Mutations TBL, 2024-25, RAK College of Medical Sciences PDF

RAK Medical & Health Sciences University, Ras Al Khamiah, UAE RAK College of Medical Sciences Course: Genetics Year: 2024-25 Course code:...

RAK Medical & Health Sciences University, Ras Al Khamiah, UAE RAK College of Medical Sciences Course: Genetics Year: 2024-25 Course code: Program: MD Y 2 Date of TBL Session: 21st October Semester: 3 Topic: Mutations By the end of this lesson, students will be able to: 1. Understand the concept of mutations 2. Classify and explain types of gene and chromosomal mutations 3. Understand the causes, detection, and repair of mutations -------------------------------------- What is Mutation A mutation is defined as a heritable alteration or change in the genetic material (alterations in the genetic material (DNA) of a cell). These changes can occur spontaneously or due to environmental factors, but the vast majority occur spontaneously through errors in DNA replication and repair, affecting either germline or somatic cells. Sequence variants with no obvious effect on phenotype may be termed polymorphisms. Somatic mutations may cause adult-onset disease, such as cancer, but cannot be transmitted to offspring. A mutation in gonadal tissue or a gamete can be transmitted to future generations, unless it affects fertility or survival into adulthood. Types of Mutations by Affected Cell Population 1. Germline mutations: o Occur in reproductive cells (sperm or eggs). o Can be passed on to offspring. 2. Somatic mutations: (acquired mutation): o Occur in non-reproductive cells. o Cannot be inherited but may lead to cancer or other diseases.  3. Mosaicism: o The presence of two or more populations of cells within an organism, each with a different genetic composition o Chromosomal mosaicism o The presence of cell populations with different karyotypes in one organism o Example: sex chromosome mosaicism is frequently seen in Turner syndrome 4. Chimerism: The presence of two genetically distinct cell lines that arise from two different zygotes that fused into one single embryo. Types of gene Mutations by Mechanism 1. Substitution: Can change a single nucleotide. Types: o Transition: Purine replaced by purine (A ↔ G) or pyrimidine by pyrimidine (T ↔ C). o Transversion: Purine replaced by pyrimidine or vice versa. 2. Insertions and Deletions: Insertion: Addition of one or more nucleotide pairs. Deletion: Removal of one or more nucleotide pairs. 3. Frameshift Mutations: Caused by insertions or deletions that change the reading frame. Results in altered protein structure and function. 4. Nonsense Mutation: A point mutation resulting in a premature stop codon, leading to truncated and usually nonfunctional proteins. 5. Missense Mutation: A point mutation leading to the substitution of one amino acid for another in the protein product. Example: Sickle cell disease. 6. Silent Mutation: A point mutation that does not change the amino acid due to redundancy in the genetic code. Effects of gene mutation Point Mutation Example: Sickle Cell Anemia Explanation: A single nucleotide change in the HBB gene (GAG to GTG) (HBB gene provides instructions for making a protein called beta-globin.) results in the substitution of glutamic acid with valine in the hemoglobin protein beta globin, causing abnormal hemoglobin thereby abnormal red blood cells. 2. Insertion Mutation Example: Huntington’s Disease Explanation: Insertion of multiple CAG trinucleotide repeats in the HTT gene leads to the production of an abnormal huntingtin protein, causing neurodegenerative symptoms. 3. Deletion Mutation Example: Cystic Fibrosis Explanation: one of the cause for cystic fibrosis is A three-base pair deletion (ΔF508) in the CFTR gene results in a missing phenylalanine, which impairs the function of the CFTR protein, causing thick mucus buildup. 4. Frameshift Mutation Example: Tay-Sachs Disease Explanation: A deletion or insertion of nucleotides in the HEXA gene alters the reading frame, leading to defective production of the enzyme hexosaminidase A, causing lipid accumulation in the brain. 5. Nonsense Mutation Example: Duchenne Muscular Dystrophy Explanation: A mutation in the DMD gene introduces a premature stop codon, leading to the production of a truncated dystrophin protein, which results in muscle degeneration. 