:cytoplasmic ratio and absence of dilated rER. c, SEDL chondrocyte cytoplasm. The abundant Golgi complexes are indicated by g, and dilated loops of rER are indicated by arrows (original magnification, 23,830×). d, SEDL extracellular matrix. Arrows indicate collagen fibrils that are short and frayed, and arrowheads indicate fibrils of variable diameter (original magnification, 23,830×). The American Journal of Human Genetics 2001 68, 1398-1407DOI: (10.1086/320594) Copyright © 2001 The American Society of Human Genetics Terms and Conditions

Figure 4 Splice mutation in SEDL. a, PCR amplification of a fragment of the SEDL gene spanning the exon 3/intron 3 junction. The mutant allele contains a +5G→A transition at the intron 3 splice-donor site, which disrupts a MaeII restriction site. The proband of family 1 is the affected man in the third generation of the pedigree as drawn. b, Sequencing of cDNA from a lymphoblastoid cell line from the proband of family 1. Sequencing reveals two transcripts (each missing exon 3, which contains the translational start site). The American Journal of Human Genetics 2001 68, 1398-1407DOI: (10.1086/320594) Copyright © 2001 The American Society of Human Genetics Terms and Conditions

Figure 5 Expression of genes from active or inactive X-containing hybrids. cDNA from mouse/human somatic-cell hybrids that retained either the human active (Xa) or inactive (Xi) X chromosome was amplified with gene-specific primers. A negative image of ethidium bromide–stained products separated by agarose gel electrophoresis is shown. Lanes contain human female cell line (lane 1); mouse tsA1S9az31b cell line (lane 2); t60-12 (lane 3); Aha11aB1 (lane 4); t86-B1maz1b-3a (lane 5); t11-4Aaz5 (lane 6); t75-2maz34-4a (lane 7); t48-1a-Daz4a (lane 8); LT23-1E2Buv5Cl26-7A2 (lane 9); L23-4B (lane 10); t51-S2 (lane 11); tHM-1a (lane 12); tHM-1d (lane 13); A23-1aCl5 (lane 14); genomic DNA from a somatic-cell hybrid cell line retaining human chromosome 19 (lane 15). PCR products in all lanes have been digested with BsaJ1 to distinguish SEDL product from pseudogene SEDLP product, since only the latter is cleaved by BsaJ1. Control transcripts A007K03 (which is subject to inactivation) and MIC2 (which escapes inactivation) demonstrate the inactivation status for each hybrid shown. The American Journal of Human Genetics 2001 68, 1398-1407DOI: (10.1086/320594) Copyright © 2001 The American Society of Human Genetics Terms and Conditions