updated: November 13, 2022 21:21 IST
Washington [US], Nov 13 (ANI): Researchers have long looked for genetic influences in schizophrenia, a neurodevelopmental disorder that disrupts brain activity resulting in hallucinations, delusions and other cognitive disorders. However, disease genetic mutations have been identified in only a small fraction less than a quarter of serial patients. A new study shows that “somatic” genetic mutations in brain cells could be responsible for some neurodegenerative diseases.
The study, led by senior author Jeong Ho Lee, MD, PhD, at the Korea Advanced Institute of Science and Technology and the Stanley Institute for Medical Research team, appeared in Biological Psychiatry, published by Elsevier.
Traditional genetic mutations, called germline mutations, occur in the sperm or egg cells and are passed on from parents to offspring. By contrast, somatic mutations occur in the fetus after fertilization, and can appear throughout the body or in isolated pockets of tissue, making them more difficult to detect than blood or saliva samples, which are typically used for such sequencing studies.
Recently, more advanced genetic sequencing techniques have allowed researchers to detect somatic mutations, and studies have shown that even mutations found at very low levels can have functional consequences. A previous study suggested that somatic mutations in the brain were associated with schizophrenia (SCZ), but were not strong enough to support such an association.
In the current study, the researchers used whole-exome deep sequencing to determine the genetic code for all exomes, the parts of genes that encode proteins. The scientists sequenced postmortem samples from 27 people with schizophrenia and 31 participants from brain and from liver, heart or spleen tissue, allowing them to compare the sequences in tissues. Using a robust analytical technique, the team identified an average of 4.9 somatic single-nucleotide variants (SNVs), or mutations, in brain samples from people with SCZ and 5.6 somatic SNVs in brain samples from controls.
Although there was no significant quantitative difference in somatic SNV between SCZ and control tissues, the researchers found that mutations in SCZ patients were found in genes already associated with SCZ. Among germline mutations previously associated with schizophrenia, genes affected encoded proteins associated with synaptic communication, particularly in a brain region called the dorsolateral prefrontal cortex.
The researchers then identified proteins that might be affected by the newly identified somatic mutations. Remarkably, a protein called GRIN2B appeared to be severely affected, and two patients with SCZ carried somatic mutations on the same GRIN2B gene. GRIN2B is a protein component of the NMDA-type glutamate receptor, which is essential for neuronal signaling. Defective glutamate receptors have long been suspected to contribute to SCZ pathology; GRIN2B ranks among the most studied genes in schizophrenia.
John Crystal, MD, editor of Biological Psychiatry, said of the work, “The genetics of schizophrenia has received extensive study for several decades. A new possibility is now emerging, which is that, in some cases, mutations in the DNA of brain cells contribute to the biology of Remarkably, this new biology tells an old story about schizophrenia: a defect in the NMDA glutamate receptor. Perhaps the pathway by which somatic mutations contribute to schizophrenia converge with other sources of abnormalities in glutamate signaling in this disorder.”
Dr. Lee and the team next wanted to evaluate the functional consequences of the somatic mutations. Because of the location of the GRIN2B mutations found in SCZ patients, the researchers hypothesized that they might interfere with the receptor’s localization in neurons. Experiments with cortical neurons from mice showed that the mutations actually disrupted the usual receptor localization of dendrites, the “listening” ends of neurons, which in turn prevents the formation of normal synapses in neurons. The results suggest that somatic mutations can disrupt neural communication, thus contributing to the pathology of SCZ.
The somatic mutations identified in the study had a variable allele frequency of only about 1 percent, indicating that mutations were rare among brain cells as a whole. However, they have the potential to create widespread cortical dysfunction.
About the findings, Dr. Lee said of the findings: “Besides comprehensive genetic analysis of brain mutations only in postmortem tissues from patients with schizophrenia, this study experimentally demonstrated the biological outcome of the identified somatic mutations, which resulted in SCZ-related neurological abnormalities. The study indicates that Somatic mutations in the brain could be a major cryptic contributor to SCZ and provide new insights into the molecular genetic structure of SCZ.” (Ani)