Myotone Dystrophien – Phänotypen, Pathogenese, Diagnostik und Therapie

2007 ◽  
Vol 26 (01/02) ◽  
pp. 74-78 ◽  
Author(s):  
B. G. H. Schoser
Keyword(s):  
Untranslated Region ◽  
Dystrophia Myotonica ◽  
Intron 1 ◽  
Diagnostik Und Therapie ◽  
Cctg Repeat

ZusammenfassungZwei Formen der myotonen Dystrophie (DM1, DM2) sind bisher beschrieben. 1992 konnte als genetische Ursache der DM1 ein abnorm expandiertes CTG-Triplettrepeat im 3´-UTR (untranslated region) des Dystrophia myotonica Proteinkinasegens (DMPK) auf Chromosom 19 gefunden werden. Die DM2 wurde 1994 durch Ricker und Thornton beschrieben und 2001 konnte ein abnorm expandiertes Tetranukleotid CCTG-Repeat im Intron 1 des Zinkfinger-9-Gens (ZNF-9) auf Chromosom 3q als kausal identifiziert werden. Multisystemische Symptome betreffen Skelettmuskulatur, Gehirn, Auge, Herz und Endokrinum. Der heterogenen Ätiologie mit zwei genetischen Loci liegt pathogenetisch eine RNA-Prozessierungsstörung mit alternativem Spleißen von organspezifischen Genen zugrunde (sogenanntes Konzept der Spleißeopathie).Unser Symposium umfasste Beiträge zu aktuellen Aspekten der Klinik, Diagnostik, Bildgebung, Geburtshilfe und Schwangerschaft, molekularen RNA-Pathogenese sowie symptomatischen und molekularen Therapieoptionen.

Unusual structures of CCTG repeats and their participation in repeat expansion

2016 ◽  
Vol 7 (5-6) ◽  
pp. 331-340 ◽  
Author(s):  
Pei Guo ◽  
Sik Lok Lam
Keyword(s):  
Conformational Dynamics ◽  
Structural Diversity ◽  
Repeat Expansion ◽  
Nucleic Acid Binding ◽  
Myotonic Dystrophy Type 2 ◽  
Unusual Structure ◽  
Intron 1 ◽  
Repeat Expansions ◽  
Cctg Repeat ◽  
The One

AbstractCCTG repeat expansion in intron 1 of the cellular nucleic acid-binding protein (CNBP) gene has been identified to be the genetic cause of myotonic dystrophy type 2 (DM2). Yet the underlying reasons for the genetic instability in CCTG repeats remain elusive. In recent years, CCTG repeats have been found to form various types of unusual secondary structures including mini-dumbbell (MDB), hairpin and dumbbell, revealing that there is a high structural diversity in CCTG repeats intrinsically. Upon strand slippage, the formation of unusual structures in the nascent strand during DNA replication has been proposed to be the culprit of CCTG repeat expansions. On the one hand, the thermodynamic stability, size, and conformational dynamics of these unusual structures affect the propensity of strand slippage. On the other hand, these structural properties determine whether the unusual structure can successfully escape from DNA repair. In this short overview, we first summarize the recent advances in elucidating the solution structures of CCTG repeats. We then discuss the potential pathways by which these unusual structures bring about variable sizes of repeat expansion, high strand slippage propensity and efficient repair escape.

scholarly journals Reduced translation efficiency due to novel splicing variants in 5′ untranslated region and identification of novel cis-regulatory elements in canine and human BRCA2

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Yasunaga Yoshikawa ◽  
Hajime Kozuma ◽  
Masami Morimatsu ◽  
Kaori Sugawara ◽  
Koichi Orino
Keyword(s):  
Homologous Recombination ◽  
Untranslated Region ◽  
Cultured Cells ◽  
Regulatory Elements ◽  
Expression Level ◽  
Serum Starvation ◽  
Translational Efficiency ◽  
Translation Efficiency ◽  
Intron 1 ◽  
Splicing Variants

Abstract Background Breast cancer 2, early onset (BRCA2) is a tumor suppressor gene. The protein encoded by this gene plays an important role in homologous recombination (HR)-mediated DNA repair. Deleterious mutations in BRCA2 and downregulation of its expression have been associated with tumorigenesis in dogs and humans. Thus, regulation of BRCA2 expression level is important for maintaining homeostasis in homologous recombination. Results In this study, the mechanisms that regulate the expression of BRCA2 were proposed. Novel splicing variants were identified in the 5′ untranslated region (UTR) of canine and human BRCA2 in canine testis, canine ovary, and canine and human cultured cell lines. In cultured cells, the ratio of BRCA2 splicing variants at the 5′ UTR was altered by serum starvation. These novel splicing variants, excluding one of the canine splicing variants, were found to reduce the translational efficiency. Additionally, the DNA sequence in human BRCA2 intron 1 harbored novel cis-regulatory elements. Three silencer and two enhancer cis-regulatory elements were identified in human BRCA2 intron 1. Conclusions This study demonstrates that BRCA2 expression level is regulated via 5′ UTR splicing variants and that the BRCA2 intron 1 region harbors cis-regulatory elements.

