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

Slides:

Advertisements

Similar presentations

Date of download: 6/22/2016 Copyright © The American College of Cardiology. All rights reserved. From: Clinical Features of Hypertrophic Cardiomyopathy.

Advertisements

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

Homozygous Defects in LMNA, Encoding Lamin A/C Nuclear-Envelope Proteins, Cause Autosomal Recessive Axonal Neuropathy in Human (Charcot-Marie-Tooth Disorder.

STEVE S. SOMMER, M.D., Ph.D. Mayo Clinic Proceedings

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

Mutations in the Beta Propeller WDR72 Cause Autosomal-Recessive Hypomaturation Amelogenesis Imperfecta Walid El-Sayed, David A. Parry, Roger C. Shore,

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

Quantitative Analysis of Survival Motor Neuron Copies: Identification of Subtle SMN1 Mutations in Patients with Spinal Muscular Atrophy, Genotype-Phenotype.

Volume 63, Issue 1, Pages (January 2003)

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

Andrea Gaedigk, Amanda K. Riffel, J. Steven Leeder

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

Mutations in PADI6 Cause Female Infertility Characterized by Early Embryonic Arrest Yao Xu, Yingli Shi, Jing Fu, Min Yu, Ruizhi Feng, Qing Sang, Bo Liang,

Severe Palmo-Plantar Hyperkeratosis in Dowling–Meara Epidermolysis Bullosa Simplex Caused by a Mutation in the Keratin 14 Gene (KRT14) Carrie S. Shemanko

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

Volume 54, Issue 3, Pages (September 1998)

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

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

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

Peter Ianakiev, Michael W

Haplotype-Sharing Analysis Implicates Chromosome 7q36 Harboring DPP6 in Familial Idiopathic Ventricular Fibrillation Marielle Alders, Tamara T. Koopmann,

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.

Genotype/Phenotype Analysis of a Photoreceptor-Specific ATP-Binding Cassette Transporter Gene, ABCR, in Stargardt Disease Richard Alan Lewis, Noah F.

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

Identification of a Genetic Locus for Ichthyosis Vulgaris on Chromosome 10q22.3– q24.2 Ping Liu, Qingyu Yang, Xu Wang, Aiping Feng, Tao Yang, Rong Yang,

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

Homozygous and heterozygous Arg614Cys mutations (1840C→T) in the ryanodine receptor gene co-segregate with malignant hyperthermia susceptibility in a.

A Kerato-Epithelin (βig-h3) Mutation in Lattice Corneal Dystrophy Type IIIA Shuji Yamamoto, Masaki Okada, Motokazu Tsujikawa, Yoshikazu Shimomura, Kohji.

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

J. H. D. Bassett, S. A. Forbes, A. A. J. Pannett, S. E. Lloyd, P. T

A Presenilin-1 Truncating Mutation Is Present in Two Cases with Autopsy-Confirmed Early-Onset Alzheimer Disease Carolyn Tysoe, Joanne Whittaker, John.

Volume 63, Issue 1, Pages (January 2003)

A Mutation Hot Spot for Nonspecific X-Linked Mental Retardation in the MECP2 Gene Causes the PPM-X Syndrome Sabine M. Klauck, Susan Lindsay, Kim S. Beyer,

Volume 6, Issue 6, Pages (June 1996)

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

Mutations of the Ephrin-B1 Gene Cause Craniofrontonasal Syndrome

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

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,

Lack of EVER2 Protein in Two Epidermodysplasia Verruciformis Patients with Skin Cancer Presenting Previously Unreported Homozygous Genetic Deletions in.

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

Volume 58, Issue 2, Pages (August 2000)

Systematic Analysis of Molecular Defects in the Ferrochelatase Gene from Patients with Erythropoietic Protoporphyria U.B. Rüfenacht, L. Gouya, X. Schneider-Yin,

Relationship between CFTR and CTRC Variants and the Clinical Phenotype in Late- Onset Cystic Fibrosis Disease with Chronic Pancreatitis Anna C. Tomaiuolo,

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

Gabriella Esposito, Giuseppe Rescigno, Francesco Salvatore

Recurrence of the T666M Calcium Channel CACNA1A Gene Mutation in Familial Hemiplegic Migraine with Progressive Cerebellar Ataxia A. Ducros, C. Denier,

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

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,

Infantile Alexander Disease: Spectrum of GFAP Mutations and Genotype-Phenotype Correlation Diana Rodriguez, Fernande Gauthier, Enrico Bertini, Marianna.

Identification of Recurrent Mutations in the ARS (Component B) Gene Encoding SLURP-1 in Two Families with Mal de Meleda Kimberley Morine Ward, Jülide.

Volume 71, Issue 6, Pages (March 2007)

Arun Kumar, Satish C. Girimaji, Mahesh R. Duvvari, Susan H. Blanton

Volume 93, Issue 1, Pages (April 1998)

Volume 57, Issue 1, Pages (January 2000)

Mutations in CHEK2 Associated with Prostate Cancer Risk

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

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

Is Screening of the Candidate Gene Necessary in Unrelated Partners of Members of Families with Herlitz Junctional Epidermolysis Bullosa? Alfred Klausegger,

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

Quantitative Analysis of Survival Motor Neuron Copies: Identification of Subtle SMN1 Mutations in Patients with Spinal Muscular Atrophy, Genotype-Phenotype.

