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

Jan Radvanszky,Tomas Szemes,Alica Valachova,Ludevit Kadasi,Michaela Hyblova,Peter Spalek,Csaba Bognar,Emil Polak,Eva Radvanska,Gabriela Magyarova

doi:10.3390/jcm10173934

Abstract

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.

Highlights

Licensee MDPI, Basel, Switzerland.Short tandem repeats (STRs), or microsatellites, are responsible for a great part of interindividual and intraindividual genomic variability, and they belong to the most polymorphic regions of the human genome [1]
Myotonic dystrophy type 2 (DM2; OMIM_#602668), is connected to expansion of a (CCTG)n repeat tract located in the first intron of the cellular retroviral nucleic acid-binding protein (CNBP; called zinc finger protein 9, ZNF9) gene
CCTG alleles in the CNBP gene, which represented possible premutation-range alleles. These were initially identified in one affected member from family_1, in the only affected member of family_2, in the only affected member of family_3 and in the asymptomatic sister of the only affected member of family_4 (Figure 1, Table 1). Since these alleles fell into the range of poorly characterised grey-zone alleles while they were identified in families with neuromuscular complaints, it was necessary to exclude their pathogenic/causative nature in each family for correct counselling purposes

Summary

Introduction

Short tandem repeats (STRs), or microsatellites, are responsible for a great part of interindividual and intraindividual genomic variability, and they belong to the most polymorphic regions of the human genome [1] Their physiological and pathophysiological significance is of immense importance, since they are connected to the fine regulation of expression levels of many genes [2], or they regulate their alternative splicing [3], but they have severe pathological conditions, mainly associated with dynamic expansions. The onset of symptoms, and their specific constellation as well as their severity tend to depend on the repeat numbers and/or on the presence of interruptions in the repeat motifs themselves One of these disorders, myotonic dystrophy type 2 (DM2; OMIM_#602668), is connected to expansion of a (CCTG)n repeat tract located in the first intron of the cellular retroviral nucleic acid-binding protein (CNBP; called zinc finger protein 9, ZNF9) gene.

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Conclusion