Loss of muscleblind-like 1 results in cardiac pathology and persistence of embryonic splice isoforms

Abstract

Cardiac dysfunction is a prominent cause of mortality in myotonic dystrophy I (DM1), a disease where expanded CUG repeats bind and disable the muscleblind-like family of splice regulators. Deletion of muscleblind-like 1 (Mbnl1ΔE2/ΔE2) in 129 sv mice results in QRS, QTc widening, bundle block and STc narrowing at 2–4 months of age. With time, cardiac function deteriorates further and at 6 months, decreased R wave amplitudes, sinus node dysfunction, cardiac hypertrophy, interstitial fibrosis, multi-focal myocardial fiber death and calcification manifest. Sudden death, where no end point illness is overt, is observed at a median age of 6.5 and 4.8 months in ~67% and ~86% of male and female Mbnl1ΔE2/ΔE2 mice, respectively. Mbnl1 depletion results in the persistence of embryonic splice isoforms in a network of cardiac RNAs, some of which have been previously implicated in DM1, regulating sodium and calcium currents, Scn5a, Junctin, Junctate, Atp2a1, Atp11a, Cacna1s, Ryr2, intra and inter cellular transport, Clta, Stx2, Tjp1, cell survival, Capn3, Sirt2, Csda, sarcomere and cytoskeleton organization and function, Trim55, Mapt, Pdlim3, Pdlim5, Sorbs1, Sorbs2, Fhod1, Spag9 and structural components of the sarcomere, Myom1, Tnnt2, Zasp. Thus this study supports a key role for Mbnl1 loss in the initiation of DM1 cardiac disease.

RBM20 and RBM24 cooperatively promote the expression of short enh splice variants

“…One possible candidate could be the splicing factor MBNL1 (muscleblind‐like 1). Recently, the knockout of MBNL1 splicing factor was shown to result in the re‐expression of embryonic splicing isoforms of many cardiac genes . In this mouse, the skipping of exon 7 and exon 8 of Enh was promoted, suggesting that MBNL1 favors the expression of LIM‐containing isoforms.…”

Thick Filament Protein Network, Functions, and Disease Association

“…DM1 is an autosomal dominant disease, which is caused by expansion of the CTG repeat in the 3′-UTR of the dystrophia myotonica protein kinase ( DMPK ) gene (29, 71, 76, 221). Aberrant alternative splicing is a distinctive feature of DM1 as the expanded CUG repeats bind and therefore sequester the muscleblind-like family of RNA splice regulators, resulting in deregulation of normal exon shuffling (127). More than 30 genes have been identified to be abnormally spliced in DM1 (465), including MYOM1 (284).…”

Derepressing muscleblind expression by miRNA sponges ameliorates myotonic dystrophy-like phenotypes in Drosophila

“…A Mbnl1 knock-out (KO) mouse model displays myotonia, missplicing of muscular transcripts and cataracts, which are all characteristic symptoms of DM1 disease22. More recently, relevant cardiac dysfunction features have been described in 2 month-old Mbnl1 mutant mice (hypertrophy, interstitial fibrosis and splicing alterations), which suggests a role for Mbnl1 reduction in the cardiac problems in DM123. However, Mbnl1 KO mice do not display the whole set of symptoms of DM1.…”