RNA-binding protein key to understanding myotonic dystrophy type 1

Oct 12 2007

Increased levels of a protein called CUGBP1 play an important role in the adult-onset form of muscular dystrophy called myotonic dystrophy type 1, said Baylor College of Medicine researchers in a report that appears in the journal Molecular Cell.

Myotonic dystrophy type 1 is one of a growing number of newly recognized RNA diseases. RNA (ribonucleic acid) or messenger RNA takes the “message” about which proteins to make from the DNA to the protein manufacturing apparatus in the cell's interior or cytoplasm.

Myotonic dystrophy type 1 is the most common adult-onset form of muscular dystrophy. It is associated with hundreds and even thousands of repeats of the nucleotides CTG within a gene called DM kinase protein gene or DMPK. [Cytosine (C), thymine (T), guanine (G) and adenine (A) are all nucleotides that make up DNA. C, G, A, and uracil (U) make up RNA.]

In myotonic dystrophy type 1, the levels of CUGBP1 go up in heart and skeletal muscle, two tissues affected in the disease, because the protein becomes phosphorylated or acquires a phosphate molecule, which causes it to remain in the cell longer than it normally would.

“Normally, during heart development, CUGBP1 regulates alternative splicing (the building of the RNA message that determines which proteins are made by the cell),” said Dr. Thomas A. Cooper, professor of pathology at BCM and senior author of the paper. “But CUGBP1 goes away during normal heart development. In adults, the levels of CUGBP1 should be low.”

However, when the RNA nucleotide repeats are expressed, they stimulate a signal that is normally present in embryonic tissues and not in adults. Specifically, the protein kinase C pathway is reactivated resulting in the addition of the phosphate molecules to CUGBP1. With the addition of the phosphate molecules, CUGBP1 levels increase to those observed in the embryonic period.

“This affects alternative splicing,” said Cooper. “It changes the splicing from an adult pattern to an embryonic pattern. Adult tissues express embryonic proteins, and that's why people get sick.”

Another RNA-binding protein called muscleblind like 1 (MBNL1) is also involved in the disease. It binds genetic material in the nucleus of the cell, trapping the RNA there and preventing it from transporting the RNA messages into the cell's cytoplasm. MBNL also becomes trapped with the RNA rendering it unable to function.

“In addition to gaining a better understanding of what causes this disease, we have learned that both CUGBP1 and MBNL1 regulate splicing of many genes during normal muscle development,” said Cooper.