BMS100_PAT1-03v1_F2022.pptx.pdf

Pathology Concepts III Principles of Genetic Disorders BMS 100 Week 9 Genetic Mutations 1. Gene mutations 1. 2. 3. 4. Frameshift Mutation Point mutation Trinucleotide-repeat mutations Mutations within noncoding sequences 2. Complex multigenic disorders 3. Chromosomal disorders Genes and Disease geno...

Pathology Concepts III Principles of Genetic Disorders BMS 100 Week 9 Genetic Mutations 1. Gene mutations 1. 2. 3. 4. Frameshift Mutation Point mutation Trinucleotide-repeat mutations Mutations within noncoding sequences 2. Complex multigenic disorders 3. Chromosomal disorders Genes and Disease genotype commonly contributes to disease ▪ Estimated that lifetime frequency is 670/1000 ▪ 50% of spontaneous abortions/miscarriages have a chromosomal abnormality ▪ 5% of those under age 25 develop a disease with a significant genetic component ▪ … and these are just the diseases we understand Classification of mutations Point mutations ▪ 3 types of point mutations: all involving changes at one (or very few) nucleotides SUBSTITUTION ▪ THE FAT CAT ATE THE RAT ▪ THE FAT HAT ATE THE RAT INSERTION ▪ THE FAT CAT ATE THE RAT ▪ THE FAT HCA TAT ETH ERA T DELETION ▪ THE FAT CAT ATE THE RAT ▪ THE FAT ATA TET HER AT C is missing Classification: Substitution Substitutions can be: -Transitions -interchanges of purines (A, G) or of pyrimidines (C, T) - involve bases of similar shape (both one ring or both two ring) -Transversions -interchanges of purine for pyrimidine bases - involve exchange of one-ring and two-ring structures Classification of mutations Insertions or deletions of nucleotide(s) ▪ Insertions or deletions of single nucleotides can lead to frameshift mutations – all of the triplets are off by one These are often called “frame-shifting indels” Often results in total loss of function of the protein: ▪ “O” blood type results from a frameshift mutation and loss of function of the red blood cell antigen ▪ Tay-Sachs disease ▪ If a multiple of three nucleotides are inserted or deleted, then the reading frame is preserved These are often called non-frameshifting “indels” Example – most common cystic fibrosis mutation Nucleotide deletions One nucleotide deletion – frameshift Protein is no longer functional Three nucleotide deletion – non-frameshift, but loss of an amino acid Most common mutation in cystic fibrosis Classification of mutations Point mutations ▪ Silent or conservative missense point mutation = little or no change in function ▪ nonconservative missense point mutation = significant change in function Example – sickle cell anemia ▪ If the nucleotide triplet being changed becomes a stop codon, then premature ending of translation → truncated (shortened) protein = non-sense mutation Example – some types of thalassemia Codon Chart Adenine (A) Cystosine (C) Guamine (G) Thymine (T) Point mutations Non-conservative missense sickle-cell anemia Nonsense beta-thalassemia Mutations aren’t all bad Due to a mutation, some people can’t be infected by the HIV virus ▪ HIV uses a chemokine receptor, CCR5, to enter cells; a deletion in the CCR5 gene thus protects from HIV infection Sickle-cell trait – protects against malaria ▪ RBCs that have some sickle-cell hemoglobin are not good hosts for the parasite that causes sickle cell disease – thus the trait (heterozygote patient) is protective ▪ However, the homozygote (all hemoglobin is sickle-cell hemoglobin) is more vulnerable to the disease than rest of the population Genetic disorders Mendelian Disorders ▪ Autosomal mutations Dominant: structural proteins ▪ Marfan Syndrome (structural protein defect) Recessive: enzyme defects ▪ Lysosomal storage diseases ▪ X-Linked disorders Hemophilia Pedigree Drawing Mendelian disorders Due to mutations in single genes that have large effects ▪ Thought that everyone has 5 – 8 non-beneficial gene mutations Most of these have relatively small effects on phenotype ▪ 80 – 85% familial, rest are new mutations this can differ depending on the type of disorder – 80% of those with achondroplasia (defect in elongation of the bone growth plate) are new mutations ▪ Traits can be dominant, recessive, or codominant Autosomal dominant disorders Manifested in heterozygous or homozygous state Usually have at least one parent with the disorder ▪ Exception is if a spontaneous mutation occurs ▪ New mutations more common when father is older Usually manifests in each generation Autosomal dominant disorders Penetrance = how likely the mutated gene is to be expressed ▪ So, if something is autosomal dominant but has a 50% penetrance, a heterozygote may only have a 50% chance of showing the disease phenotype Expressivity = how “much” the disorder-causing gene is expressed ▪ All heterozygotes still show the trait ▪ The “intensity” of the trait differs from person to person, though Unsure of the molecular mechanisms behind this variability for most conditions Autosomal dominant disorders Most mutations lead to a protein that has reduced function, or is produced less (loss of function mutations) ▪ Autosomal dominant disorders tend to involve genes that are part of metabolic pathways or regulation of these pathways ▪ Some involve defects in structural proteins Disorders due to insufficient production of an enzyme tend to be recessive ▪ Why? Gain of function mutations are rare, but can be autosomal dominant Marfan syndrome - basics disorder of connective tissues, manifested principally by changes in the skeleton, eyes, and cardiovascular system Epidemiology: prevalence of 1 in 5000 Etiology: ▪ Disorder due to a defect in gene for fibrillin-1 75 – 85% are familial; the rest are new mutations Autosomal dominant ▪ chromosome 15 ▪ 600 distinct mutations – most are missense Marfan syndrome Pathophysiology ▪ Fibrillin is an important component of elastic connective tissue, provides a “scaffold” for elastic fibre deposition ▪ Loss of fibrillin-1 explains many findings i.e. aneurysm formation, ligamentous laxity, defects in eye structure Others are more difficult to