Rare Mutations May Have Big Impact on Schizophrenia Pathology | Nutrition Fit

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Summary: “Somatic” gene mutations in brain cells could account for some of the pathology of schizophrenia.

Source: Elsevier

Schizophrenia is a neurodevelopmental disorder that disrupts brain activity producing hallucinations, delusions, and other cognitive disturbances. Researchers have long searched for genetic influences in the disease, but genetic mutations have been identified in only a small fraction–fewer than a quarter–of sequenced patients. A new study now shows that “somatic” gene mutations in brain cells could account for some of the disease neuropathology.

The study, led by senior author Jeong Ho Lee, MD, PhD, at Korea Advanced Institute of Science and Technology and the team of Stanley Medical Research Institute, appears in Biological Psychiatry, published by Elsevier.

Traditional genetic mutations, called germline mutations, occur in sperm or egg cells and are passed on to offspring by their parents. Somatic mutations, in contrast, occur in an embryo after fertilization, and they can appear throughout the body or in isolated pockets of tissues, making them much harder to detect from 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 present at very low levels can have functional consequences. A previous study hinted that brain somatic mutations were associated with schizophrenia (SCZ), but it was not powerful enough to cement such an association.

In the current study, the researchers used deep whole-exome sequencing to determine the genetic code of all exomes, the parts of genes that encode proteins. The scientists sequenced postmortem samples from 27 people with schizophrenia and 31 control participants both from brain and from liver, heart or spleen tissue, allowing them to compare the sequences in the two tissues.

Using a powerful analytic technique, the team identified an average of 4.9 somatic single-nucleotide variants (SNV), or mutations, in brain samples from people with SCZ and 5.6 somatic SNVs in brain samples from control subjects.

Although there was no significant quantitative difference in somatic SNVs between SCZ and control tissues, the researchers found that the mutations in SCZ patients were found in genes already associated with SCZ. Of the germline mutations that had previously been associated with schizophrenia, the genes affected encoding proteins associated with synaptic neural communication, particularly in a brain region called the dorsolateral prefrontal cortex.

The researchers then determined which proteins might be affected by the newly identified somatic mutations. Remarkably, a protein called GRIN2B emerged as highly affected, and two patients with SCZ carried somatic mutations on the GRIN2B gene itself. GRIN2B is a protein component of NMDA-type glutamate receptors, which are critical for neural signaling. Faulty glutamate receptors have long been suspected to contribute to SCZ pathology; GRIN2B ranks among the most-studied genes in schizophrenia.

John Krystal, MD, Editor of Biological Psychiatry, said of the work, “The genetics of schizophrenia has received intensive study for several decades. Now a new possibility emerges, that in some cases, mutations in the DNA of brain cells contributes to the biology of schizophrenia. Remarkably this new biology points to an old schizophrenia story: NMDA glutamate receptor dysfunction. Perhaps the path through which somatic mutations contribute to schizophrenia converges with other sources of abnormalities in glutamate signaling in this disorder.”

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A previous study hinted that brain somatic mutations were associated with schizophrenia (SCZ), but it was not powerful enough to cement such an association. Image is in the public domain

Dr. Lee and the team next wanted to assess 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 receptors’ localization on neurons.

Experiments in cortical neurons from mice showed that the mutations indeed disrupted the receptors’ usual localization to dendrites, the “listening” ends of neurons, which in turn prevented the formation of normal synapses in the neurons. The finding suggests that the somatic mutations could disrupt neural communication, contributing to SCZ pathology.

The somatic mutations identified in the study had a variant allele frequency of only about 1 percent, indicating that the mutations were rare among brain cells as a whole. Nevertheless, they have the potential to create widespread cortical dysfunction.

Dr. Lee said of the findings: “Besides the comprehensive genetic analysis of brain-only mutations in postmortem tissues from schizophrenia patients, this study experimentally showed the biological consequence of identified somatic mutations, which led to neuronal abnormalities associated with SCZ. Thus, this study suggests that brain somatic mutations can be a hidden major contributor to SCZ and provides new insights into the molecular genetic architecture of SCZ.”

About this genetics and schizophrenia research news

Source: Elsevier
Contact: Rhiannon Bugno – Elsevier
Image: The image is in the public domain

Original Research: Closed access.
Low-level brain somatic mutations are implicated in schizophrenia” by Myeong-Heui Kim, Il Bin Kim, Junehawk Lee, Do Hyeon Cha, Sang Min Park, Ja Hye Kim, Ryunhee Kim, Jun Sung Park, Yohan An, Kyungdeok Kim, Seyeon Kim, Maree Webster, Sanghyeon Kim, Jeong Ho Lee. Biological Psychiatry


Abstract

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Low-level brain somatic mutations are implicated in schizophrenia

Background

Somatic mutations arising from the brain have recently emerged as significant contributors to neurodevelopmental disorders, including childhood intractable epilepsy and cortical malformations. However, whether brain somatic mutations are implicated in schizophrenia (SCZ) is not well established.

Methods

We performed deep whole exome sequencing (average read depth>550x) of matched dorsolateral prefrontal cortex and peripheral tissues from 27 SCZ and 31 age-matched control individuals, followed by comprehensive and strict analysis of somatic mutations, including mutagenesis signature, substitution patterns, and involved pathways. Particularly, we explored the impact of deleterious mutations in GRIN2B through primary neural culture.

Results

We identified an average of 4.9 and 5.6 somatic mutations per exome per brain in SCZ and control individuals, respectively. These mutations presented with average variant allele frequencies of 8.0% in SCZ and 7.6% in controls. Although mutational profiles, such as the number and type of mutations, showed no significant difference between SCZ and controls, somatic mutations in SCZ brains were significantly enriched for SCZ-related pathways, including dopamine receptor, glutamate receptor, and long-term potentiation pathways. Furthermore, we showed that brain somatic mutations in GRIN2B (encoding glutamate ionotropic receptor NMDA type subunit 2B), which were found in two SCZ patients, disrupted the location of GRIN2B across the surface of dendrites among primary cultured neurons.

Conclusions

Taken together, this study shows that brain somatic mutations are associated with the pathogenesis of SCZ.

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