L16: Mutation - Consequences at a gene, protein and chromosomal level Flashcards
What is the primary focus of clinical genetic testing in cases of suspected genetic disease?
To investigate if a genetic variant is pathogenic and determine its role in the disease
What is ataxia-telangiectasia (A-T)?
A rare, autosomal recessive disorder that causes progressive neurodegeneration, immune deficiencies, and increased cancer risk
What is the inheritance pattern of ataxia-telangiectasia?
Autosomal recessive, requiring both parents to pass on the mutated gene
How do clinical geneticists differentiate between pathogenic and benign genetic variants?
By assessing factors like frequency, evolutionary conservation, and functional analysis through in silico and laboratory methods
What does “compound heterozygous” mean?
Having two different mutations in the same gene, one from each parent, leading to a recessive disorder
What is a “missense variant,” and why is it challenging to classify?
A genetic alteration that alters one amino acid, disrupting protein structure, function and interactions; challenging because it might or might not disrupt function
What tools are used for in silico analysis of mutations?
- Computational tools and algorithms used to predict potential impacts of genetic variants without immediate lab testing
- Software like Mutation Taster, which predicts pathogenicity based on conservation, amino acid changes, and other factors
What is a “variant of uncertain significance” (VUS)?
A genetic variant that lacks sufficient evidence to classify it as either pathogenic or benign
How is a pathogenic mutation affecting protein function typically confirmed?
Through functional assays such as Western blots to analyse protein expression and activity
What role does the ATM gene play in the context of A-T?
It encodes a protein critical for DNA repair; mutations can lead to loss of function, increasing cancer risk and neurodegeneration
What is the significance of “genotype-phenotype correlation”?
Specific genetic mutations (genotype) influence the observable characteristics or disease severity (phenotype), with some mutations leading to more severe presentations than others
How can X chromosome inactivation contribute to certain syndromes?
- In females, one X chromosome is randomly inactivated in each cell, leading to a mosaic effect that can impact phenotype
- This can also protect and reduce impacts of harmful mutations
What can tortoiseshell cats teach us about X-chromosome inactivation?
Their coat colors are determined by X-linked genes, and random X inactivation leads to a mosaic of color patches
What is chromosomal nondisjunction and its consequence?
Failure of chromosomes to separate during meiosis, leading to aneuploidies like trisomy 21 (Down syndrome)
Describe the Philadelphia chromosome’s role in cancer
It’s a chromosomal abnormality where parts of chromosomes 9 and 22 exchange, causing a cancer fusing gene, resulting in chronic myeloid leukemia (CML)
Why are modifier genes significant in genetic disorders?
They can influence the severity of a disease, even in individuals with the same primary mutation
What is “nonsense-mediated mRNA decay”?
A process where unstable mRNA is degraded, often resulting from mutations that introduce premature stop codons
What are the typical clinical features of ataxia-telangiectasia?
Progressive cerebellar ataxia, telangiectasia (dilated blood vessels), immune deficiencies, and increased sensitivity to radiation
What is the role of kinase activity in the ATM protein?
ATM kinase is activated by DNA damage and initiates DNA repair, particularly after ionizing radiation
Explain the term “loss of function” mutation
A mutation that results in reduced or no functional protein, often linked to severe disease phenotypes
What is the importance of evolutionary conservation in assessing mutation impact?
Highly conserved amino acids across species indicate functional importance; mutations here are more likely to be pathogenic
Describe “dominant negative” mutations
Mutations where a faulty allele interferes with the function of the normal allele, potentially worsening the phenotype
What is a “Bayes classifier” in genetic testing?
A statistical tool that evaluates the probability of a variant being disease-causing based on various data points/multiple genetic indicators
How do geneticists approach “variants of uncertain significance” (VUS)?
They analyze VUS with caution, often requiring additional functional or familial data to classify the variant definitively
What are the different types of mutations that can impact gene function?