6. Missense Mutation Example 1: Achondroplasia Explanation: A point mutation in the FGFR3 gene causes a change in amino acid from glycine to arginine, leading to abnormal bone growth and resulting in dwarfism. Example 2: Sickle Cell Anemia Explanation: A point Mutation in which a single nucleotide change in the HBB gene (GAG to GTG) (HBB gene provides instructions for making a protein called beta-globin.) results in the substitution of glutamic acid with valine in the hemoglobin protein beta globin, causing abnormal hemoglobin thereby abnormal red blood cells. 7. Silent Mutation  Example: Often occurs without clinical significance Explanation: A nucleotide change that does not alter the amino acid sequence (due to redundancy in the genetic code), resulting in no change in the protein's function. 8. Trinucleotide Repeat Expansion Example: Fragile X Syndrome Explanation: Expansion of CGG repeats in the FMR1 gene leads to gene silencing, resulting in intellectual disability and characteristic physical features. Expansion of the CAG repeat in the coding region of the HTT gene results in a protein with an elongated polyglutamine tract that forms toxic aggregates within certain cells, causing Huntington disease. In fragile X syndrome, the CGG repeat expansion in the 5′ untranslated region (UTR) results in methylation of promoter sequences and lack of expression of the FMR1 protein. Ribonucleotide repeat expansion diseases Mode of Affected gene Chromosome Trinucleotide Typical features inheritance repeat Huntington Autosomal HTT 4 CAG Chorea, akinesia, cognitive disease dominant decline, behavioral changes Fragile X X-linked FMR1 X CGG Large protruding chin, large syndrome dominant genitalia (testes), hypermobile joints, mitral valve prolapse Myotonic Autosomal DMPK 19 CTG Cataracts, premature hair loss dystrophy dominant in men, myotonia, arrhythmia, gonadal atrophy (men), ovarian insufficiency (women) Splice mutation: an alteration (especially point mutations) in the nucleotide sequence required for splicing (e.g., the exon-intron border or at the junction).Results in defective mRNA (e.g., due to a retained intron) → shortened proteins that are either defective or exert an altered function Examples include:Some forms of β-thalassemia, Gaucher disease, Marfan syndrome, Dementia,Epilepsy Dominant-negative mutation o A gene mutation that produces a nonfunctional protein that exerts a dominant effect  o This nonfunctional protein impairs the function of the normal protein encoded by the wild-type allele in heterozygous individuals (e.g., mutant, nonfunctional p53, binds DNA and prevents the attachment of the functional p53 protein) BRAC 1 & 2 Mutations can lead to diseases like cancer, where somatic mutations alter key regulatory genes. Inherited mutations, such as in BRCA1 and BRCA2, increase cancer risk, while mutations like in the HBB ( Hemoglobin beta ) gene cause sickle cell anemia. Introduction to Chromosomal Mutations Chromosomal mutations, also known as chromosomal aberrations, are changes in the structure or number of chromosomes. Unlike gene mutations, which affect individual genes, chromosomal mutations affect large segments of DNA, sometimes entire chromosomes, leading to significant changes in an organism’s traits or development. 2. Types of Chromosomal Mutations A. Structural Mutations These involve changes in the structure of one or more chromosomes. The main types are: 1. Deletion: o Definition: A segment of the chromosome is removed or lost. o Effect: The genes in the deleted region are completely missing. This can lead to significant health issues because important genetic information is lost. o Example: Cri du Chat Syndrome – caused by a deletion on the short arm of chromosome 5, resulting in developmental delays, a distinctive high-pitched cry, and intellectual disabilities. 2. Duplication: o Definition: A segment of the chromosome is copied and inserted into the genome. o Effect: This results in multiple copies of certain genes, which can lead to developmental disorders or gene dosage imbalances. o Example: Charcot-Marie-Tooth Disease – caused by duplication on chromosome 17, leading to nerve damage and muscle weakness. o Caused by duplication of the PMP22 gene on chromosome 17, leading to peripheral neuropathy and muscle weakness. 