the GAD1 gene; interacts with diseases of dyskinesia (depending on the drug), schizophrenia, peripheral neuropathy, diabetes, hyperprolactinemia.

GAD1 GENE (Glutamic acid decarboxylase 1)

Gene type: Protein coding

Organism: Homo sapiens

This gene encodes one of several forms of glutamic acid decarboxylase that has been identified as a major autoantigen in insulin-dependent diabetes. The encoded enzyme is responsible for catalyzing the production of gamma-aminobutyric acid (GABA) from L-glutamic acid. Since it has been identified as an autoantigen and autoreactive T cell target in insulin-dependent diabetes, a pathogenic role for this enzyme has been identified in the human pancreas. It has been shown that this enzyme deficiency leads to pyridoxine (vitamin B) dependence with seizures. There is a dominant 67-kD form of this gene and a less frequent 25-kD form.

Progeny: Eukaryota; metazoa; Chordata; Craniata; vertebrata; Euteleostomy; Mammalia; Eutheria; Euarchontoglires; primates; haplorrhini; Catarrhini; Hominidae; Homo

GAD is located in the pancreas where it is required for insulin secretion. GAD67, which converts glutamate to GABA (γ-amino butyric acid), is found in the hypothalamus, cerebellum (which controls motor function), and various brain regions. In the hypothalamus, GAD is located in the suprachiasmatic nucleus (SCN), where GABA plays a central role in the circadian rhythm. Low GAD level disrupts the circadian rhythm. GAD 1 is a gene that produces GAD67. This enzyme breaks down the anxiety-inducing neurotransmitter glutamate into the calming neurotransmitter GABA. So the more of this enzyme, the more comfortable we will be. Increasing the gene is often good.

GABA (γ-aminobutyrate, 4-aminobutyrate) was first discovered in 1883. It acts as a neurotransmitter in 20% of the junctions in the central nervous system (CNS). GABA is the best known presynaptic inhibitor in the central nervous system and retina. It is an important transmitter for brain metabolism and functioning. GABA is formed by the decarboxylation of glutamate; The enzyme glutamate carboxylase (GAD), which has been shown to exist in nerve endings in many parts of the brain by immunohistochemical methods, catalyzes the reaction. Body fluids contain gamma aminobutyrate. GABA is found in every class of living organisms. In higher organisms, GABA functions as an inhibitory neurotransmitter; For those without a nervous system, such as plants and bacteria, GABA is considered an important signaling molecule. GAD catalyzes the synthesis of GABA from glutamate.

GABA is mainly metabolized by transamination to succinic semialdehyde.

Pyridoxal phosphate is the cofactor of GAD and GABA-T. Succinate semialdehyde can either be reduced to γ-hydroxybutyrate by reaction catalyzed by L-lactate dehydrogenase or oxidized to succinate, an intermediate of the citric acid cycle, and from there to CO 2 and H 2O. A vesicular transporter carries the GABA formed at the nerve endings to the secretory vesicles. There is also efficient reuptake of GABA by a GABA transporter located in the plasma membrane. The transmembrane transporter has 10 domains while the vesicular transporters have 12 domains.

A low level of GABA increases the level of excitatory neurotransmitters. Studies have shown that GABA levels are low in multiple sclerosis, movement tremor, tardive dysnesia, other movement-related diseases, panic attacks, anxiety, depression, alcoholism, and bipolar disorders. In addition to its positive effects on the central nervous system, medical studies have shown that GABA has various effects on the body. Among these effects, increase in growth hormone, regulation of sleep, stabilization of blood pressure, analgesic effect in chronic pain such as arthritis and low back pain, increase in the effect of insulin hormone, appetite suppressant and reducing premenstrual symptoms can be counted.

Disorders of GABA metabolism identified to date;

  1. Pyridoxine dependent convulsions (glutamic acid dehydrogenase deficiency)
  2. GABA transaminase (GABA-T) deficiency
  3. Succinic semialdehyde dehydrogenase (SSADH) deficiency
  4. Homocarnosinosis

In the autopsy study, the amount of GABA was found to be low in the brain tissue of one patient and in the CSF of another patient. The cofactor of the glutamic acid dehydrogenase enzyme is pyridoxine. In these cases, it is thought that there is a defect in cofactor binding to the enzyme. It has been revealed that the enzyme has two different molecular weight forms of 65 and 67 kDa. The enzyme with a weight of 65 kDa has been found to be associated with insulin-dependent diabetes and stiff-man syndrome.