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:

Early Onset of Severe Familial Amyotrophic Lateral Sclerosis with a SOD-1 Mutation: Potential Impact of CNTF as a Candidate Modifier Gene Ralf Giess, Bettina Holtmann, Massimiliano Braga, Tiemo Grimm, Bertram Müller-Myhsok, Klaus V. Toyka, Michael Sendtner The American Journal of Human Genetics Volume 70, Issue 5, Pages 1277-1286 (May 2002) DOI: 10.1086/340427 Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 1 Characterization of mutations in the genes that encode SOD-1 and CNTF in a family with autosomal dominant ALS. A, Family pedigree with FALS. Squares denote male family members, circles denote female family members, black symbols denote affected family members, gray symbols denote affected members who are possibly affected on the basis on family history, and slash marks (/) through symbols denote deceased family members. The arrow indicates the 25-year-old male index patient who carried both a V148G mutation in SOD-1 and a null mutation in CNTF. B, Heterozygous T→G transition at position 1513 within exon 5 of the SOD-1 gene in genotyped family members. Arrows indicate the T→G transition in family members III.4, IV.3, and IV.4, as revealed by automated DNA sequencing of the PCR product of exon 5 of the SOD-1 gene. Family members III.3, III.5, IV.1, and IV.2 do not show the T→G transition. The large arrow indicates index patient IV.4. C, CNTF genotyping in family members. Demonstration of the G→A transition within the intron-exon boundary of the second exon of the CNTF gene, leading to a truncated, biologically inactive CNTF protein. CNTF+/+ (i.e., no mutation) was found in subjects IV.2 and IV.3; CNTF+/− (i.e., a heterozygous G→A transition) was found in subjects III.3, III.4, III.5, and IV.1; and CNTF−/− (i.e., a homozygous G→A transition) was found in index patient IV.4. D, Identification of the CNTF null mutation by HaeIII-restriction-polymorphism analysis of PCR-amplified genomic DNA. The three different genotypes were identified by characteristic digestion patterns: CNTF+/+ showed two bands of 94 and 40 bp (in subjects IV.2 and IV.3); CNTF+/− showed three bands of 134, 94, and 40 bp (in subjects III.3, III.4, III.5, and IV.1); and CNTF−/− showed one band of 134 bp (in index patient IV.4). “M” denotes the Phi-x-174/HaeIII marker. The American Journal of Human Genetics 2002 70, 1277-1286DOI: (10.1086/340427) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 2 Motoneuron disease in mice with combined CNTF and SOD-1 gene defects. A, CNTF genotyping of mice. Ethidium bromide–stained 2% agarose gel reveals bands of 97 bp for the wild-type allele (CNTF+/+) and 1.197 bp for the mutated allele (CNTF−/−). Heterozygous mice (CNTF+/−) show both bands. “M” denotes the Phi-x-174/HaeIII marker. B, Automated DNA sequencing of PCR products of exon 4 of the human SOD-1 gene, showing either the wild-type sequence of the human SOD-1 gene in transgenic hSOD-1wt mice (arrow) or the guanine→cytosine transition at position 1087 (arrow) that leads to an amino acid exchange from glycine to alanine at position 93 of the SOD-1 protein in transgenic hSOD-1 G93A mice. C, Kaplan-Meier curves, showing survival of hSOD-1G93A/CNTF+/+(n=25), hSOD-1G93A/CNTF+/− (n=24), and hSOD-1G93A/CNTF−/− mice (n=32) (P<.001 by log-rank test). D and E, Motoneuron numbers in lumbar spinal cord and facial nuclei. Values shown are mean ± SD of motoneuron numbers in lumbar spinal cord (L1–L5; D) and facial nuclei (E) corrected for split nuclei as described (Oppenheim et al. 2001). The differences between the four groups of mice were tested by one-way ANOVA; at the levels for which P<.0001, differences were significant. D, Motoneuron counts of the lumbar spinal cord. Comparison of individual groups by Bonferroni's multiple-comparison test gave the following results: P<.01 (**) and P<.001 (***). E, Motoneuron counts of the facial nucleus. Comparison of individual groups by Bonferroni's multiple comparison test gave the following results: P<.05 (*), P<.01 (**), and P<.001 (***). F–I, Morphology of degenerating motoneurons in the lumbar spinal cord of mice with combined SOD-1 and CNTF gene mutations. In hSOD-1wt/CNTF+/+ mice (F), the spinal cord appeared to be histologically normal. In hSOD-1wt/CNTF−/− (G) and hSOD-1G93A/CNTF+/+ (H) mice, evident reduction in motoneuron number is detectable. In mice carrying the double mutation, hSOD-1G93A/CNTF−/− (I), the spinal cord appeared to be nearly void of motoneurons. The more severe reduction in motoneuron number of the spinal cord compared to the facial nucleus and the obvious gliosis suggests a caudorostral progression of the disorder, confirming the clinical phenotype. Bar = 50 μm. The American Journal of Human Genetics 2002 70, 1277-1286DOI: (10.1086/340427) Copyright © 2002 The American Society of Human Genetics Terms and Conditions