Normal Gene Properties: Gene Expression and Regulation
Discuss About The Connection Between A Gene Protein Disease?
According to the World Health Organization (1), genes and proteins provide a connection to diseases .Genes determine the order of amino acids used to make proteins, they undergo mutation that cause diseases and gene disorders such as sickle cell anaemia. Furthermore, genes affect the occurrence of non-communicable diseases such as diabetes and cancer (3). Genes and proteins play a major role in the genetics and occurrence of major diseases of the world therefore understating the connection between genes, proteins and disease is of much help to the patients medicine and the society. This essay is aimed at investigating the connection between a gene, protein, and disease, focusing mainly on the link between protein structure and function in the disease and a further analysis of the relevance to patients, medicine, and the society.
University of Leicester (6) defines gene expression as a process where the gene’s nucleotide sequence directs synthesis of proteins and production of cell structures. The process involves two main stages, First is transcription, a process that involves production of messenger RNA (mRNA) .Transcription also involves the processing of the resultant mRNA molecule. Second is translation, a process where mRNA directs protein synthesis and a further processing of the protein molecule (6).Gene regulation involves cellular processes that regulate manner and rate of gene expression (6). Gene regulation first involves regulating the transcription rate regulating how RNA molecules are processed and regulation of stability in mRNA molecules(6).
The gene structure has elements such as the protein coding sequence and a sequence for regulation of gene expression. Furthermore, they are expressed by a promoter sequence.RNA polymerase and transcription factors bind and allow for the recognition of promoters to initiate transcription. Weakly transcribed genes have a weak promoter sequences that rarely initiate transcription while genes that are strongly transcribed have promoter sequences that are strong and ensure a perfect bind to initiate transcription to proteins (6).Genes are located on the chromosome in a linear fashion like beads on string(6).
Regina (8) states that a nucleotide sequence in the DNA undergoes changes that lead to gene mutation . The alteration affects either one-nucleotide sequence or the gene segments in a chromosome. Often when a nucleotide sequence is altered, it results in the formation of nonfunctioning proteins. The most common types of mutations are the point mutations .They include silent mutations, which do not produce a visible change in the protein.In addition to that, misense mutations allow for the production of different amino acids. Finally, nonsense mutations alter the nucleotide sequence leading to the coding of a stop codon that stops transcription.(8).
Gene Structure and Localization
Base pair insertions or deletions occur when nucleotide base pairs are deleted or inserted to the original gene sequence (7).The Human Genome institute states that almost all diseases have a genetic factor. Diseases are caused by various kinds of mutations in the gene (7).
Ellen (9) summarizes that proteins are versatile macromolecules since they perform an array of functions. Proteins are involved in growth and maintenance of tissues. Proteins provide energy and they are involved in hormone production. Hormones regulate functions in the body that relate to many organs. For example, insulin controls the amount of glucose in blood. (9).Enzymes are proteins that catalyze the body’s chemical reactions. Proteins are also involved in the storage and transport of molecules such as haemoglobin, moreover, they form antibodies that fight diseases and infections (9).
The primary structure of proteins is generally made up of amino acids. Proteins have twenty essential and non-essential amino acids, which have an amino group and a carboxyl group. This functionality structure enables each amino acid to link to another and form peptide bonds. Peptides are formed when 50 amino acids with short sequences link together while longer sequences form polypeptides or proteins (11).Amino acids have different structures because of the differences that occur in their side chains. Proteins are synthesized during transcription and translation. Posttranslational modifications such as phosphorylation and glycosylation are important for function of a protein (4).
The secondary structure depend on hydrogen bonding. The structure is divided into an α helix and a β sheet, the alpha helix is right handedly coiled with an external extension inside chain substituents of amino groups. Formation of hydrogen bonds involves the oxygen molecule of one peptide bond and hydrogen molecule of another peptide bond and these bonds ensure the stability of the structure (11).β sheet hydrogen bonds are formed between two strands. The sheets can be parallel or anti parallel based on similar or different directions of the N-terminus or C- terminus strand. An antiparallel β sheet has well aligned hydrogen bonds therefore; it is more stable than a parallel β sheet (11).
This is the general 3-D shape of a protein. The protein twists in a manner it can attain a low energy state or maximum stability (11).The protein 3D shape appears random and irregular but it is shaped by several stabilizing forces such as disulfide bridges, hydrogen bonds, and salt bridges because of the interaction of bonds between amino acids side chains(10).Protein molecules are composed of many protein subunits that interact and arrange themselves to form an aggregate bigger protein complex known as a quaternary structure (4).
