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Image credit by Amy Burkhat, @TheCeliacMD
Image credit by Amy Burkhat, @TheCeliacMD
Image credit by Amy Burkhat, @TheCeliacMD
Pablo Avalos Prado
Pablo Avalos Prado
Pablo Avalos Prado
Neuroscientist & Medical Writer
Neuroscientist & Medical Writer
Neuroscientist & Medical Writer
July 12, 2023
July 12, 2023
July 12, 2023
Mosaic mutations during embryonic development contribute to the genetic puzzle of schizophrenia
Mosaic mutations during embryonic development contribute to the genetic puzzle of schizophrenia
Mosaic mutations during embryonic development contribute to the genetic puzzle of schizophrenia
A new study has identified two non-inherited mutations associated with schizophrenia that could arise during early embryonic development in the utero.
Schizophrenia is a severe neurological disease with a strong environmental component which is the subject of extensive research. However, schizophrenia is also featured by its high heritability, which involves a number of genetic factors that are equally important for the onset of the disease.
A new study conducted by researchers of the Boston Children’s Hospital have found a non-inherited genetic mechanism that might contribute to up to 0.4 % of schizophrenia cases. This mechanism consists in spontaneous genetic alterations that occur in the DNAduring embryonic development that are not inherited from parents.
The authors of this study, recently published in Cell Genomics, analyzed blood samples from more than 24.000 participants belonging to the Psychiatric Genomic Consortium and identified two mutations which are associated with schizophrenia.
Mutations during pregnancy can lead to schizophrenia
During embryonic development, the early cells start to divide exponentially forming groups of cells and tissues that eventually give rise to organs. However, when a mutation occurs spontaneously (these are non-inherited mutations) in one of the early cells, some of the descendant cells will express this mutation whereas others will not, a phenomenon called mosaic mutation due to this mixed nature.
The authors of this study have found a rare mosaic mutation (5 over 12.834 patients with schizophrenia) in the gene Neuronexin-1 (NRXN1), which encodes a protein involved in synaptic transmission, an altered feature exhibited by patients with this disease. Such mutations consisted in the deletion of exons from NRXN1, which are segments of RNA carrying information for the generation of the final protein. Since this mutation was only found in the group of schizophrenia patients and not in the control cohort, and NRXN1 has been linked to other neurodevelopmental disorders, the authors suggest that mosaic deletions of NRXN1 might also contribute to schizophrenia risk.
Early developmental mutations in dopaminergic neurons contribute to schizophrenia
In addition to the mosaic deletion of NRXN1, the same study identified another mosaic mutation in six schizophrenia cases in the gene ABCB11. The protein encoding for this gene is an ATP-binding cassette (ABC) transporter of bile acids across the in hepatocytes, which are involved in a wide range antipsychotic metabolism. As a matter of fact, mosaic deletions of this gene were only present in schizophrenia cases that show high resistance to anti-psychotic medications, which globally affects 30 % of patients.
The authors found that ABCB11 is also expressed in dopaminergic neurons, specifically within the dorsal stream of the substantia nigra. Interestingly, most of anty-psychotics to treat schizophrenia target the dopaminergic circuitry, which suggests that ABCB11 in this brain area may play an important role in the disease and the metabolism of antipsychotic drugs.
Although promising, the authors also underline an important limitation of this work: the study only studied gene variants present in blood at a high cellular fraction, restricting variants characterized to those that might have arisen during early development, which are predicted to also be mosaic in the brain. However, they hope that future research using brain-derived tissue might allow further characterization of the potential risk of these mutations in schizophrenia.
Original article
A new study has identified two non-inherited mutations associated with schizophrenia that could arise during early embryonic development in the utero.
Schizophrenia is a severe neurological disease with a strong environmental component which is the subject of extensive research. However, schizophrenia is also featured by its high heritability, which involves a number of genetic factors that are equally important for the onset of the disease.
A new study conducted by researchers of the Boston Children’s Hospital have found a non-inherited genetic mechanism that might contribute to up to 0.4 % of schizophrenia cases. This mechanism consists in spontaneous genetic alterations that occur in the DNAduring embryonic development that are not inherited from parents.
The authors of this study, recently published in Cell Genomics, analyzed blood samples from more than 24.000 participants belonging to the Psychiatric Genomic Consortium and identified two mutations which are associated with schizophrenia.
Mutations during pregnancy can lead to schizophrenia
During embryonic development, the early cells start to divide exponentially forming groups of cells and tissues that eventually give rise to organs. However, when a mutation occurs spontaneously (these are non-inherited mutations) in one of the early cells, some of the descendant cells will express this mutation whereas others will not, a phenomenon called mosaic mutation due to this mixed nature.
