Term
| What are the different types of genetic defects? |
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Definition
Single Gene Defect
Multifactorial Defect (combination of multiple genes)
Chromosomal Defect (can be visualized - cytogenetics)
Inherited Genetic Defect (may occur during meiosis)
Somatic Cell Genetic Defect (change in somatic cell, not transmitted to offspring) |
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Term
| What are some examples of the entire structural gene being deleted? |
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Definition
Hemophilia - entire factor VIII gene is removed.
Beta-Thalassemia (disease severity depends on number of genes deleted).
major- lethal,mutations of both beta globin genes.
minor- mild,microcytic anemia, mutation in one beta globin gene |
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Term
| What is an example of a partial deletion of a gene? |
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Definition
Duchenne muscular dystrophy/Becker muscular dystrophy
Gene responsible is dystrophin.
DMD (caused by an out-of-frame deletion) is a more severe disease than Becker disease (caused by in-frame deletion).
X-linked
Also exons can be duplicated (5% of the cases in DMD/Becker MD) |
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Term
| How can insertion or amplification of DNA sequences cause problems? |
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Definition
Polymorphic tri-nucleotide repeats can cause problems
Greatly increased numbers of tri-nucleotide repeats are involved in Fragile X, Myotonic Dystrophy,and Huntington's |
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Term
| What is genetic anticipation? |
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Definition
| In Huntington's disease the repeats between 27 and 35 can be meoitically unstable in parental transmission and sons will have an expansion in trinucleotide repeats (X-linked) |
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Term
| How is microsatellite instability related to cancer? |
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Definition
| MSI is due to a defective mismatch repair (MMR) gene in certain cancers. Approximately 13% of colorectal, gastric and endometrial carcinomas have a defective MMR gene. |
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Term
| What are Alu elements and how do they relate to molecular pathology? |
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Definition
Alu sequences resemble 7SL RNA.
• Transcribed (by RNA Pol III), but are usually not translated.
• Populate ≈ 5-10% genome.
• Insertion of mobile or “jumping” Alu elements into coding sequences will be lethal.
Insertion into coding sequences will interrupt the reading frame |
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Term
| What is the example of disease caused by a codon deletion? |
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Definition
| In cystic fibrosis, the most common mutation involves deletion of the codon that codes for Phe at 508 in the cystic fibrosis transmembrane regulator. |
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Term
| What are some different effects of point mutations? |
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Definition
• Amino Acid Substitution or Stop Codon.
- Sickle Cell S and C are caused by point mutations
• Transcription Levels.
- promoter sequences
• Post-Transcription Processing:
- impaired mRNA splicing. (altered alpha- or beta-globin genes)
- poly-adenylation signal - mutations destabilize mRNA
• Loss of proteolytic cleavage site on the protein
• Loss of phosphorylation sites on the protein
- TCC (Ser) -> GCC (Ala |
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Term
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Definition
Difference in DNA sequence among individuals
- nucleotide substitution
- nucleotide insertion/deletion
- tandem repeats, tri-nucleotide repeats
If the polymorphism occurs in the coding sequence then the amino acid will change (protein polymorhpism) |
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Term
| What is the molecular pathology of Ehlers-Danlos syndrome |
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Definition
It is an autosomal dominant point mutation that prevents post-transcriptional processing
The point mutation causes exon loss (exon 6) |
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Term
| What is the molecular pathology of Factor V Leiden? |
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Definition
Arg 506 Gln mutation -> loss of proteolytic cleavage site. Prevents inactivation of Factor Va.
Associated with 90% of DVT (deep venous thrombosis).
Mutation results in poor response to activated protein C (APC-resistance).
Heterozygotes have increased susceptibility to thombosis events.
2% of Caucasian population carry homozygote mutation. |
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Term
| What is the molecular pathology of genetic predisposition to drug side effects? |
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Definition
Aminoglycoside antibiotics: mutation in 12S RNA makes the mitochondrial rRNA structurally more similar to its bacterial counterpart, resulting in a predisposition to ototoxic-induced deafness.
