Different types of genetic disorders are caused by a variation or mutation in a gene. A genetic disease is a disease due to one or more abnormalities on one or more chromosomes that cause malfunction of certain cells of the body. These cells make proteins. The activity and structure of each protein are determined by the genetic information contained in a gene. If the gene is altered, it causes the cell to malfunction, which can become, at any age of life, with the expression of disease.
A mutation is a rare, accidental or induced modification of genetic information – a sequence of DNA or RNA (ribonucleic acid) – in the genome.
All of the recent findings show how far-reaching comparisons and analyzes of large populations, relying on computing power that would have been unimaginable only a few years ago, are creating a new approach global structure of the brain and pathologies that can affect it.
Researchers from Oxford University (UK) in a study published in Nature in July 2015 identified two different types of genetic disorders related to major depressive disorder.
Major depressive disorder, one of the most common forms of mental illness and the leading cause of disability in the world, is a major challenge to genetic analysis.
The team analyzed more than six million gene variants in the genomes of more than 10,000 Chinese women between 30 and 60 years of age who had had at least two episodes of major depressive disorder. They identified two genetic variants – located in the SIRT1 and LHPP genes – that were strongly linked to depression.
Previous studies have suggested that genetics have an influence on depression, but after analyzing more than 9,000 cases, scientists failed to find a strong relationship between genetic variants and this mental disorder.
The team replicates their results in another group of about 6,000 Chinese men and women, which shows that the results are not gender-specific. However, while both genetic variants are very common in the Chinese population, they are relatively rare in European populations.
Their analysis revealed the existence of two zones, both located in chromosome 10, associated with a major depressive disorder.
One of these regions is close to the SIRT1 gene, known for its role in the production of mitochondria, generating energy structures that can be linked in some way with depression.
The second area is an intron of the LHP gene, whose function is to code a specific protein.
Although these findings represent an important advance for understanding depression, the authors point out that this complex mental disorder depends on the existence of several environmental and genetic factors.
The team anticipates that their discovery will lead to more discoveries of genetic variants related to depression.
II – Do Creativity and Psychosis
According to a British study by researchers at CODE Genetics (Iceland) and King’s College London, published in June 2015 in the journal Nature Neuroscience, there is a link between creativity and psychosis.
Researchers see creative people as people who are able to have an innovative approach using mental processes different from dominant patterns of thought or expression.
Thus the artistic fiber and certain mental illnesses, such as schizophrenia and bipolarity, would at least partially have common genetic roots.
They studied the genome of more than 86,000 Icelanders. Members of national artistic societies of dancers, actors, musicians or writers were considered creative. Clerical workers, farmers, salespeople or manual workers were not included in this category.
The researchers then crossed their genomes with different genetic variations that would seem to be linked to schizophrenia and bipolarity.
Result: statistically, the genetic code of the artists would be halfway between that of psychotic people and that of “normal” people. Creative people may have a genetic predisposition to think differently, which, when combined with other adverse biological or environmental factors, could lead to mental illness.
If the idea that a link exists between mental disorders and artistic sense seems easy to accept, this study has many points to clarify. The authors admit that the underlying biological mechanisms of these diseases are still little known. In these two diseases, a multitude of genes can intervene. What is undeniable is that there is in no case a single gene for bipolarity, schizophrenia, or creativity. Be it the roots of creativity or those of psychoses, they intimately mix the genetic part and the experiences of life.
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III – The TUBB5 Gene Is Responsible for Microcephaly
According to a study led by Julian Heng, a researcher at the Institute of Regenerative Medicine at the University of Monash (Australia) published in Human Molecular Genetics in June 2014, disruptions to the cytoskeleton gene called TUBB5 could be responsible for impaired mental function in humans. children born with an intellectual disability.
The study shows that TUBB5 is essential for the production and maturation of neurons in the development of the nervous system in mammals. Mutations in the β-tubulin gene TUBB5 cause microcephaly with structural abnormalities of the brain in humans.
The researchers explain that while TUBB5 is necessary for the correct generation and migration of neurons, little is known about the role it plays in neuronal differentiation and connectivity.
Disturbances at TUBB5 disrupt the morphology of cortical neurons, their neuronal complexity, axonal outgrowth, and the density and shape of dendritic spines in the postnatal murine cortex. The characteristics described are compatible with defects in synaptic signaling.
Studies show that TUBB5 is essential for neuronal differentiation and dendritic spine formation in vivo.
