Curation DM1 DMPK

PMID:32851192 showed that DM1 individuals with repeat interruptions had milder motor/neurocognitive/behavioral outcomes than matched pure-repeat DM1 cases. PMID:39643839 summarizes that DMPK CTG expansion length influences disease severity/age at onset, while variant interruptions and somatic instability modify phenotype.

In a Mexican cohort of 50 clinically/electrophysiologically diagnosed DM1 patients, 45/50 (90%) had pathogenic DMPK CTG expansions detected by fluorescent PCR plus TP-PCR/capillary electrophoresis; 400 unrelated controls showed non-expanded alleles ranging from 5 to 34 repeats.

Case-control study was carried out on 25 patients with myotonic dystrophy (MyD) and 25 healthy subjects (p < 0.0001).

In CUG960 heart-specific DM1 mice expressing 960 interrupted CUG repeats in the human DMPK 3' UTR, AAV9-mediated MBNL1 and/or MBNL2 overexpression partially rescued conduction delays, contractile dysfunction, hypertrophy, and misregulated splicing/gene expression.

In 293T cells and myoblasts expressing an EGFP-(CUG)85 reporter, siRNA knockdown of hnRNP H restored EGFP expression and relieved nuclear retention of expanded CUG-repeat RNA; hnRNP H binding required expanded CUG repeats and a distal branch point.

DMSXL transgenic mice carrying a human DM1 allele with ~CTG1300 repeats yielded ALP-positive skeletal muscle pericytes that expressed transgenic DMPK and showed nuclear CUG RNA foci, averaging 1-2 foci/nucleus in heterozygotes and 5-10 in homozygotes.

ALP-positive skeletal muscle pericytes were isolated from six DM1 patients and two unaffected controls; patient pericytes showed nuclear CUG RNA foci with MBNL1 colocalization in several lines while maintaining proliferation and myogenic differentiation potential comparable to controls.