3. Inversion: o Definition: A chromosome segment breaks, flips 180 degrees, and reattaches in reverse orientation. o Effect: Although no genetic material is lost, the inversion can disrupt gene function if it occurs within a gene. It may also affect how genes interact with regulatory elements. o Example: Inversions can contribute to infertility if they affect chromosomes involved in meiosis. A chromosome segment is reversed end-to-end. Disease: Hemophilia A (Inversion of Chromosome X)  Explanation: An inversion on the X chromosome disrupts the F8 gene, leading to a deficiency in clotting factor VIII and resulting in bleeding disorders. 4. Translocation: o Definition: A segment of one chromosome breaks off and attaches to another, non-homologous chromosome. o Effect: Can cause problems if the break occurs within a gene or if it creates fusion genes that lead to cancer. o Example: Chronic Myeloid Leukemia (CML) – caused by a translocation between chromosomes 9 and 22, creating the "Philadelphia chromosome” leading to the production of the BCR-ABL fusion protein, which drives uncontrolled cell division. o Unbalanced translocations: Unbalanced translocation o Unbalanced translocations can result in chromosomal imbalance (e.g., Patau syndrome), multiple malformations, stillbirth, and repeated miscarriages) o Trisomy 13 (also called Patau syndrome) is a genetic disorder in which a person has 3 copies of genetic material from chromosome 13, instead of the usual 2 copies. o Robertsonian Translocation Disease: Down Syndrome Explanation: Caused by a Robertsonian translocation involving chromosomes 14 and 21 (46,XX, rob(14;21)). Leading to features of Down syndrome such as intellectual disability and characteristic facial features. B. Numerical Mutations These involve changes in the number of chromosomes rather than their structure. Definition: The failure of chromosomes to separate properly during cell division (meiosis), leading to an abnormal number of chromosomes in the offspring. o Effect: Results in an extra or missing chromosome, which can cause developmental disorders. Examples: Trisomy 21 (Down Syndrome): Caused by an extra copy of chromosome 21. Symptoms: Developmental delays, intellectual disabilities, characteristic facial features (such as a flat nasal bridge), heart defects, and an increased risk of Alzheimer's disease. ▪ Turner Syndrome (Monosomy X): Occurs when a female has only one X chromosome (45,X). ▪ Symptoms: Short stature, infertility, heart defects, and normal intelligence but possible learning difficulties. ▪ Klinefelter Syndrome (XXY): Males with an extra X chromosome (47,XXY) may have reduced fertility, less muscle mass, and learning difficulties. Uniparental Disomy  Disease: Prader-Willi Syndrome Explanation: Occurs when a child inherits both copies of chromosome 15 from the mother (maternal uniparental disomy). This leads to hypotonia, obesity, and intellectual disability. 4. Causes of Chromosomal Mutations Chromosomal mutations can arise spontaneously during cell division or be caused by environmental factors. Some common causes include: 1. Errors in Meiosis: o During the formation of sperm or eggs, chromosomes may not separate correctly (non- disjunction), leading to aneuploidy in the offspring. 2. Exposure to Mutagens: o Radiation, chemicals, and certain drugs can damage chromosomes, causing structural mutations like deletions or translocations. 3. Inherited Mutations: o Some chromosomal mutations can be passed down from parents to offspring if they occur in germ cells (sperm or eggs). 5. Detection of Chromosomal Mutations Chromosomal mutations can be detected using techniques like: 1. Karyotyping: o This is the process of photographing chromosomes during cell division. Chromosomes are stained, arranged, and analyzed to detect abnormalities in number or structure. o Example: Down syndrome is diagnosed by identifying three copies of chromosome 21 in a karyotype. 2. Fluorescent In Situ Hybridization (FISH): o A more advanced technique that uses fluorescent probes to bind to specific parts of chromosomes, allowing scientists to detect specific mutations like translocations or deletions. 