CSHL scientists clarify editing error underlying genetic neurodegenerati...( Two molecular biologists at Cold Spr...)

Two molecular biologists at Cold Spring Harbor Laboratory have uncovered important new details about how a gene mutation causes a cellular editing error that results in a devastating disease called pontocerebellar hypoplasia (PCH). The new findings were published online, ahead of print, on January 25th in the journal Nature Structural and Molecular Biology.

Typically striking during early childhood, PCH is characterized by the slow wasting away of certain parts of the brain, resulting in abnormal brain function and cognitive impairment characteristic of mental retardation. Although scientists have known about the gene mutation that causes the disease, they haven't been able to explain why the mutation causes a defect in an essential cellular function called RNA splicing.

RNA splicing is an essential step in the process in cell nuclei whereby instructions encoded in DNA are transcribed to RNA copies, which subsequently leave the nucleus to serve as templates for the cellular machinery to manufacture protein molecules. The RNA intermediaries (called "messengers"), in order to function properly in this role, are typically "edited" by special enzymes, which perform a procedure analogous to the editing of frames in a film, where unnecessary frames are left out of the final version.

An 'atypical' splice site

The new discovery stems from a program of research by Professor Adrian Krainer, Ph.D., and members of his lab at CSHL, to understand how cells process the information encoded in genes. For reasons that remain poorly understood, the raw or unedited RNA copy of DNA includes excess RNA segments called introns that need to be edited out in order for the RNA's message to be functional. Once the introns are removed, the remaining segments -- called exons -- are pasted together, forming a mature messenger RNA transcript.

In an unedited RNA molecule, the boundaries between an intron and its two flanking exons
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