Stif-person syndrome (SPS), originally called Stiffman syndrome, is a disease characterized by progressive rigidity and spasm of trunk and extremity muscles. Antibodies to the enzyme glutamic acid decarboxylase (GAD) are present in approximately 60% of patients. The presence of GAD in the insulin-secreting B cells of the pancreas, in the junctional vesicles-like roofs, is also interesting, and GABA may be a paracrine mediator in islets. Insulin-dependent diabetes mellitus is an autoimmune disease characterized by destruction of B cells, and the most abundant antibody in this picture is that against GAD. Mental retardation is also seen when recurrent convulsions are not treated. Inheritance is autosomal recessive and chromosome locus is 2q31.

GAD enzyme;

It is synthesized in the cell body and transported to the terminal by axonal transport. This enzyme removes the α-carboxyl group of glutamate at axon terminals, resulting in GABA. It needs pyridoxal phosphate as a cofactor.

VitB6, manganese, taurine and lysine increase the synthesis and effect of GABA. In addition, pitresin is converted to Ɣ-aminobutyrate in two separate ways. One is the deamination with which diamine oxidase is involved, and the other is the reaction using N-acetylated intermediates. The significance of this pathway is variable among different tissues.

GAD 1 is effective in beta-alanine metabolism, GABA synthesis, glucose-energy metabolism pathways. It is associated with cytosol, mitochondria, peroxisome in beta-alanine metabolism. It is associated with cytosol, mitochondria and peroxisome in GABA synthesis. In the glucose-energy metabolism pathway, it is associated with cytosol, ER, extracellular, mitochondria, peroxisome.

SNP; Single nucleotide polymorphism is commonly referred to as nucleotide changes in DNA between individuals. Methods for detecting these point changes can also find small insertions or deletions of one or more bases. Polymorphisms are also frequently defined as regions where a variant is less common than at least 1% of the population. Although these variants are of low frequency, in some cases they are very important. SNPs in two ways; useful for finding genes that contribute to disease. Some SNP alleles are DNA sequence variants that lead to differences in gene function or regulation that directly contribute to disease. Many SNP alleles contribute small amounts to the disease.

The results of SNPs vary depending on where they are located.

-It may not produce any results.

Affects gene transcription structurally or quantitatively

It can change the structure and function of the protein.

It can change gene regulation.

SNPs can produce different effects.

•SNPs may have no effect. That is, its effects are neutral for the protein, remaining as silent mutations.

•The impact of SNPs may be negligible. Like arginine replacing lysine (both polar and basic amino acids).

•SNPs can produce measurable changes such as decreased activity.

•SNPs can alter protein function. Can recognize new substrates.

•SNPs can completely abolish the function of the protein.

Nucleotide changes or rearrangements that occur in the DNA molecule are called “mutations”. We can group mutations in different ways:

Hereditary mutations (Germline mutation)-It is present in every cell of the body.

Acquired (Somatic mutation) – Occurs during life and is found in certain cells of the body. Since only somatic cells are affected, they are not transferred to the next generations.

According to the formation mechanism;


Chromosome Mutations (Translocation)

Gene mutations (Point mutations)

Changes seen in more than 1% of the population are called polymorphisms.

They cause missense mutations. Missense mutation; It occurs when the amino acid synthesized from the codon changes after a point mutation in the DNA triplet codon. It is the conversion of one amino acid to another amino acid as a result of a single nucleotide change. They cause function change. 50% of the mutations that cause genetic diseases are caused by these mutations.

In a study, a GAD1 sequence change G (36) C was determined in 4 siblings with autosomal recessive spastic CP (cerebral palsy). This nucleotide substitution changes serine (12) to a cysteine ​​in the N-terminal domain, resulting in a missense mutation. This serine remnant is conserved among all mammals for which data are available (human/mouse/rabbit/pig). The S(12)C amino acid substitution can thus exert subtle effects on cellular localization, protein-protein interactions, and protein processing, and then act on GABA production. This is associated with mouse GAD1 knockout, in which complete loss of GAD1 enzymatic function (approximately 20% reduction of total GAD activity in the cerebral cortex) results in a cleft palate phenotype and neonatal death.

the GAD 1 gene; interacts with diseases of dyskinesia (depending on the drug), schizophrenia, peripheral neuropathy, diabetes, hyperprolactinemia.