scholarly journals Reduced translation efficiency due to novel splicing variants in 5′ untranslated region and identification of novel cis-regulatory elements in canine and human BRCA2

2020 ◽  
Author(s):  
Yasunaga Yoshikawa ◽  
Hajime Kozuma ◽  
Masami Morimatsu ◽  
Kaori Sugawara ◽  
Koichi Orino
Keyword(s):  
Untranslated Region ◽  
Cultured Cells ◽  
Regulatory Elements ◽  
Suppressor Gene ◽  
Expression Level ◽  
Serum Starvation ◽  
Translational Efficiency ◽  
Translation Efficiency ◽  
Intron 1 ◽  
Splicing Variants

Abstract Background: Breast cancer 2, early onset (BRCA2) is a tumor suppressor gene. The protein encoded by this gene plays an important role in homologous recombination (HR)-mediated DNA repair. Deleterious mutations in BRCA2 and downregulation of its expression have been associated with tumorigenesis in dogs and humans. Thus, regulation of BRCA2 expression level is important for maintaining homeostasis in homologous recombination.Results: In this study, the mechanisms that regulate the expression of BRCA2 were proposed. Novel splicing variants were identified in the 5′ untranslated region (UTR) of canine and human BRCA2 in canine testis, canine ovary, and canine and human cultured cell lines. In cultured cells, the ratio of BRCA2 splicing variants at the 5′ UTR was altered by serum starvation. These novel splicing variants, excluding one of the canine splicing variants, were found to reduce the translational efficiency. Additionally, the DNA sequence in human BRCA2 intron 1 harbored novel cis-regulatory elements. Three silencer and two enhancer cis-regulatory elements were identified in human BRCA2 intron 1.Conclusions: This study demonstrates that BRCA2 expression level is regulated via 5′ UTR splicing variants and that the BRCA2 intron 1 region harbors cis-regulatory elements.

scholarly journals Reduced translation efficiency due to novel splicing variants in 5′ untranslated region and identification of novel cis-regulatory elements in canine and human BRCA2

2020 ◽  
Author(s):  
Yasunaga Yoshikawa ◽  
Masami Morimatsu ◽  
Hajime Kozuma ◽  
Kaori Sugawara ◽  
Koichi Orino
Keyword(s):  
Homologous Recombination ◽  
Untranslated Region ◽  
Cultured Cells ◽  
Regulatory Elements ◽  
Expression Level ◽  
Serum Starvation ◽  
Translational Efficiency ◽  
Translation Efficiency ◽  
Intron 1 ◽  
Splicing Variants

Abstract Background Breast cancer 2, early onset (BRCA2) is a tumor suppressor gene. The protein encoded by this gene plays an important role in homologous recombination (HR)-mediated DNA repair. Deleterious mutations in BRCA2 and downregulation of its expression have been associated with tumorigenesis in dogs and humans. Thus, regulation of BRCA2 expression level is important for maintaining homeostasis in homologous recombination. Results In this study, the mechanisms that regulate the expression of BRCA2 were proposed. Novel splicing variants were identified in the 5′ untranslated region (UTR) of canine and human BRCA2 in canine testis, canine ovary, and canine and human cultured cell lines. In cultured cells, the ratio of BRCA2 splicing variants at 5′ UTR was altered by serum starvation. These novel splicing variants, excluding one of the canine splicing variants, were found to reduce the translational efficiency. Additionally, the DNA sequence in human BRCA2 intron 1 harbored novel cis-regulatory elements. Three silencer and two enhancer cis-regulatory elements were identified in human BRCA2 intron 1. Conclusions This study demonstrates that BRCA2 expression level is regulated via 5′ UTR splicing variants and that the BRCA2 intron 1 region harbors cis-regulatory elements.

scholarly journals A 14-Year Italian Experience in DM2 Genetic Testing: Frequency and Distribution of Normal and Premutated CNBP Alleles

2021 ◽  
Vol 12 ◽  
Author(s):  
Annalisa Botta ◽  
Virginia Veronica Visconti ◽  
Luana Fontana ◽  
Paola Bisceglia ◽  
Mario Bengala ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Italian Population ◽  
Myotonic Dystrophy Type 2 ◽  
Italian Experience ◽  
Testing Frequency ◽  
Intron 1 ◽  
Clinical Consequences ◽  
Cctg Repeat ◽  
Testing And Counseling

Myotonic dystrophy type 2 (DM2) is a multisystemic disorder caused by a (CCTG)n in intron 1 of the CNBP gene. The CCTG repeat tract is part of a complex (TG)v(TCTG)w(CCTG)x(NCTG)y(CCTG)z motif generally interrupted in CNBP healthy range alleles. Here we report our 14-year experience of DM2 postnatal genetic testing in a total of 570 individuals. The DM2 locus has been analyzed by a combination of SR-PCR, TP-PCR, LR-PCR, and Sanger sequencing of CNBP alleles. DM2 molecular diagnosis has been confirmed in 187/570 samples analyzed (32.8%) and is mainly associated with the presence of myotonia in patients. This set of CNBP alleles showed unimodal distribution with 25 different alleles ranging from 108 to 168 bp, in accordance with previous studies on European populations. The most frequent CNBP alleles consisted of 138, 134, 140, and 136 bps with an overall locus heterozygosity of 90%. Sequencing of 103 unexpanded CNBP alleles in DM2-positive patients revealed that (CCTG)5(NCTG)3(CCTG)7 and (CCTG)6(NCTG)3(CCTG)7 are the most common interruption motifs. We also characterized five CNBP premutated alleles with (CCTG)n repetitions from n = 36 to n = 53. However, the molecular and clinical consequences in our cohort of samples are not unequivocal. Data that emerged from this study are representative of the Italian population and are useful tools for National and European centers offering DM2 genetic testing and counseling.