IV – Genetic Origin of Calcification of the Brain
An international team coordinated by Giovanni Coppola at UCLA, in collaboration with the Molecular Genetics Institute of Montpellier, Rouen University Hospital and Fundación Pública Galega de Xenómica (Spain), in a study published in the journal Nature Genetics in May 2015, establishes a direct link between a defect in phosphate metabolism and brain calcification by characterizing a new gene, XPR1, that encodes a phosphate exporter.
Primary familial calcification, a rare disease that can occur between the ages of 3 and 80 and is associated with neuropsychiatric and motor disorders, is characterized by phosphocalcic deposits in the brain and cerebellum.
Phosphate is one of the most abundant minerals in our body and a major constituent of cellular structures and physiological balances. It is notably a component of nucleic acids and membranes, and the balance of energy equilibrium between the coenzyme ADP (adenosine diphosphate) and ATP (adenosine triphosphate). In addition, it controls the activity of enzymes and essential regulatory proteins that are kinases and phosphatases, while at the physiological level, it is the ionic counterweight of calcium.
As a result, disturbances in phosphate concentration are associated with various severe pathologies. Among these, primary family calcification, which is a rare genetic disorder, formerly known as Fahr’s disease, is characterized by calcification of the brain, particularly in the basal ganglia and some nuclei of the cerebellum. It is manifested by the appearance of neurological disorders that can occur at any age, but more generally in adulthood. The patient may lose intellectual, motor and cognitive abilities and present psychiatric disorders.
These studies demonstrate that XPR1 is a new phosphate transporter involved in familial primary brain calcification. The researchers hypothesize that inhibition of phosphate export by XPR1 mutations increases the intracellular phosphate concentration, leading to calcium precipitation. The direct involvement of XPR1 in phosphate export and its expression profile in the brain is consistent with its role in cerebral phosphate homeostasis and also opens up new perspectives regarding the involvement of phosphate homeostasis in calcification phenomena in general.
V – The Causes of Autism and Intellectual Disability Begin in the Synapse
A study by researchers at MIT’s Picower Institute for Learning and Memory, published in Nature Neuroscience in January 2015, showed that the two very different genetic causes of autism and intellectual disability disrupt the synthesis of synaptic proteins, and a treatment developed for one disease produces a cognitive benefit in the other.
Many genetic diseases lead to intellectual disability and autism. Historically, these genetic brain diseases have been considered incurable. However, in recent years neuroscientists have shown in animal models that it is possible to reverse the debilitating effects of these genetic mutations. But the question remains whether the different gene mutations disrupt common physiological processes. If this were the case, a treatment developed for a genetic cause of autism and intellectual disability could be helpful for many others.
One of the inherited causes of intellectual disability and autism is the fragile X syndrome, which occurs when a single gene in the X chromosome, called FMR1, is extinguished during brain development. Fragile X is rare, affecting one in about 4,000 people.
In previous studies using mouse models of fragile X, it was discovered that the loss of this gene leads to the exaggerated synthesis of synaptic proteins, specialized sites in communication between neurons. This protein synthesis was stimulated by the neurotransmitter glutamate, through a glutamate receptor called mGluR5. This led to the theory called mGluR, according to which excess protein synthesis triggers activation of the mGluR5 receptor, resulting in many of the psychiatric and neurological symptoms of fragile X. This theory has been tested in mice, finding that inhibition of mGluR5 restores equilibrium in protein synthesis and reverses many defects in animal models.
Another cause of autism and intellectual disability is the loss of a series of genes in human chromosome 16, called micro-deletion 16p11.2.
Some of the 27 genes involved play a role in the regulation of protein synthesis, which has led researchers to question whether the 16p11.2 micro-deletion syndrome and fragile X syndrome affect synapses of the same way. To answer this question, the researchers used a mouse model with the 16p11.2 micro-deletion.
Using electrophysiological, biochemical and behavioral analyses, the team compared this 16p11.2 mouse with what they had already established in fragile X-mice. Synthesis of synaptic proteins has indeed been disrupted in the hippocampus, a part of the brain important for memory formation. In addition, when they tested memory in these mice, they discovered a severe deficit, similar to fragile X.
These results encouraged researchers to attempt to improve memory function in 16p11.2 mice with the same approach used on fragile X-mice. Treatment with an inhibitor of mGluR5 significantly improved cognition in these mice. This benefit was obtained with one month of treatment that started well after birth.