Dyskinesia is a movement disorder whose etiology has not been determined exactly, therefore it does not have a definite treatment, can be permanent, and significantly affects the life of the person. They are abnormal, involuntary movements that can occur in the extremities and trunk, especially involving the mouth, tongue and face. Various treatment methods are tried in the treatment of dyskinesia, from drug-free monitoring to deep brain stimulation.

More than 100 markers were examined in studies to detect a possible biomarker in the brains of schizophrenia patients, and glutamic acid decarboxylase (GAD) was frequently studied. It has been reported that there is an increase in H3-K4 methylation of GAD and other gene promoters during the development of the human prefrontal cortex, starting from the prenatal period and lasting until adolescence. It has been reported that this increase in methylation parallels the increase in mRNA expression of related genes. It has been determined that there is a decrease in the H3-K4 methylation of the GAD1 gene in female schizophrenic patients, and clozapine (a drug used in schizophrenia) reverses this decrease.

It is H3-K4 lysine methyltransferase and activates genes in the euchromatin region.

To understand peripheral neuropathy, one must first know what the peripheral nervous system is. This is the communication network within us and is responsible for sending information back and forth from our brain and spinal cord to all parts of our body. For example, when we want to walk somewhere, it is our peripheral nervous system that tells our legs to start moving. If we cut our finger, the same system sends a message to our brain that something is wrong and we are in pain. Peripheral neuropathy is a condition that occurs when this communication system is damaged. Typically, this damage is caused by the side effects of systemic diseases (diseases that affect our entire body rather than just a particular part or organ) and trauma or disease to the peripheral nervous system. Instead of running smoothly as usual, A system suffering from peripheral neuropathy often distorts or cuts off messages altogether. Symptoms; temporary numbness, tingling, burning sensations, sensitivity to touch, muscle weakness, muscle wasting, inability to sweat normally, organ dysfunction, gland dysfunction, digestive problems, paralysis, organ failure. No matter how bad it is, peripheral neuropathy rarely leads to death unless the symptoms are complicated by other conditions or diseases.

Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction and especially to organs, eyes, kidneys, nerves, heart and blood vessels. Various pathogenic processes are involved in the development of diabetes. These range from autoimmune destruction of pancreatic β cells due to insulin deficiency to abnormalities that result in resistance to insulin action. The basis of abnormalities in carbohydrate, fat and protein metabolism in diabetes is the insufficient effect of insulin on target tissues. Insufficient insulin action results from decreased tissue responses to inadequate insulin secretion to insulin at one or more points in the complex pathways of hormone action.

Hyperprolactinemia is a condition in which a person has a higher-than-normal level of the hormone prolactin in the blood. The main function of prolactin is to stimulate breast milk production after delivery, so high prolactin levels are normal during pregnancy. Prolactin also affects sex hormone levels (estrogen and testosterone) in both men and women. Prolactin is secreted by the pituitary gland, a pea-sized organ located at the base of the brain.

A common cause of hyperprolactinemia is a growth or tumor in the pituitary gland called a prolactinoma. The tumor produces high levels of prolactin. These tumors can be large or small and are usually benign, meaning they are not cancerous. Small tumors (less than 1 cm) are called microprolactinomas and larger tumors (greater than 1 cm) are called macroprolactinomas. Large tumors can also cause headaches, vision problems, or both. Prolactinomas are more common in women than men and rarely occur in children.

It has been observed that the expression of glutamate transporters (SLC1A2 and SLC1A3) and the enzyme that synthesizes gamma-aminobutyric acid [glutamic acid decarboxylase 1 (GAD1)] in the dorsolateral prefrontal cortex (dlPFC) is decreased in people with major depressive disorder.

Decreases in SLC1A2 and GAD1 mRNA expression are associated with attenuation of the RAF/MEK/ERK signaling pathway in the dlPFC.



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