Myotonic Dystrophy Type 2 Caused by a CCTG Expansion in Intron 1 of <i>ZNF9</i>

TLDR

Myotonic dystrophy is the most common adult muscular dystrophy, caused by CTG or CCTG repeat expansions on chromosomes 19q13 or 3q21 that disrupt RNA function and lead to multisystemic symptoms. We identified that DM2 results from a CCTG expansion of approximately 5,000 repeats in intron 1 of the zinc finger protein 9 (ZNF9) gene.

Abstract

Myotonic dystrophy (DM), the most common form of muscular dystrophy in adults, can be caused by a mutation on either chromosome 19q13 (DM1) or 3q21 (DM2/PROMM). DM1 is caused by a CTG expansion in the 3′ untranslated region of the dystrophia myotonica–protein kinase gene ( DMPK ). Several mechanisms have been invoked to explain how this mutation, which does not alter the protein-coding portion of a gene, causes the specific constellation of clinical features characteristic of DM. We now report that DM2 is caused by a CCTG expansion (mean ∼5000 repeats) located in intron 1 of the zinc finger protein 9 ( ZNF9 ) gene. Parallels between these mutations indicate that microsatellite expansions in RNA can be pathogenic and cause the multisystemic features of DM1 and DM2.