The competing mini-dumbbell mechanism: new insights into CCTG repeat expansion

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.

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

SAGE Open Medical Case Reports ◽

10.1177/2050313x17703021 ◽

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.

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CANVAS is a common form of late-onset hereditary ataxia

Nauchno-prakticheskii zhurnal «Medicinskaia genetika» ◽

10.25557/2073-7998.2020.04.51-52 ◽

2020 ◽

pp. 51-52

Author(s):

Е.П. Нужный ◽

Н.Ю. Абрамычева ◽

Е.Г. Воробьева ◽

Е.О. Иванова ◽

Ю.А. Шпилюкова ◽

...

Keyword(s):

Cerebellar Ataxia ◽

Clinical Picture ◽

Autosomal Recessive ◽

Late Onset ◽

Repeat Expansion ◽

Hereditary Ataxia ◽

Recessive Ataxia ◽

Autosomal Recessive Ataxia

Синдром CANVAS (мозжечковая атаксия, невропатия и вестибулярная арефлексия) - аутосомно-рецессивная атаксия с поздним дебютом, обусловленная носительством биаллельной экспансии (AAGGG)n во 2-м интроне гена RFC1. До настоящего момента отсутствуют сведения о распространенности данного заболевания в российских семьях. Нами был проведен поиск биаллельной экспансии AAGGG-повторов у 35 российских пациентов с поздней мозжечковой атаксией. Верифицированы 5 пациентов (14,3%) с синдромом CANVAS и характерной клинической картиной. CANVAS (cerebellar ataxia, neuropathy and vestibular areflexia) is a late-onset autosomal recessive ataxia due to biallelic (AAGGG)n repeat expansion in the 2nd intron of the RFC1 gene. There is no information on the CANVAS prevalence in Russian families. We searched for biallelic expansion of AAGGG repeats in 35 Russian patients with late-onset cerebellar ataxia. Five patients (14.3%) with CANVAS syndrome and a characteristic clinical picture were verified.

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