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 The Unstable CCTG Repeat Responsible for Myotonic Dystrophy Type 2 Originates from an AluSx Element Insertion into an Early Primate Genome

PLoS ONE ◽  
2012 ◽  
Vol 7 (6) ◽  
pp. e38379 ◽  
Author(s):  
Tatsuaki Kurosaki ◽  
Shintaroh Ueda ◽  
Takafumi Ishida ◽  
Koji Abe ◽  
Kinji Ohno ◽  
...  
Keyword(s):  
Myotonic Dystrophy ◽  
Myotonic Dystrophy Type ◽  
Myotonic Dystrophy Type 2 ◽  
Primate Genome ◽  
Element Insertion ◽  
Cctg Repeat

Dysautonomia as Onset Symptom of Myotonic Dystrophy Type 2

2018 ◽  
Vol 79 (3-4) ◽  
pp. 166-170
Author(s):  
Salvatore Rossi ◽  
Angela Romano ◽  
Anna Modoni ◽  
Francesco Perna ◽  
Valentina Rizzo ◽  
...  
Keyword(s):  
Myotonic Dystrophy ◽  
Peripheral Nerves ◽  
Autosomal Dominant ◽  
Disease Onset ◽  
Clinical Signs ◽  
Myotonic Dystrophy Type ◽  
Multisystem Disorder ◽  
Myotonic Dystrophy Type 2 ◽  
Cctg Repeat

Myotonic dystrophy type 2 (DM2) is an autosomal dominant muscular dystrophy caused by the expansion of an intronic tetranucleotide CCTG repeat in CNBP on chromosome 3. As DM1, DM2 is a multisystem disorder affecting, beside the skeletal muscle, various other tissues, including peripheral nerves. Indeed, a subclinical involvement of peripheral nervous system has been described in several cohorts of DM2 patients, whereas DM2 patients manifesting clinical signs and/or symptoms of neuropathy have been only rarely reported. Here, we describe 2 related DM2 patients both of whom displayed an atypical disease onset characterized by dysautonomic symptoms, possibly secondary to peripheral neuropathy.

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.

Genetic testing of individuals with pre-senile cataract identifies patients with myotonic dystrophy type 2

2017 ◽  
Vol 24 (11) ◽  
pp. e79-e80 ◽  
Author(s):  
V. Rakočević-Stojanović ◽  
S. Perić ◽  
J. Pešović ◽  
I. Senćanić ◽  
M. Božić ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Myotonic Dystrophy ◽  
Senile Cataract ◽  
Myotonic Dystrophy Type ◽  
Myotonic Dystrophy Type 2

scholarly journals Characterisation of Non-Pathogenic Premutation-Range Myotonic Dystrophy Type 2 Alleles

2021 ◽  
Vol 10 (17) ◽  
pp. 3934
Author(s):  
Jan Radvanszky ◽  
Michaela Hyblova ◽  
Eva Radvanska ◽  
Peter Spalek ◽  
Alica Valachova ◽  
...  
Keyword(s):  
Myotonic Dystrophy ◽  
Intergenerational Transmission ◽  
Grey Zone ◽  
Myotonic Dystrophy Type ◽  
Nucleic Acid Binding ◽  
Pathogenic Role ◽  
Myotonic Dystrophy Type 2 ◽  
Family Structures ◽  
Cctg Repeat

Myotonic dystrophy type 2 (DM2) is caused by expansion of a (CCTG)n repeat in the cellular retroviral nucleic acid-binding protein (CNBP) gene. The sequence of the repeat is most commonly interrupted and is stably inherited in the general population. Although expanded alleles, premutation range and, in rare cases, also non-disease associated alleles containing uninterrupted CCTG tracts have been described, the threshold between these categories is poorly characterised. Here, we describe four families with members reporting neuromuscular complaints, in whom we identified altogether nine ambiguous CNBP alleles containing uninterrupted CCTG repeats in the range between 32 and 42 repeats. While these grey-zone alleles are most likely not pathogenic themselves, since other pathogenic mutations were identified and particular family structures did not support their pathogenic role, they were found to be unstable during intergenerational transmission. On the other hand, there was no observable general microsatellite instability in the genome of the carriers of these alleles. Our results further refine the division of CNBP CCTG repeat alleles into two major groups, i.e., interrupted and uninterrupted alleles. Both interrupted and uninterrupted alleles with up to approximately 30 CCTG repeats were shown to be generally stable during intergenerational transmission, while intergenerational as well as somatic instability seems to gradually increase in uninterrupted alleles with tract length growing above this threshold.

