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Texas A&M Professor Awarded Grants For Autism Research

By: Texas A&M Press Release
By: Texas A&M Press Release

Work underway at Texas A&M University, sponsored by two foundations with a deep interest in autism, may one day provide clues to one type of autism. Autism spectrum disorders (ASD) are a set of complex developmental disorders characterized by persistent deficits in social communication and interaction, as well as restricted behaviors, interests or activities.

Dr. Scott Dindot, assistant professor in the Department of Veterinary Pathobiology (VTPB) at the Texas A&M College of Veterinary Medicine & Biomedical Sciences, recently received two grants to create mouse models of chromosome 15q duplication syndrome (Dup15q syndrome), one of the most frequent known genetic mutations in those with ASD. In this disorder, an individual has too many copies (as many as seven or eight) of a series of genes located on a region of chromosome 15q (hence the name Dup15q).

Oddly, only duplications on the chromosome inherited from the mother seem to determine whether an individual will be affected. Rarely are paternally derived duplications seen in patients with autistic-like behaviors. This is because genes within 15q, including one called UBE3A, are subject to genomic imprinting, a phenomenon where the allele from one parent is active and the one from the other is silent. In the brain, the UBE3A gene is active only on the maternal chromosome. Therefore, scientists believe that an overabundance of UBE3A in the brain causes the neurological deficits seen in patients with Dup15q syndrome.

Mouse models are essential to advance understanding of the biological processes that cause ASDs, as well as to test potential therapies. A good model — which Dindot is trying to create — has both construct validity (meaning that they carry a mutation in a known risk gene) and face validity (some physical or behavioral resemblance to the human disorder).

The first grant, from the Dup15q Alliance (a nonprofit run entirely on grants and donations with over 900 affiliated families from around the world), for $40,000 has allowed for the creation of Dindot’s first mouse model of Dup15q syndrome. Although the first mouse was an important initial step, more than one model is needed. The second grant, from the Simons Foundation Autism Research Initiative (SFARI), for $85,000 will help Dindot and his team to generate and characterize a series of five more mouse models of Dup15q syndrome.

In the brain, the gene codes for at least three separate isoforms, or types of UBE3A, each a slightly different protein with very subtle variances in their amino acid sequences. However, researchers don’t currently understand what these differences mean.

“Each line of mice we are generating will overexpress a particular UBE3A isoform,” Dindot said. “This will allow us to determine the role of each isoform in the development of Dup15q syndrome.”

Furthermore, mouse models of human genetic conditions express, in some instances, different characteristics, depending on the genetic background of the mouse the researchers originally used. This can be a particularly important issue when performing behavioral studies in mice. So, to account for the effect of the “background strain,” (as the genetic backgrounds are called) Dindot and his colleagues are making each of the three models using two very different strains of mice, for a total of six. The Texas A&M Institute of Genomic Medicine will be assisting in this collaborative effort.

Once these models are molecularly validated, (in other words, shown to be expressing high levels of Ube3a in the brain), they will be made widely available to the scientific community through a partnership between SFARI and The Jackson Laboratory, a nonprofit genetics research organization that maintains a vast database of mice that can be ordered and used by scientists around the world.

“Dr. Dindot’s work on mouse models for Dup15q syndrome has the potential to unlock new pathways of discovery for treatments and therapies for autism spectrum disorders,” said Dr. Robert Burghardt, acting associate dean for Research and Graduate Studies. “These two grants recognize the importance of his work, and the tremendous expertise that is brought together through this collaborative effort.”

The development of an inducible UBE3Atransgenicmouse model will facilitate studies of the behavior associated with UBE3Aover-expression in the brain on a cellular level. The model could also be used to test potential therapies and to determine the period of development during which a therapeutic intervention could be optimal.

“Dr. Dindot’s research encompasses basic, clinical, and translational research and is, therefore, ideally suited for the Veterinary Medicine setting,” said Dr. Linda Logan, professor and pead of VTPB. “Given that most successful investigators tend to take either one path or the other, it is very difficult to find high quality scientist who can fluently speak the languages of basic science and clinical research. Dr. Dindot has been successful in both arenas, which is a rare accomplishment. The impact and scope of his current work along with his passion for research bodes well for his future endeavors and I am confident that he will continue to be successful in his scholarly pursuits.”

“We are very grateful to the Dup15q Alliance and SFARI for providing funds to generate these mouse models of Dup15q syndrome,” Dindot said. “I would like to particularly thank Kadi Luchsinger and Guy Calvert at the Dup15q Alliance, Alice Luo Clayton and Marta Benedetti at SFARI, and Larry Reiter at the University of Tennessee, who is a co-principal investigator on the Dup15q Alliance grant. This is an important project; we are humbled and honored to be a part of it.”


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