Examination and Analysis of Gene Dysfunction (Common and Rare Mutations)
Protein dysfunctions might induce a loss of a function or a gain of a function, furthermore, they can cause a complete loss of protein or reduction on the ability of the protein to perform its functions (4). Classification of proteins mainly depends on the similarities of amino acid sequences and structures. The classification is aimed at determining evolutionary relationships in proteins. Proteins are classified into class, fold, super family, family, protein domains, species and domain. The taxonomy enables a proper understanding of drugs, production of vaccines, or antibodies for biomedical research (7).
The disease is signified by the deposition of amyloid on cortical arteries and leptomeningeal arterioles and it is associated with old age.Hereditary forms of CAA are rare in the population, they are more acute and severe on the onset, and furthermore, they occur in the young people .The action of secretases on the amyloid precursor protein results in the deposition of amyloid peptides, proving some aspects of pathophysiology of Alzheimer’s disease (13).
Fifty percent of individuals who get the disorder are over 70 years therefore it can be asymptomatic since it can be displayed as evidence of normal aging. Deposition of amyloid in the cerebral blood vessels causes their rupture, this leads to asymptomatic micro bleeds. Amyloid deposits that lead to ischemia. Clinical manifestations related to it such as leokoaraiosis, incomplete infarction, and cerebral infarction obliterate the vessel lumen. This can lead to unconsciousness, cognitive decline or death. Focal neurological deficits and seizures occur in CAA patients (13, 12).
An affected brain tissue obtained via brain biopsy or at autopsy is used in histological investigations, often CAA evidence is found in postmortem investigations. Furthermore, another proposed non-invasive method of diagnosis is emission tomography imaging with a compound that binds β amyloid. Histological diagnosis requires the use of special stain under light microscopy. The standard staining method of amyloid has been Puchtler alkaline Congo red stain but it has a low sensitivity (15). A more sensitive Thioflavin S stain can be used with Congo red stain. Fluorescent microscopy and immunohistochemistry with antibodies specific for a particular precursor protein can be used as a diagnostic tool(15).
The disease is a common clinical entity and there have been frequent findings in pathology among the elderly people.According to an analysis done on brains at Harvard Brain Tissue Resource Center, 2.3 % of 65 to 74 year olds were graded as severe or moderate carriers 80% in 75 to 84 years old and 12% for those over 85 years old. It can be present in 10% to 40% of most of the elderly brains. (14).
The disease is characterized by a point mutation, which translates to Leucine for a Glycine change at position 68 of cystatin C protein. In the hydrophobic core of the protein, a mutated residue, and the substitution of the amino acid affects the molecule stability thus destabilizing the alpha helical structure, which leads to a molecule that is more unfolded with an ability to form dimeric assemblies. A study on the crystal structure of the molecule reveals that through the three-dimensional domain swapping, dimerization occurs which leads to the formation of larger structures that resemble amyloid (12).
Cerebral amyloid angiopathy is a disorder that damages the adventitia and media of the leptomeningeal and cortical vessels, stenosis of lumen and it enhances fragmentation of internal lamina. This process of disease manifestation leads to microaneurysm, fibrinoid necrosis thus predisposing the body to cerebral hemorrhage. The disorder also induces changes in the brain that include lobar cerebral hemorrhage, cortical ischemic infarcts, leukoencephalopathy and plague deposition in tissues (13).Ravi (13) argues that the mild condition of the disease affects a smaller portion of the superficial cortical and leptomeningeal vessels while in severe conditions of the disease, there is a significant amyloid deposition in arteries and arterioles. The most affected are medium sized arteries with deposition of amyloid outside the tunica media to tunica adventitia(13).
Masahito(14) states that since there are no therapies for modifying the CAA disease, current and future potential for the treatment lie in the presence of biomarkers and risk factors. Deposition of cerebrovascular amyloid is a primary target for treatment and prevention. Therapies for anti amyloid include Ponezumab, a monoclonal antibody which specifically attaches itself to the carboxyl region in the Aβ40.Currently, the therapy has been applied to individuals with CAA.A trial is going on currently to assess the tolerability, safety and efficacy of ponezumab in adults(14). Several non-genetic factors such as hypertension and thrombolytic anticoagulation have been associated to CAA, and they are to be avoided. Future considerations in regards to treatment and preventation should involve protection of blood vessels walls against causes of degradation and research on anti-amyloid therapies.
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