explain Thought that increased skeletal growth is due to increased bioavailability of TGF-beta, which is affected by fibrillin levels (TGF-beta can also impact smooth muscle development) Marfan syndrome Clinical findings: ▪ Tall, with very long extremities and lax ligaments ▪ Dislocation of the lens ▪ Cardiovascular changes: Mitral valve prolapse – malformed and “weak” heart valve Weakness in the muscular layers of the aorta, which can lead to aortic valvular incompetence and development of serious aneurysms ▪ Variable expressivity – some individuals may be lacking certain clinical findings i.e. skeletal findings with no ocular findings Prognosis: Variable, main cause of mortality and morbidity are aneurysms and valvular defects ▪ Surgical repair of aneurysms, heart valves Autosomal Dominant Disorders: Marfan Syndrome Autosomal recessive disorders Largest category of Mendelian disorders Basic rules of Mendelian inheritance apply As well: ▪ The expression of the defect tends to be more uniform than in autosomal dominant disorders. ▪ Complete penetrance is common. ▪ Onset is frequently early in life. ▪ Although new mutations associated with recessive disorders do occur, they are rarely detected clinically, since the individual with a new mutation is an asymptomatic heterozygote ▪ Many of the mutated genes encode enzymes In heterozygotes, equal amounts of normal and defective enzyme are synthesized Usually the natural “margin of safety” ensures that cells with half the usual complement of the enzyme function normally Consequences of Enzyme Defects Accumulation of a substrate ▪ Sometimes the substrate can be toxic in high concentrations Blockade of a metabolic pathway Failure to inactivate another enzyme or substrate ▪ i.e. alpha-1 anti-trypsin deficiency Lysosomal storage diseases A wide variety, but only Gaucher disease will be discussed today Lysosomal storage disorders can be from a range of problems with lysosomal enzymes: ▪ Lack of the enzyme, leading up to a build-up of a substrate within a cell that is toxic ▪ Misfolding of the lysosomal enzyme ▪ Lack of a protein “activator” that binds to the substrate and improves the ability of the enzyme to act on it Pathophysiogy of lysosomal storage diseases In the example shown, a complex substrate is normally degraded by a series of lysosomal enzymes (A, B, and C) into soluble end products deficiency or malfunction of one of the enzymes (e.g., B) → incomplete catabolism → insoluble intermediates that accumulate in the lysosomes → “primary storage” problem ▪ huge, numerous lysosomes interfere with cellular function secondary storage problem = toxic effects from defective autophagy ▪ autophagy = “cellular housecleaning” FYI Gaucher Disease Most common lysosomal storage disease ▪ Between 1 in 20,000 and 1 in 40,000 live births ▪ Autosomal recessive inheritance Defect in the gene for glucocerebrosidase ▪ Enzyme cleaves the glucose residues from ceramide, found in cell membranes glucosylceramide accumulates in lysosomes ▪ Metabolites accumulate mainly within macrophages and other phagocytic cells as they phagocytose dying cells and metabolize the membranes This can lead to the activation or loss of function of the phagocytes Gaucher Disease Type I – involves organs outside the central nervous system – 99% of cases ▪ Findings are mostly within the spleen and bone Enlargement of the spleen and liver Weakened bones → frequent fractures ▪ Often relatively mild course Type II – involves the CNS as well as other organs ▪ Hepatosplenomegaly and rapid neurological deterioration, with death in early childhood ▪ CNS macrophage activation → production of toxic signals by macrophages → neuronal death X-Linked Disorders All sex-linked disorders are X-linked, and the vast majority are recessive ▪ Males with mutations affecting the Y-linked genes are usually infertile, and hence there is no Y-linked inheritance Features: ▪ An affected male does not transmit the disorder to his sons, but all daughters are carriers. Sons of heterozygous women have a 1 in 2 chance of receiving the mutant gene ▪ The heterozygous female usually does not express the full phenotypic change because of the paired normal allele X-linked disorders Gene carried on the X chromosome and usually only manifests in males ▪ A male with a mutant allele on his single X chromosome = hemizygous for the allele X-linked recessive inheritance: ▪ transmitted by healthy heterozygous female carriers to affected males ▪ affected males to their obligate carrier daughters consequent risk to male grandchildren through these daughters affected males can’t transmit to sons X-linked recessive disorders – a few examples X-linked recessive – Hemophilia A Loss of function of a coagulation factor necessary for clotting ▪ Affects over 20,000 men in North America ▪ Different mutations confer different bleeding risk – thousands of mutations have been identified with variable impacts on coagulation Clinical Features ▪ Bruising and prolonged bleeding with minimal trauma ▪ Mucosal bleeding, hematomas in joint spaces (hemarthrosis) Pedigree drawing – how genetic diseases “appear” in families The person being “examined” (usually the one with a genetic condition) is known as the proband ▪ Position of the proband in the family tree is indicated by an arrow ▪ A complete family history is then taken “centered” around the proband Diagram developed is called a pedigree Pedigree drawing Pedigree – autosomal dominant Frequent appearance of the disease throughout generations ▪ may not show typical 50% chance of transmission (remember reduced penetrance) Affects both males and females Pedigree – autosomal recessive The risk of autosomal recessive disorders manifesting increases if there is consanguinity ▪ if a homozygote has offspring with a heterozygote, can also look deceptively frequent Often parents of affected proband not affected Pedigree – X-linked recessive Only males appear affected Trait is never passed from father to son May see “knight’s move” pattern of transmission