The implication is that some cognitive aspects of this disease, which was thought to be an intractable consequence of early altered brain development, may instead result from ongoing changes in synaptic signaling that can be corrected by drugs.
VI – New Method Detects Different Types of Genetic Disorders That Cause Brain Disorders
A study conducted at the Boston Children’s Hospital, published in the New England Journal of Medicine in August 2014, used the deep sequencing technique, able to identify some not-very-common mutations in patients with brain disorders.
Disease-causing mutations do not necessarily affect all cells in the body, and it is easy for them to go unnoticed, even when looking for them with the most modern techniques of genome sequencing.
The researchers explain that there are two kinds of somatic mutations that go unnoticed. These are mutations that are limited to specific tissues: If one does a blood test, but the mutation is only in the brain, it is not found. Other mutations can be in all tissues but occur only in a fraction of cells, this is the mosaic pattern. These may be detectable by a blood test, but they are not frequent enough to be easily detectable.
The team used the deep sequencing technique in 158 patients with brain malformations of an unknown genetic cause, causing symptoms such as seizures, intellectual disability and speech, and language disorders.
Instead of analyzing the entire genome or exome – the regions of the genome that translate into proteins – deep sequencing focuses on known or suspected gene panels, but the form of analysis is deeper. The genome exome or the entire sequencing usually breaks the DNA into small fragments which are read several times, usually for pathogenic mutations. But 30 readings are not enough to reliably catch mutations that occur in only 15 to 20 percent of our cells, especially since mutations can affect only one of our two copies of a gene.
The team increased the number of reads of each candidate gene on a larger scale, not 30 times, but at least 200 times. Thanks to this in-depth reading, they found mutations in 27 of 158 patients (17%).
Eight of the 27 mutations occurred in only a portion of their blood cells (mosaic mutations). Five of the eight were not detected by traditional Sanger genomic sequencing. Another had undergone sequencing of the exome without being detected.
With deep sequencing, they were able to identify mutations that affect 10 percent of the cells in a blood sample.
The findings may help explain other brain-based disorders such as autism, intellectual disability, and epilepsy that have escaped genetic diagnosis.
The study creates a paradigm shift, providing evidence that a significant proportion of the mutations responsible for brain disorders occur after conception and are not detected by routine testing.
VII – CLP1 Gene Mutation Causes Brain Disorders
Two scientific teams, one from the Yale University School of Medicine and the Academic Medical Center in the Netherlands, and the other from the Austrian Academy of Sciences, whose studies were published in Cell in April 2014, identified a genetic disorder associated with degeneration of central and peripheral nervous systems in humans.
The CLP1 protein plays an important role in the generation of functional mature molecules called transfer RNAs (tRNAs), which shuttle for the amino acids of subunits called cellular ribosomes for protein assembly.
Ribosomes are ribonucleoprotein complexes (protein and RNA compounds) present in eukaryotic and prokaryotic cells. Their function is to synthesize proteins by decoding the information contained in the messenger RNA.
By sequencing the DNA of more than 4,000 families affected by neurological problems, the two research teams independently discovered that a disease marked by reduced brain size and sensory and motor defects is caused by a mutation in the brain. a gene called CLP1, which is known to regulate metabolism in cells via tRNAs.
DNA sequencing was performed on children with neurological problems. Seven of the more than 4,000 families studied share a similar CLP1 mutation, which has been associated with motor disorders, slurred speech, seizures, brain atrophy, and neuronal death.
Each child tested was affected by undiagnosed neurological problems. All children have been found to have a mutation in the CLP1 gene and have the same symptoms, such as brain malformations, intellectual disabilities, seizures and sensory and motor defects.
Mutations affecting molecules involved in tRNA production have been implicated in human neurological disorders, such as pontocerebellar hypoplasia (PCH), an incurable neurodegenerative disease currently affecting children. Although CLP1 mutations were linked to motor neuronal defects in mice, the role of CLP1 in human disease was not known until now.
VIII – Identification of New Genes Associated with Autism
Researchers at the University of Barcelona in a study published in the journal Molecular Psychiatry in October 2013, focused on changes in DNA, in order to identify the candidate genes that may be associated with autism.
Scientists analyzed the DNA of families with 2 or 3 children affected by autism. This is the first time that science has been dealing with a genomic perspective of this mental disorder, emphasizing the role of genetic inheritance.