Abstract:

Myotonic dystrophy type 1 (DM1) is an RNA-mediated disorder characterized by muscle weakness, cardiac defects and multiple symptoms and is caused by expanded CTG repeats within the 3' untranslated region of the DMPK gene. In this study, we found abnormal splicing of actin-binding LIM protein 1 (ABLIM1) in skeletal muscles of patients with DM1 and a DM1 mouse model (HSA(LR) ). An exon 11 inclusion isoform is expressed in skeletal muscle and heart of non-DM1 individuals, but not in skeletal muscle of patients with DM1 or other adult human tissues. Moreover, we determined that ABLIM1 splicing is regulated by several splice factors, including MBNL family proteins, CELF1, 2 and 6, and PTBP1, using a cellular splicing assay. MBNL proteins promoted the inclusion of ABLIM1 exon 11, but other proteins and expanded CUG repeats repressed exon 11 of ABLIM1. This result is consistent with the hypothesis that MBNL proteins are trapped by expanded CUG repeats and inactivated in DM1 and that CELF1 is activated in DM1. However, activation of PTBP1 has not been reported in DM1. Our results suggest that the exon 11 inclusion isoform of ABLIM1 may have a muscle-specific function, and its abnormal splicing could be related to muscle symptoms of DM1.

日本語要旨:

筋強直性ジストロフィー1型(DM1)は筋力低下、心筋障害を含む多様な症状を呈する遺伝性疾患である。今回の我々の研究により、actin-binding LIM protein 1 (ABLIM1)という蛋白がMBNL、CELF、PTBP1という蛋白による調節を受けている事、そしてABLIM1のスプライシング異常によりDM1の筋症状が生じる可能性がある事が示された。