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 ◽  
...  

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.

PLoS ONE ◽  
2012 ◽  
Vol 7 (6) ◽  
pp. e38379 ◽  
Author(s):  
Tatsuaki Kurosaki ◽  
Shintaroh Ueda ◽  
Takafumi Ishida ◽  
Koji Abe ◽  
Kinji Ohno ◽  
...  

2018 ◽  
Vol 79 (3-4) ◽  
pp. 166-170
Author(s):  
Salvatore Rossi ◽  
Angela Romano ◽  
Anna Modoni ◽  
Francesco Perna ◽  
Valentina Rizzo ◽  
...  

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.


2018 ◽  
Vol 38 (14) ◽  
Author(s):  
Christina Wei ◽  
Lauren Stock ◽  
Christiane Schneider-Gold ◽  
Claudia Sommer ◽  
Nikolai A. Timchenko ◽  
...  

ABSTRACT Myotonic dystrophy type 2 (DM2) is a neuromuscular disease caused by an expansion of intronic CCTG repeats in the CNBP gene, which encodes a protein regulating translation and transcription. To better understand the role of cellular nucleic acid binding protein (CNBP) in DM2 pathology, we examined skeletal muscle in a new model of Cnbp knockout (KO) mice. This study showed that a loss of Cnbp disturbs myofibrillar sarcomeric organization at birth. Surviving homozygous Cnbp KO mice develop muscle atrophy at a young age. The skeletal muscle phenotype in heterozygous Cnbp KO mice was milder, but they developed severe muscle wasting at an advanced age. Several proteins that control global translation and muscle contraction are altered in muscle of Cnbp KO mice. A search for CNBP binding proteins showed that CNBP interacts with the α subunit of the dystroglycan complex, a core component of the multimeric dystrophin-glycoprotein complex, which regulates membrane stability. Whereas CNBP is reduced in cytoplasm of DM2 human fibers, it is a predominantly membrane protein in DM2 fibers, and its interaction with α-dystroglycan is increased in DM2. These findings suggest that alterations of CNBP in DM2 might cause muscle atrophy via CNBP-mediated translation and via protein-protein interactions affecting myofiber membrane function.


2021 ◽  
pp. 1-8
Author(s):  
M.J. Damen ◽  
M.M.V.A.P. Schijvenaars ◽  
A.M. Schimmel Naber ◽  
J.M. Groothuismink ◽  
M.J.H. Coenen ◽  
...  

Background: Myotonic dystrophy type 2 (DM2) is caused by a CCTG repeat expansion in intron 1 of the CCHC-Type Zinc Finger Nucleic Acid Binding Protein (CNBP) gene. Previous studies indicated that this repeat expansion originates from separate founders. Objective: This study was set out to determine whether or not patients with DM2 originating from European and non-European countries carry the previously described European founder haplotypes. Methods: Haplotype analysis was performed in 59 DM2 patients from 29 unrelated families. Twenty-three families were from European descent and 6 families originated from non-European countries (India, Suriname and Morocco). Seven short tandem repeats (CL3N122, CL3N99, CL3N59, CL3N117, CL3N119, CL3N19 and CL3N23) and 4 single nucleotide polymorphisms (SNP) (rs1871922, rs1384313, rs4303883 and CGAP_886192) in and around the CNBP gene were used to construct patients’ haplotypes. These haplotypes were compared to the known DM2 haplotypes to determine the ancestral origin of the CNBP repeat expansion. Results: Of 41 patients, the haplotype could be assigned to the previously described Caucasian haplotypes. Three patients from Morocco and Portugal had a haplotype identical to the earlier reported Moroccan haplotype. Twelve patients from India and Suriname, however, carried a haplotype that seems distinct from the previously reported haplotypes. Three individuals could not be assigned to a specific haplotype. Conclusion: The ancestral origin of DM2 in India might be distinct from the Caucasian families and the solely described Japanese patient. However, we were unable to establish this firmly due to the limited genetic variation in the region surrounding the CNBP gene.


2017 ◽  
Vol 5 ◽  
pp. 2050313X1770302
Author(s):  
Josef Finsterer ◽  
Georg Safoschnik ◽  
Martina Witsch-Baumgartner

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.


2020 ◽  
Author(s):  
Eleni Kontou ◽  
Constantinos Papadopoulos ◽  
Giorgos Papadimas ◽  
Argyris Toubekis ◽  
Gregory Bogdanis ◽  
...  

2013 ◽  
Vol 9 (2) ◽  
pp. 130 ◽  
Author(s):  
Ana Nikolic ◽  
Vidosava Rakocevic Stojanovic ◽  
Stanka Romac ◽  
Dusanka Savic ◽  
Ivana Basta ◽  
...  

2004 ◽  
Vol 251 (10) ◽  
pp. 1173-1182 ◽  
Author(s):  
Giovanni Meola ◽  
Richard T. Moxley

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