Genetic polymorphism may result in inter-individual drug responses to a metabolizing enzyme. |
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Term
| How can mutations in the mitochondrial genome result in pathologies |
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Definition
Myoclonus Epilepsy Associated with Ragged-Red Fibers (MERRF). - mutations in mito. proteins
Clinical phenotype is due to mutation in different mitochondrial proteins (complex 1 or IV); tRNAlys.
Affects mitochondrial translational system - mutations in mito. tRNA
e.g. MELAS (Myopathy encephalopathy lactic acidosis and recurrent stroke-like episode) is due to a mutation in mitochondria tRNAleu. |
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Term
| What is an example of a point mutation being beneficial? |
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Definition
Apolipoprotein-A1
• Gene mutation - Apolipoprotein A-1 Milano gene (Apo A-1 Milano) - Mutation at codon 173 results in cysteine substituted for arginine (R173C).
• Individuals have a decreased risk of atherosclerosis relative to their low level of HDL.
• Apo A-1 Milano forms disulfide-bonded dimers with other Apo-AI Milano molecules as well as other HDL proteins such as Apo-AII.
• Mutant form of Apo A-1 appears to be anti-atherogenic. |
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Term
| What are the different ways a tumor suppressor gene can be silenced? |
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Definition
Partial gene deletion or loss of sequences observed as loss of heterozygosity (LOH).
Point mutation.
Epigenetic defect - doesn't affect actual nucleotide level
methylation at CpG sites in the promoter. |
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Term
| Explain loss of heterozygosity |
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Definition
| A somatic mutation causes a deletion of a fragment which causes a loss of the allele in the germline |
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Term
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Definition
| Post-zygotic mutations produce distinct cell lines that have either different sets of chromosomes or different gene mutations for a single gene in different cells |
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Term
| What are some examples of numerical chromosomal defects? |
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Definition
Polyploidy: Any multiple of the haploid number of chromosomes, e.g., 3N, 4N (common in spontaneous abortions).
Aneuploidy:Change in the number of one chromosome.
• Autosome, e.g., trisomy 21 (Down syndrome)
• Sex chromosome, e.g,., Klinefelter’s syndrom (47,XXX); Turner syndrome (45,X0). |
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Term
| What are some trisomies that cause spontaneous fetal loss |
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Definition
decent survival of trisomy 21 - down syndrome
poor survival of trisomy 13 (Patau syndrome) and 18 (Edwards syndrome)
no survival of trisomy 16 |
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Term
| What is uniparental disomy? |
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Definition
Both copies of a single chromosome (or major part of that chromosome) is inherited from the same parent. The other parent contributes nothing to that portion of the embryo’s genome
Homozygosity arises as a result of UPD
Loss of Mendelian Principles -> even segregation and independent assortment of chromosomes
- Rare cases of cystic fibrosis (a common autosomal recessive disease). The child receives two copies of the mutant chromosome 7 from the carrier parent and no chromosome 7 from an unaffected parent |
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Term
| What are some structural chromosomal defects? |
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Definition
Micro-deletions - a specific region of a chromosome has been deleted. ex's - Angelman/Prader-Wili
Translocation - Burkitt's lymphoma
Inversions, insertions, duplications
Interchange between X and Y chromosomes |
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Term
| How is DNA repair related to cancer? |
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Definition
Problems with genes involved in Non-homologous DNA End Joining (Ku/DNA-PK, ATM, BRCA1) are associated with cancer
It is the same for genes involved in homologous end joining (BRCA2, RAD)
End-joining is necessary after physiologic or pathologic DS strand breaks |
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Term
| What is a method to detect chrosomal changes? |
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Definition
Fluorescence in situ hybridization (FISH)
It involves fluorescent labeling, denaturation, and hybridization
It cannot detect DNA base pair mutations |
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Term
| What is sex reversal and how is it caused? |
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Definition
Illegitimate recombination between X and Y chromosomes during paternal meiosis caused by chromosomal re-arrangement
46 XX males contain portion of p arm of chromosome Y containing SRY gene (testis determining factor).
46 XY females have missing short arm of chromosome Y (Y chromosome doesn't have an effect) |
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Term
| How are mutations that involve entire chromosomes detected (base pair substitutions/insertions/deletions, change in number of repetitive sequence repeats)? |
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Definition
Southern hybridization
PCR followed by restriction and gel electrophoresis |
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