MMD1: Lost Proteins’ Roles Revealed?

Scientists at several U.S. institutions have added yet another piece of the puzzle of type 1 myotonic dystrophy (MMD1, also called DM1).

Much of the problem in this disease appears to be caused by the loss of contributions normally made to cells by a protein called MBNL1. In MMD1-affected cells, MBNL1 can't do its job properly because it's trapped in tangles of abnormally expanded genetic material in the cell nucleus. (For more on this, see Coming Unglued.)

It's been found that a protein called MBNL2 seems to be similarly entrapped, and it now appears that its loss may also account for problems in this complex disease, according to a paper published online Jan. 24, 2010, in Nature Structural and Molecular Biology.

It may be that some of the problems in MMD1, such as myotonia (difficulty relaxing muscles), abnormalities in muscle growth and altered sugar metabolism are related to the loss of MBNL1; and that others, such as muscle atrophy and weakness, stem from the loss of MBNL2.

About MMD1's molecular underpinnings

In type 1 myotonic muscular dystrophy, extra-long strands of genetic material called RNA trap proteins called MBNL1 and MBNL2. Loss of the normal contributions of these two proteins appear to underlie many of the problems seen in this disease.

MMD1 is a complex disease involving abnormal muscle growth, skeletal muscle atrophy and myotonia, as well as cardiac, gastrointestinal, ocular and sometimes cognitive abnormalities.

The genetic cause of the disease is an expanded section of DNA in a gene on chromosome 19. The expanded DNA results in synthesis of longer-than-normal strands of RNA, a close relative of DNA, which act like spider webs in cell nuclei.

In MMD1, the long strands of RNA stay in the nuclei of cells, and protein molecules, such as MBNL1 and MBNL2, become stuck to them.

Loss of MBNL1's normal function leads to improper "splicing" of several proteins, such as some of those involved in muscle contraction and growth.

About the new findings

The new findings suggest that the normal contribution of MBNL2 is to help maintain the groutlike mixture in which muscle fibers are embedded. This mixture, known as the "extracellular (outside the cell) matrix," is made up of several proteins, such as collagens, integrins and elastin, without which -- like tiles without enough grout -- the muscle fibers aren't properly anchored to their surroundings.

Hongqing Du at the University of California-Santa Cruz and colleagues, coordinated by Manuel Ares, also at UC Santa Cruz, say that the "vast majority" of splicing dysregulation caused by the genetic defect in MMD1 is due to "catastrophic loss" of MBNL1 activity; but that loss of a different protein, probably MBNL2, appears to lead to a loss of correct production and localization of several extracellular matrix proteins. MBNL2 appears to act at the genetic level to help maintain muscle-fiber structure.

"We were very surprised to see so many extracellular matrix genes affected and are really excited about the possibility that MBNL2 contributes to muscle integrity," said Ares.

It is this latter loss, they postulate, that may account for the weakness and muscle atrophy in MMD1, while several other aspects of the disease can be accounted for by the entrapment of MBNL1 and perhaps other proteins.

MDA's role

Manuel Ares at UC Santa Cruz, though not MDA-supported for this particular study, has a current MDA grant to study splicing misregulation in MMD.

Another study author, Maurice Swanson, at the University of Florida in Gainesville, also not funded for this particular project, is a longtime MDA grantee who has current MDA funding to study the role of the MBNL3 protein. He's also a member of MDA's Scientific Advisory Committee.

And study author Charles Thornton, at the University of Rochester (N.Y.), is a past recipient of MDA funding for work in MMD1 and is currently co-director of the MDA clinic at his institution, and is a member of MDA's Medical Advisory Committee.

"Even though we didn't have MDA funding for this project, the synergism among MDA-supported researchers is worth many dollars in terms of progress, which is the bottom line," Ares commented.

Meaning for people with MMD1

Although there is no immediate implication for therapy, the deciphering of the mechanisms underlying MMD1 offer avenues through which these disease mechanisms can be corrected.

For example, giving patients MBNL1 and/or MBNL2 genes or proteins could be an approach for treating MMD1. Disrupting the abnormal genetic expansion in MMD1, with the goal of freeing MBNL1, MBNL2 and other trapped molecules, is also an avenue for therapeutic development.

Disease: 
Link: 
GUID: 
14 301
Time Stamp: 
1 265 189 401
Thumbnail: 
http://quest.mda.org/sites/default/files/imagecache/mda_org_frontpage100x75/mosaic%20tile%20and%20grout.JPG
Node Type: 
Quest News