Phenotypic Variability Flashcards
What are 6 causes of phenotypic variability in the presentation of illness?
- Different disease or causal gene but same name
- Environmental effect
- Same diseases can affect the sexes differently
- Effects of other genes
- Different mutations in the same gene can lead to different phenotypes
- Unstable mutations
Why would different diseases or different causal genes be called the same name?
Many genetic diseases are rare and classified by symptoms but has led to conditions not being caused by same gene or same causes and yet have same name due to presentation. This can be reduced by reclassifying diseases into sub-types, example being osteogenesis imperfect which has 9 subtypes depending on gene and inheritance pattern.
How can the environment affect phenotype of a disease?
Environment plays large role in the progress and outcome of the disease hence history + prognosis of many diseases will be affected by environment
How is phenotype of Multiple Endocrine Neoplasia type 1 altered?
Carrier’s chance of developing adenoma in endocrine tissue is increased and caused by mutation in MEN 1 which is a tumour suppressor gene (autosomal dominant) However, a second event has to occur to prompt tumour formation so environment impact the course of disease.
How is phenotype of Hereditary haemochromatosis altered?
Is autosomal recessive and caused by mutation in human homeostatic iron regulator protein (HFE). Affects dietary iron absorption which means too much is absorbed. Leads to iron build-up which can cause organ damage but this iron accumulation only occurs in small number of people as dietary load of iron varies and lower intake means better prognosis so environmental differences affect phenotype. Affects sexes differently symptoms begin in men between 40-60 whereas don’t start until many years after menopause for females as lose significant amount of blood during menstruation and so prevents build-up of iron in other tissues. Men also tend to have more severe phenotypes.
Why can the same disease affect the sexes differently? Provide an example
Physiological differences like presence/absence of organs/tissues can affect phenotype displayed for same mutation. Men with mutation in BRCA 1/2 have an increased risk of prostate cancer but since females don’t have a prostate, have an increased risk of ovarian cancer – however, still dependent as men also have risk of breast cancer but just not as high.
Why are females more likely to get congenital long-QT syndrome?
Positive selection of mutated allele due to reproductive advantage that arises during gametogenesis, fertilisation, implantation or post-implantation linked to changes in potassium ion influx through mutated channels mean mothers more likely to pass on KCNQ1/2 mutations and females more likely to inherit mutation causing congenital long-QT syndrome.
How can other genes affect phenotype? Provide example
In addition to the presence of the disease gene the life course of a disease and the symptoms present are commonly modified by the presence of other gene.
Eye colour relies on OCA-2 which determines melanin production but this gene is controlled by HERC-2 which controls OCA-2 activity.
What conditions have a phenotype resulting from multiple gene interactions and how?
- Cystic Fibrosis - Number of gene variations that interact with the cystic fibrosis mutation to change the phenotype of the disease - great variability of pulmonary phenotype and survival, even among patients homozygous for most prevalent mutation, delF508.
- Lung disease - Depends on TGFB-1 (transforming growth factor beta-1), variants of which are associated with severe lung disease. Chance of infection also influenced by unrelated genes such as immunoglobulin Fc-gamma receptor II (FCGR2A) where if you have a variant, increases chance of risk.
- Von-Hippel Lindau Syndrome - variation in cyclin D1 (CCND1) alters the phenotype of VHL. The number of retinal angiomas is significantly higher in individuals harbouring the G allele compared with AA homozygotes. Possession of 1 or more G alleles is associated with earlier diagnosis of CNS hemangioblastoma by almost 2-fold.
What is an example of different mutations in the same gene leading to different phenotypes?
Duchenne and Becker muscular dystrophy are caused by mutations in the dystrophin gene however have different severities and prognosis. Both are the result of deletions in the dystrophin gene but in DMD the mutation is a frame shift deletion and therefore no active dystrophin is produced. In Becker Muscular dystrophy the mutation does not result in a frame shift and so active dystrophin is produced in a shorter form but retains some activity of longer form.
What group of disorders are an example of unstable mutations and how is severity of phenotype determined?
Large group of diseases trinucleotide repeat disorders - mutation in which a region of three repeated nucleotides in the genome increases in number during DNA replication.
=27: these tend to be stable and the function of the protein remains normal
>27: Reaches a threshold above which they are no longer stable during DNA replication and the number of repeats increases during subsequent rounds of DNA replication. This increase in trinucleotide repeats changes the protein function and a greater number of repeats results in a more severe phenotype.
How do unstable mutations arise?
A slip strand mispairing mutation is the mechanism by which this happens: During replication of repeated CAG sequences within DNA replication often pauses. This can allow the new strand of the DNA to loop out and reanneal then DNA replication proceeds. This results in the insertion of additional copies of the CAG repeat.
