Identification of variants in MBNL1 in patients with a myotonic dystrophy-like phenotype

Abstract

The myotonic dystrophies (DMs) are the most common inherited muscular disorders in adults. In most of the cases, the disease is caused by (CTG) n /(CCTG) n repeat expansions (EXPs) in non-coding regions of the genes DMPK (dystrophia myotonica-protein kinase) and CNBP (CCHC-type zinc-finger nucleic acid-binding protein). The EXP is transcribed into mutant RNAs, which provoke a common pathomechanism that is characterized by misexpression and mis-splicing. In this study, we screened 138 patients with typical clinical features of DM being negative for EXP in the known genes. We sequenced DMPK and CNBPassociated with DM, as well as CELF1 (CUGBP, Elav-like family member 1) and MBNL1 (muscleblind-like splicing regulator 1) -associated with the pathomechanism of DM, for pathogenic variants, addressing the question whether defects in other genes could cause a DM-like phenotype. We identified variants in three unrelated patients in the MBNL1 gene, two of them were heterozygous missense mutations and one an in-frame deletion of three amino acids. The variants were located in different conserved regions of the protein. The missense mutations were classified as potentially pathogenic by prediction tools. Analysis of MBNL1 splice target genes was carried out for one of the patients using RNA from peripheral blood leukocytes (PBL). Analysis of six genes known to show mis-splicing in the skeletal muscle gave no informative results on the effect of this variant when tested in PBL. The association of these variants with the DM phenotype therefore remains unconfirmed, but we hope that in view of the key role of MBNL1 in DM pathogenesis our observations may foster further studies in this direction.

Hereditary Basis of Coat Color and Excellent Feed Conversion Rate of Red Angus Cattle by Next-Generation Sequencing Data

“…Moreover, two significant SNPs (CHIR18_12999497 and CHIR18_14389309) that exceeded the threshold were annotated in ZCCHC14 and ANKRD11 , respectively. Some studies determined that one cause of myotonic dystrophy is CCHC type zinc finger nucleic acid binding protein [ 44 , 45 , 46 , 47 ]. A series of widely confirmed muscle developmental genes (e.g., FHL3 , MYOG , BAG3 , SMAD3 , and HIF1AN ) [ 48 ], such as MYOG , which acts as an essential regulator of adult myofiber growth and muscle stem-cell homeostasis, interacted with ZCCHC14 [ 49 ].…”

Establishment of quantitative and consistent in vitro skeletal muscle pathological models of myotonic dystrophy type 1 using patient-derived iPSCs

“…Importantly, mis-splicing events of DMD, BIN1 and ATP2A1 www.nature.com/scientificreports/ are associated with muscle dystrophy, muscle weakness and dysregulation of calcium metabolism, respectively, which are all DM1 manifestations 26,27,34 . In the pathogenesis of DM1, both human studies 7,44 as well as animal studies 6,45,46 have identified MBNL1 as the main pathogenic regulator. Therefore, the recovery of endogenous MBNL1 function is necessary for effective DM1 therapies, and our quantitative methods investigating MBNL1mediated pathology are promising for judging the potential of therapeutics for DM1.…”

“…The intranuclear MBNL1 aggregation is associated with foci of CUGexp 5 . Importantly, functional loss of MBNL1 results in numerous alternative splicing defects and represents the central pathogenetic mechanism of DM1 6 , 7 .…”

DM1 Phenotype Variability and Triplet Repeat Instability: Challenges in the Development of New Therapies

“…Genomic variants may also affect RNA or proteins, which could explain, in part, the clinical variability observed in DM1 patients. Muscleblind-like splicing regulator 1 (MBNL1) variants have been identified and may be an alternative cause of clinical variability in DM1 [71,72]. The rs323622 polymorphism in MBNL1 has been associated with a more severe phenotype and may explain about 2% of the variance in disease severity [72].…”