Myotonic muscular dystrophy (MMD) is an inherited disorder caused by mutation in one of two genes: the DMPK (dystrophia myotonica protein kinase) gene or the ZNF9 (zinc finger 9) gene. MMD causes a wide variety of symptoms, including muscle weakness, myotonia, cataracts, disturbances of circadian (daily) rhythms including sleep, insulin resistance, and gastrointestinal disturbance. MMD affects so many different body systems because the gene mutations, acting through an indirect route, affect a host of other genes in different tissues.
Both gene mutations lead to the accumulation of a long, repetitive, and “sticky” clump of a cellular molecule called RNA, which can trap cell proteins. The most important protein trapped by the RNA called muscleblind 1 (MBNL1). Depletion of other proteins, as yet unidentified, may also contribute to the disease.
MBNL1 controls the formation of a wide variety of proteins because it regulates “splicing,” or formation of proteins from different gene segments. For many proteins, humans create one form during fetal development, and another during adulthood, by splicing together different parts of the same gene (called exons). MBNL1 is required to produce an adult, rather than fetal, form of many proteins Muscleblind splicing targets include a muscle-specific chloride channel, a contractile protein in skeletal muscles called fast skeletal troponin T, a heart muscle-specific contractile protein called cardiac troponin T, the insulin receptor, and a structural protein called tau. Loss of MBNL1 leads to reduced expression of the adult forms of these proteins, and aberrant expression of the fetal forms.
Not every feature of MMD is explained by loss of MBNL1, and recent work has highlighted a role for MBNL2, and a protein called CELF1.
Current strategies for treatment of MMD focus on reducing the amount of toxic RNA, reducing the effect of the toxic RNA on MBNL1 and CELF1, compensating for the loss of MBNL1, and increasing production of MBNL1 to overcome its depletion. Additional strategies are also being investigated to mitigate the symptomatic effects of the disease.