The authors of this study have found a rare mosaic mutation (5 over 12.834 patients with schizophrenia) in the gene Neuronexin-1 (NRXN1), which encodes a protein involved in synaptic transmission, an altered feature exhibited by patients with this disease. Such mutations consisted in the deletion of exons from NRXN1, which are segments of RNA carrying information for the generation of the final protein. Since this mutation was only found in the group of schizophrenia patients and not in the control cohort, and NRXN1 has been linked to other neurodevelopmental disorders, the authors suggest that mosaic deletions of NRXN1 might also contribute to schizophrenia risk.
Early developmental mutations in dopaminergic neurons contribute to schizophrenia
In addition to the mosaic deletion of NRXN1, the same study identified another mosaic mutation in six schizophrenia cases in the gene ABCB11. The protein encoding for this gene is an ATP-binding cassette (ABC) transporter of bile acids across the in hepatocytes, which are involved in a wide range antipsychotic metabolism. As a matter of fact, mosaic deletions of this gene were only present in schizophrenia cases that show high resistance to anti-psychotic medications, which globally affects 30 % of patients.
The authors found that ABCB11 is also expressed in dopaminergic neurons, specifically within the dorsal stream of the substantia nigra. Interestingly, most of anty-psychotics to treat schizophrenia target the dopaminergic circuitry, which suggests that ABCB11 in this brain area may play an important role in the disease and the metabolism of antipsychotic drugs.
Although promising, the authors also underline an important limitation of this work: the study only studied gene variants present in blood at a high cellular fraction, restricting variants characterized to those that might have arisen during early development, which are predicted to also be mosaic in the brain. However, they hope that future research using brain-derived tissue might allow further characterization of the potential risk of these mutations in schizophrenia.
Original article
A new study has identified two non-inherited mutations associated with schizophrenia that could arise during early embryonic development in the utero.
Schizophrenia is a severe neurological disease with a strong environmental component which is the subject of extensive research. However, schizophrenia is also featured by its high heritability, which involves a number of genetic factors that are equally important for the onset of the disease.
A new study conducted by researchers of the Boston Children’s Hospital have found a non-inherited genetic mechanism that might contribute to up to 0.4 % of schizophrenia cases. This mechanism consists in spontaneous genetic alterations that occur in the DNAduring embryonic development that are not inherited from parents.
The authors of this study, recently published in Cell Genomics, analyzed blood samples from more than 24.000 participants belonging to the Psychiatric Genomic Consortium and identified two mutations which are associated with schizophrenia.
Mutations during pregnancy can lead to schizophrenia
During embryonic development, the early cells start to divide exponentially forming groups of cells and tissues that eventually give rise to organs. However, when a mutation occurs spontaneously (these are non-inherited mutations) in one of the early cells, some of the descendant cells will express this mutation whereas others will not, a phenomenon called mosaic mutation due to this mixed nature.
The authors of this study have found a rare mosaic mutation (5 over 12.834 patients with schizophrenia) in the gene Neuronexin-1 (NRXN1), which encodes a protein involved in synaptic transmission, an altered feature exhibited by patients with this disease. Such mutations consisted in the deletion of exons from NRXN1, which are segments of RNA carrying information for the generation of the final protein. Since this mutation was only found in the group of schizophrenia patients and not in the control cohort, and NRXN1 has been linked to other neurodevelopmental disorders, the authors suggest that mosaic deletions of NRXN1 might also contribute to schizophrenia risk.
Early developmental mutations in dopaminergic neurons contribute to schizophrenia
In addition to the mosaic deletion of NRXN1, the same study identified another mosaic mutation in six schizophrenia cases in the gene ABCB11. The protein encoding for this gene is an ATP-binding cassette (ABC) transporter of bile acids across the in hepatocytes, which are involved in a wide range antipsychotic metabolism. As a matter of fact, mosaic deletions of this gene were only present in schizophrenia cases that show high resistance to anti-psychotic medications, which globally affects 30 % of patients.
The authors found that ABCB11 is also expressed in dopaminergic neurons, specifically within the dorsal stream of the substantia nigra. Interestingly, most of anty-psychotics to treat schizophrenia target the dopaminergic circuitry, which suggests that ABCB11 in this brain area may play an important role in the disease and the metabolism of antipsychotic drugs.
Although promising, the authors also underline an important limitation of this work: the study only studied gene variants present in blood at a high cellular fraction, restricting variants characterized to those that might have arisen during early development, which are predicted to also be mosaic in the brain. However, they hope that future research using brain-derived tissue might allow further characterization of the potential risk of these mutations in schizophrenia.
Original article