December 17, 2020 (Huntsville, Ala.) – In a fascinating story that began with a spontaneous genetic mutation, a research team from the HudsonAlpha Institute for Biotechnology and Auburn University College of Veterinary Medicine have identified a gene involved in the development of the cerebral cortex.
The discovery of the cats
Several years ago, a spontaneous disease arose in a colony of cats at Auburn University’s Scott-Ritchie Research Center that caused the animals to have tremors beginning shortly after birth. As the cats aged, they also developed sensory abnormalities and often became aggressive. Since the colony had been studied for such a long time at Auburn, the researchers knew there must be something new going on with these cats.
“The cats in this colony have been critical in the study of lysosomal storage diseases for many years,” said Auburn University Department of Pathobiology Assistant Professor Emily Graff, DVM, PhD. “The emergence of the spastic movements and gait problems in some of these cats could not be easily attributed to any other mutations we had seen in this population before. Based on the clinical picture, we knew we needed to investigate the basis of the disease further as it could lead to some potentially exciting results in neurobiology.”
An initial assessment of the cats revealed that in addition to the spastic tremors the cats exhibited outwardly, they also had small, underdeveloped brains that were missing the characteristic folds and fissures normally seen in cat brains. There was also a forty-five percent decrease in the weight of brains from the affected cats. The team at Auburn, led by Assistant Professor Emily Graff, DVM, PhD and Professors Nancy R. Cox, DVM, PhD and Doug Martin, PhD, determined that the cats had extensive abnormalities in brain development and organization, specifically in the cerebral cortex.
The cerebral cortex is the outermost layer of the brain that gives the brain its characteristic wrinkled appearance. The folds and crevices of the brain are formed during a process called gyrification. Abnormal development of the cerebral cortex, called cerebral dysgenesis, leads to a wide variety of neurodevelopmental abnormalities such as cortical dysplasia, microcephaly, heterotopia, schizencephaly, and polymicrogyria. Individuals with cerebral dysgenesis display symptoms that can range from intellectual disability to severe epilepsy and neural tube defects.
PEA15 is critical for central nervous system development and function
The spontaneous appearance of the disease suggested to the researchers that it might be genetic in nature. So, the research team at Auburn’s College of Veterinary Medicine enlisted the help of genomics experts at HudsonAlpha to help determine the genetic cause of the neurological symptoms these cats were experiencing. Nick Cochran, PhD, a senior scientist in the Rick Myers lab, led the HudsonAlpha efforts for the project under collaborative direction from HudsonAlpha Faculty Investigator Greg Barsh, MD, PhD. Results from the study were published in PLoS Genetics this month.
Whole genome sequencing of the cats’ DNA identified a frameshift variant in the gene phosphoprotein expressed in astrocytes-15 (PEA15) as a likely candidate for the abnormalities in brain development. Frameshift variants are caused by a deletion or insertion in a DNA sequence that shifts the way the sequence is read by transcriptional machinery that copies DNA into mRNA. In this case, a single-nucleotide deletion in PEA15 prematurely stops the copying of the DNA into mRNA, meaning PEA15 protein cannot be created from the mRNA. PEA15 is known to regulate cell death in astrocytes, a type of support cell in the brain.
The researchers concluded that the pathogenic variant in PEA15 likely causes failure of the cerebral cortex to expand and fold properly, leading to the neurological symptoms in the cats.
Because cat brains have gyri like human brains, the results from this study could have implications in the field of human neurobiology, more specifically in the study of cerebral dysgenesis.
“By comparing the whole-genome sequence of these affected cats to publicly available cat genomes from the 99 Lives consortium, we were able to focus on genetic differences between the two groups, ultimately narrowing in on the PEA15 variant,” says Cochran. “This study highlights not only the importance of whole-genome sequencing and other genomic technologies, but also the value of publicly sharing information amongst researchers. The availability of the reference genomes from 99 Lives was immensely helpful for our project.”
About HudsonAlpha: HudsonAlpha Institute for Biotechnology is a nonprofit institute dedicated to developing and applying scientific advances to health, agriculture, learning, and commercialization. Opened in 2008, HudsonAlpha’s vision is to leverage the synergy between discovery, education, medicine, and economic development in genomic sciences to improve the human condition around the globe. The HudsonAlpha biotechnology campus consists of 152 acres nestled within Cummings Research Park, the nation’s second largest research park. The state-of-the-art facilities co-locate nonprofit scientific researchers with entrepreneurs and educators. HudsonAlpha has become a national and international leader in genetics and genomics research and biotech education and fosters more than 40 diverse biotech companies on campus. To learn more about HudsonAlpha, visit hudsonalpha.org.