6. Consequences of Chromosomal Mutations The consequences of chromosomal mutations depend on the type and severity of the mutation. They may include: 1. Developmental Disorders: Conditions like Down syndrome and Turner syndrome are caused by chromosomal abnormalities and result in physical, intellectual, and developmental challenges. 2. Cancer: Some cancers, such as Chronic Myeloid Leukemia (CML), are caused by chromosomal translocations that lead to uncontrolled cell growth. 3. Infertility: Structural chromosomal mutations (like inversions or translocations) can interfere with normal meiotic division, causing infertility. Mutations and Mutagenesis Naturally occurring mutations are referred to as spontaneous mutations and are thought to arise through chance errors in chromosomal division or DNA replication. Environmental agents that cause mutations are known as mutagens. These include natural or artificial ionising radiation and chemical or physical mutagens. Radiation Ionising radiation includes electromagnetic waves of very short wavelength (x-rays and γ-rays) and high- energy particles (α particles, β particles and neutrons). X-rays, γ-rays and neutrons have great penetrating power, but α particles can penetrate soft tissues to a depth of only a fraction of a millimeter, and β particles only up to a few millimeters. Chemical Mutagens In humans, chemical mutagenesis may be more important than radiation in producing genetic damage. Experiments have shown that certain chemicals, such as mustard gas, formaldehyde, benzene, some basic dyes and food additives, are mutagenic in animals. Exposure to environmental chemicals may result in the formation of DNA adducts, chromosome breaks or aneuploidy. Consequently, all new pharmaceutical products are subject to a battery of mutagenicity tests that include both in vitro and in vivo studies. DNA Repair DNA mutations, if left unrepaired, would have serious consequences for both the individual and subsequent generations. Table: DNA repair pathways, genes, and associated disorders The majority of DNA repair mechanisms involve cleavage of the DNA strand by an endonuclease, removal of the damaged region by an exonuclease, insertion of new bases by the enzyme DNA polymerase, and sealing of the break by DNA ligase. Mutations genes encoding these proteins can cause xeroderma pigmentosum, manifests as extreme sensitivity to ultraviolet light and a high frequency of skin cancer. A different set of repair enzymes is used to excise single abnormal bases (base excision repair), with mutations in the gene encoding the DNA glycosylase MYH having been shown to cause an autosomal recessive form of colorectal cancer. Naturally occurring reactive oxygen species and ionizing radiation induce breakage of DNA strands. Double-strand breaks result in chromosome breaks that can be lethal if not repaired. Post replication repair is required to correct double-strand breaks Mismatch repair (MMR) corrects mismatched bases introduced during DNA replication. Cells defective in MMR have very high mutation rates. Mutations in at least six different MMR genes cause familial colorectal cancer, Lynch syndrome (also known as hereditary non-polyposis colorectal cancer, is the most common cause of hereditary colorectal (colon) cancer. People with Lynch syndrome are more likely to get certain cancers and to develop these cancers at a younger age (before age 50). Although DNA repair pathways have evolved to correct DNA damage and hence protect the cell from the deleterious consequences of mutations, some mutations arise from the cell’s attempts to tolerate damage. One example is trans lesion DNA synthesis, in which the DNA replication machinery bypasses sites of DNA damage, allowing normal DNA replication and gene expression to proceed downstream. Human disease may also be caused by defective cellular responses to DNA damage. Cells have complex signaling pathways that allow cell-cycle arrest to provide increased time for DNA repair. If the DNA damage is irreparable, the cell may initiate programmed cell death (apoptosis). The ATM protein (a serine/threonine protein kinase) is involved in sensing DNA damage, and has been described as the “guardian of the genome.” Mutations in the ATM gene cause ataxia telangiectasia characterized by hypersensitivity to radiation and a high risk of cancer. ---------------------