Team finds clue in basic biology of X-linked mental retardation

Scientists describe process that fails to silence improper neuronal gene expression

SAN ANTONIO (Aug. 11, 2008)—Our genes express (or issue) the instructions by which our proteins operate. Disorder results when the instructions issued are incorrect and the resulting actions taken are correspondingly faulty.

In individuals who exhibit X-linked mental retardation, a complicated cascade of occurrences during development results in abnormal neuronal gene expression. Neurons are the cells that make up the nervous system, which includes the brain and spine.

Mutations associated with X-linked mental retardation are known to disrupt the function of a protein called MED12. This protein plays a key role in silencing untoward neuronal gene expression, so that the instructions to convert a cell into a neuron are issued only when needed.

In the Aug. 7 issue of Molecular Cell, scientists at The University of Texas Health Science Center at San Antonio describe the mechanism by which MED12 normally applies the silent treatment to ensure correct neuronal gene expression.

“We found that MED12 directs a histone-modifying enzyme to mark neuronal genes with a repressive signal and, further, that X-linked mental retardation-causing mutations in MED12 disrupt this repression function, leading to the inappropriate expression of neuronal genes,” said the journal article’s lead author, Thomas Boyer, Ph.D., associate professor in the Health Science Center’s Department of Molecular Medicine. The department is located at the UT Institute of Biotechnology in the Texas Research Park in western Bexar County.

Epigenetic code
Histone is an important component in what scientists call the epigenetic code. This code is active throughout life to control activities of the genome, the genetic blueprint found in every cell. Histone tags genes for either active expression or dormancy.

“Our findings suggest a possible epigenetic basis to define the role of MED12 in the origin of X-linked mental retardation through altered neuronal development,” Dr. Boyer said.

Chromosomes are coils of genetic material in cells. Humans have 23 pairs of chromosomes in each cell, one pair inherited from the father and one from the mother. Females have 22 pairs of autosomal chromosomes and two sex chromosomes (called the X chromosomes). Males have the 22 pairs of autosomal chromosomes plus X and Y sex chromosomes.

More than 60 genes on the X chromosome have been implicated in X-linked mental retardation. Most individuals with this condition are male, partly because males have one copy of the X chromosome whereas females have two.

 

The University of Texas Health Science Center at San Antonio is the leading research institution in South Texas and one of the major health sciences universities in the world. With an operating budget of $576 million, the Health Science Center is the chief catalyst for the $15.3 billion biosciences and health care sector in San Antonio’s economy. The Health Science Center has had an estimated $35 billion impact on the region since inception and has expanded to six campuses in San Antonio, Laredo, Harlingen and Edinburg. More than 23,000 graduates (physicians, dentists, nurses, scientists and allied health professionals) serve in their fields, including many in Texas. Health Science Center faculty are international leaders in cancer, cardiovascular disease, diabetes, aging, stroke prevention, kidney disease, orthopaedics, research imaging, transplant surgery, psychiatry and clinical neurosciences, pain management, genetics, nursing, allied health, dentistry and many other fields. For more information, visit www.uthscsa.edu.



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