scholarly journals Reduced translation efficiency due to novel splicing variants in 5′ untranslated region and identification of novel cis-regulatory elements in canine and human BRCA2

2020 ◽  
Author(s):  
Yasunaga Yoshikawa ◽  
Hajime Kozuma ◽  
Masami Morimatsu ◽  
Kaori Sugawara ◽  
Koichi Orino
Keyword(s):  
Homologous Recombination ◽  
Untranslated Region ◽  
Cultured Cells ◽  
Regulatory Elements ◽  
Expression Level ◽  
Serum Starvation ◽  
Translational Efficiency ◽  
Translation Efficiency ◽  
Intron 1 ◽  
Splicing Variants

Abstract Background: Breast cancer 2, early onset (BRCA2) is a tumor suppressor gene. The protein encoded by this gene plays an important role in homologous recombination (HR)-mediated DNA repair. Deleterious mutations in BRCA2 and downregulation of its expression have been associated with tumorigenesis in dogs and humans. Thus, regulation of BRCA2 expression level is important for maintaining homeostasis in homologous recombination.Results: In this study, the mechanisms that regulate the expression of BRCA2 were proposed. Novel splicing variants were identified in the 5′ untranslated region (UTR) of canine and human BRCA2 in canine testis, canine ovary, and canine and human cultured cell lines. In cultured cells, the ratio of BRCA2 splicing variants at the 5′ UTR was altered by serum starvation. These novel splicing variants, excluding one of the canine splicing variants, were found to reduce the translational efficiency. Additionally, the DNA sequence in human BRCA2 intron 1 harbored novel cis-regulatory elements. Three silencer and two enhancer cis-regulatory elements were identified in human BRCA2 intron 1.Conclusions: This study demonstrates that BRCA2 expression level is regulated via 5′ UTR splicing variants and that the BRCA2 intron 1 region harbors cis-regulatory elements.

Störungen der Stimmung und des Antriebs nach erworbenen Hirnschädigungen im Kindesalter

2001 ◽  
Vol 12 (4) ◽  
pp. 314-323
Author(s):  
Kerstin Konrad ◽  
Siegfried Gauggel
Keyword(s):  
Wird Eine ◽  
Diagnostik Und Therapie

Zusammenfassung: In diesem Beitrag wird eine Übersicht über Störungen der Stimmung und des Antriebs bei Kindern und Jugendlichen mit erworbenen Hirnschädigungen unterschiedlicher Ätiologie (Hirntumoren, Schädel-Hirn-Trauma) gegeben. Obwohl es in den letzten Jahren immense Fortschritte im Bereich der Diagnostik und Therapie von kindlichen Depressionen gegeben hat, stellen die depressiven Symptome nach Hirnschädigungen im Kindesalter ein noch weitgehend unerforschtes Gebiet dar. Ausgehend von den bislang vorhandenen empirischen Studien werden Vorschläge für Diagnostik und Therapie von organisch bedingten Stimmungs- und Antriebsstörungen im Kindesalter gemacht.

Früherkennung schizophrener Psychosen bei Männern und Frauen

2007 ◽  
Vol 64 (6) ◽  
pp. 337-343 ◽  
Author(s):  
Riecher-Rössler
Keyword(s):  
Diagnostik Und Therapie

Die Früherkennung und Frühbehandlung von schizophrenen Psychosen ist von entscheidender Bedeutung zur weiteren Verbesserung des Verlaufs dieser bisher häufig chronisch verlaufenden und zur Frühberentung führenden Erkrankungen. Frauen erkranken im Durchschnitt etwa 4–5 Jahre später als Männer, oft noch nach dem 40. Lebensjahr. Diese «Spätschizophrenien», die bei Frauen immerhin etwa 20% aller Schizophrenien ausmachen, sollten nicht übersehen werden. Prodromi und andere Vorboten der Erkrankung sind bei Frauen ganz ähnlich wie bei Männern, auch die Verzögerung von Diagnostik und Therapie zeigt keine Geschlechtsunterschiede. Durch die Tatsache, dass Frauen im Mittel erst in höherem Alter erkranken als Männer, sind sie in ihren verschiedenen sozialen Rollen schon besser etabliert. Allerdings besteht offensichtlich die Gefahr, dass bei Frauen die berufliche Integration vernachlässigt wird. Früherkennung, Frühintervention und Frührehabilitation sollten aus den genannten Gründen immer auch geschlechtersensibel sein.

Sign in / Sign up

Export Citation Format

Share Document