Deletions, nonsense mutations, frameshift mutations, missense mutations, and splice site changes
What is “compound heterozygosity”?
A condition where two different mutations are present in the same gene, one on each allele, contributing to disease
What does “chromosomal translocation” mean?
A rearrangement where parts of chromosomes break and reattach to different chromosomes, which can lead to genetic diseases
Define “locus heterogeneity.”
- The occurrence of similar clinical features caused by mutations in different genes, however these genes lead to the same disease, important in diagnostics as multiple genes may need testing
Why is whole-genome sequencing beneficial in clinical genetics?
Allows for comprehensive analysis of all genes, helping to identify potential causative genes when single-gene testing fails
What is the genetic basis of Kleinfelter syndrome?
An extra X chromosome (47, XXY), often resulting in infertility, taller stature, and normal IQ
What is aneuploidy?
A condition of having an abnormal number of chromosomes, such as trisomy (an extra chromosome) or monosomy (missing a chromosome)
How do modifying genes affect disease phenotype?
- They can alter the severity or expression of a genetic disorder, even within the same family with identical primary mutations
- Difficult to identify as they often have subtle effects on phenotype, requiring large family studies and whole-genome sequencing to pinpoint their influence
Why are modifying genes difficult to identify?
Often have subtle effects on phenotype, requiring large family studies and whole-genome sequencing to pinpoint their influence
What is the impact of “non-disjunction” in meiosis?
It can lead to conditions like Down syndrome by failing to separate chromosomes properly, resulting in extra or missing chromosomes in offspring
What are splice site mutations, and why are they significant?
Mutations that occur at the junctions of exons and introns, potentially disrupting mRNA splicing, leading to abnormal or truncated proteins
What is a “Western blot,” and how is it used in genetic testing?
A technique for detecting specific proteins in a sample; it helps assess protein levels and activity to understand mutation effects
What is “genetic heterogeneity”?
The phenomenon where different genetic mutations can cause similar phenotypes or diseases, complicating diagnosis and treatment
How can phosphorylation studies be used in mutation analysis?
Phosphorylation changes can reveal if a mutation affects protein activation, particularly in proteins involved in cell signaling like ATM
Describe “allelic heterogeneity.”
It occurs when different mutations in the same gene lead to the same or similar diseases, such as with different mutations in the ATM gene causing A-T
Explain the concept of “frameshift mutations.”
Mutations that alter the reading frame of a gene, typically causing a protein to be truncated and lose function
What is “mosaicism,” and how does it arise?
A condition where an individual has cells with different genetic compositions, often due to mutations occurring after fertilisation
How does the loss of function in ATM affect patients with A-T?
The absence or inactivity of ATM kinase impairs DNA repair, leading to cellular sensitivity to DNA damage and increased cancer risk
What is “nonsense mutation” and its usual outcome on proteins?
A mutation that introduces a premature stop codon, generally resulting in a truncated, nonfunctional protein
What role do bioinformaticians play in whole-genome sequencing?
They analyze large data sets to identify candidate genes and variants that may be implicated in genetic disorders
What is “gain of function” mutation, and how does it differ from loss of function?
A mutation that enhances or adds a new function to a protein, potentially leading to dominant or complex disease effects
Describe “X-chromosome fragility” as seen in Fragile X syndrome
The X chromosome develops breaks or gaps, especially under certain conditions, which leads to intellectual disability
What is “Locus heterogeneity,” and why is it relevant in genetic diagnostics?
It is when mutations in different genes lead to the same disease, important in diagnostics as multiple genes may need testing
How do “Western blot” and “antibody staining” help in assessing protein activity?
Western blot detects specific proteins, while antibody staining reveals post-translational modifications like phosphorylation
Why is ATM kinase activity tested with radiation exposure in A-T research?
Radiation activates ATM kinase in normal cells; lack of response indicates a defective ATM protein, helping confirm an A-T diagnosis
