Myotonic dystrophy type1 (DM1) is a multisystemic disorder caused by a CTG repeat expansion in the DMPK gene which results in nuclear entrapment of the 'toxic' mutant RNA and interacting RNA-binding proteins (such as MBNL1) in ribonuclear inclusions. In this month’s Nature Genetics Dr. Mani Mahadevan and colleagues report unanticipated data showing that mice and individuals with DM1 actually overproduce NKX2-5, yet experience the same kind of heart problems associated with too little of it. The protein, NKX2-5, is a biomarker for heart stem cells. It is also very important for the normal development of the heart. Too little of it causes major cardiac problems including slow and irregular heartbeats. Excessive NKX2-5 may explain why as many as 60 to 70 percent of individuals with DM1 develop heart problems which cause their heartbeats to become slow and irregular, often necessitating the need for pacemakers. If these irregular heartbeats are not detected, sudden death can occur. By using the mouse model of DM1 and mice genetically engineered to produce less NKX2-5, the authors showed that reducing the excessive levels of NKX2-5 seemed to protect the mice from the heart problems. Surprisingly, they also observed NKX2-5 in the skeletal muscle of mice and DM1 patients. Usually, NKX2-5 is found only in the heart of adults. This discovery could prove beneficial and lead to development of a simple diagnostic test to follow a patient’s response to potential therapies. The data from this study demonstrate a new effect of RNA toxicity and how this may cause cardiac conduction abnormalities.


Références : Nat Genet. 2008 Jan;40(1):61-8. Epub 2007 Dec 16.