scholarly journals Marathoning with myotonic dystrophy type 2 (proximal myotonic myopathy) and leukopenia

2017 ◽  
Vol 5 ◽  
pp. 2050313X1770302
Author(s):  
Josef Finsterer ◽  
Georg Safoschnik ◽  
Martina Witsch-Baumgartner
Keyword(s):  
Myotonic Dystrophy ◽  
Sport Activity ◽  
Repeat Expansion ◽  
Motor Neuropathy ◽  
Myotonic Dystrophy Type ◽  
Myotonic Dystrophy Type 2 ◽  
Continuous Exercise ◽  
Proximal Myotonic Myopathy ◽  
Cctg Repeat

Objectives: A mild, slowly progressive course of proximal myotonic myopathy, also known as myotonic dystrophy type 2, over years allowing the patient to continue with extreme sport activity, has been only rarely reported. Methods: Case report. Results: The patient is a 54-year-old female sport teacher who developed myotonia of the distal upper limbs at the age of 32 years. Over the following 22 years, myotonia spreaded to the entire musculature. Myotonia did not prevent her from doing her job and from marathoning and improved with continuous exercise. Additionally, she had developed hypothyroidism, ovarial cysts, incipient cataract, motor neuropathy, hepatopathy, leukopenia, and mild hyper-CK-emia. A heterozygous CCTG-repeat expansion of 500–9500 was found in the CNBP/ZNF9 gene. At the age of 54 years, she was still performing sport, without presenting with myotonia on clinical examination or having developed other typical manifestations of proximal myotonic myopathy. Conclusions: This case shows that proximal myotonic myopathy may take a mild course over at least 22 years, that proximal myotonic myopathy with mild myotonia may allow a patient to continue strenuous sport activity, and that continuous physical activity may contribute to the mild course of the disease.

scholarly journals Does Type 2 Diabetes Genetic Testing and Counseling Reduce Modifiable Risk Factors? A Randomized Controlled Trial of Veterans

2015 ◽  
Vol 30 (11) ◽  
pp. 1591-1598 ◽  
Author(s):  
Corrine I. Voils ◽  
Cynthia J. Coffman ◽  
Janet M. Grubber ◽  
David Edelman ◽  
Azita Sadeghpour ◽  
...  
Keyword(s):  
Risk Factors ◽  
Type 2 Diabetes ◽  
Randomized Controlled Trial ◽  
Genetic Testing ◽  
Controlled Trial ◽  
Modifiable Risk Factors ◽  
Randomized Controlled ◽  
Testing And Counseling

Molecular analysis of FVIII gene in severe HA patients of Costa Rica

2010 ◽  
Vol 30 (S 01) ◽  
pp. S150-S152
Author(s):  
G. Jiménez-Cruz ◽  
M. Mendez ◽  
P. Chaverri ◽  
P. Alvarado ◽  
W. Schröder ◽  
...  
Keyword(s):  
Factor Viii ◽  
Coagulation Factor ◽  
Costa Rican ◽  
Factor Viii Gene ◽  
Intron 22 Inversion ◽  
Intron 1 ◽  
Polymerase Chain ◽  
Inversion Analysis

SummaryHaemophilia A (HA) is X-chromosome linked bleeding disorders caused by deficiency of the coagulation factor VIII (FVIII). It is caused by FVIII gene intron 22 inversion (Inv22) in approximately 45% and by intron 1 inversion (Inv1) in 5% of the patients. Both inversions occur as a result of intrachromosomal recombination between homologous regions, in intron 1 or 22 and their extragenic copy located telomeric to the FVIII gene. The aim of this study was to analyze the presence of these mutations in 25 HA Costa Rican families. Patients, methods: We studied 34 HA patients and 110 unrelated obligate members and possible carriers for the presence of Inv22or Inv1. Standard analyses of the factor VIII gene were used incl. Southern blot and long-range polymerase chain reaction for inversion analysis. Results: We found altered Inv22 restriction profiles in 21 patients and 37 carriers. It was found type 1 and type 2 of the inversion of Inv22. During the screening for Inv1 among the HA patient, who were Inv22 negative, we did not found this mutation. Discussion: Our data highlight the importance of the analysis of Inv22 for their association with development of inhibitors in the HA patients and we are continuous searching of Inv1 mutation. This knowledge represents a step for genetic counseling and prevention of the inhibitor development.

Sign in / Sign up

Export Citation Format

Share Document