Phenotypic Variability Flashcards
Common characteristics of all classes of osteogenesis imperfects
They all result in fragile bones prone to fracture but they have different disease outcomes , inheritance patterns and underlying causes
Look at the different classes of osteogenesis imperfecta table
Look at the different classes of the osteogenesis imperfecta table
Osteogenesis imperfecta and phenotypic variability
So in the case of Osteogenesis Imperfecta there are those caused by mutations in the collagen genes and those caused by mutations in other genes, and this is one method of classification. This can also be seen that even for types one to four which are caused by mutations in the same gene, there is a variability in phenotype and this will be discussed in further respect to the effect of different mutations.
What does environment mean in terms of genetics
Factors which are external to the patient
Multiple Endocrine Neoplasia type 1 MEN 1
This is a disease which increases the carriers’ chance of developing adenomas in endocrine tissue.
It is caused by a mutation in the MEN1 gene, a tumour suppressor gene.
The condition is inherited in an autosomally dominant fashion, but despite this not all people with the mutation will develop the same types of adenoma or at the same time.
This is because a second event has to occur to promote tumour formation. Some people develop many tumours at a young age whereas others do not develop any tumours until very late in life. the exact cause of this is unknow but there is clearly an effect of environmental impact on the course of the disease.
Hereditary haemochromatosis
This is an autosomally recessive gene. It is caused by a mutation in the human homeostatic iron regulator protein (HFE).
This affects the way in which dietary iron is absorbed leading to excess iron absorbtion.
This can lead to a build up of iron in various organs and subsequent organ damage. However only 10% of people with hereditary haemochromatosis have clinically relevant iron accumulation.
Women are protected from iron accumulation due to menstrual bleeding. in men, the dietary load of iron can vary considerably and lower levels of intake are associated with improved disease prognosis.
Diseases affected by the environment
Cystic fibrosis
Sickle cell disease ( both can be exacerbated by exposure to pollen)
HH
MEN1
BCRA 1 and 2
So men with mutations in the BCRA 1 and BCRA2 have an increased risk of prostate cancer. This is obviously not the case with females as they lack a prostate and instead have an increased risk of ovarian cancer.
Men with the BRCA-1 and BRCA-2 mutation still have increased risk of breast cancer although this is not as high as in females with the same mutations. In the same way females with hypercholestrolemia have an equally elevated risk of heart disease as men.
Effects of sex on HH
The disease has a markedly different time course in males and females. In men the symptoms begin to develop between 40 and 60 whilst in women symptoms do not develop until several years after menopause. The explanation for this is that females lose a significant amount of blood during menstruation and this prevents the build of iron in other tissues. In people who are homozygous for the causative mutation symptoms are present in approximately 14% of men and approximately 4% of women. Men also tend to have more severe phenotypes. This though is not absolute as some men do not develop symptoms whilst some women do.
Congenital Lomg QT syndrome and effects of sex
Congenital long-QT syndrome is a rare cardiac disorder caused by mutations in KCNQ1 and KCNH2. As the name suggests it presents with prolonged QT interval. It can result in ventricular arrythmias and thus sudden death.
Females are more likely to be diagnosed with long QT syndrome generally, possibly due to ascertainment bias, since the diagnostic criteria is based on QTc and females have on average a longer QTc.
However a number of studies have been undertaken which have accounted for this and shown that for congenital long-QT syndrome females have a higher risk of inheriting the mutation than males and that mothers are more prone to pass on the mutation than fathers. Although the exact reason for this has not yet been found, it is thought to be due to due to positive selection of the mutated allele due to a reproductive advantage arising during the process of gametogenesis, fertilisation, implantation or post-implantation linked to changes in potassium ion fluxes through the mutant channels.
Eye colour
Autosomal dominant trait but there are a number of other genes which interact with OCA-2 and can alter eye colour.
The type of OCA-2 you inherit is responsible for approximately 80% of eye colour. The rest is controlled by other genes. The second most important gene is one called HERC2. This controls the activity of OCA-2, so even if you inherit the active form of OCA-2 gene you will have blue eyes if you inherit the inactive form of HERC2
Cystic fibrosis modifiers
Gene variations : There is great variability of pulmonary phenotype and survival in cystic fibrosis, even among patients who are homozygous for the most prevalent mutation, delF508. Variants of genes can modifiy cystic fibrosis. Patients withe the same homozygous delF508 mutation can be clasified as having either severe or mild lung disease. TGFB1, the gene encoding transforming growth factor beta-1, variants are associted with with the phenotype of severe lung disease.
The risk of developing infections in cystic fibrosis can also be modified by a large number of gene variations. Distinct from the Cystic fibrosis mutation. One such gene is immunoglobulin Fc-gamma receptor II (FCGR2A) which if you have the variant can increase your change of developing a chronic Pseudomonas aeruginosa infection by 4 fold.
BMD and DMD
Both are the result of deletions in the dystrophin gene but in In DMD the mutation is a frame shift deletion and therefore no active dystrophin is produced. In Becker Muscular dystophy the mutation does not result in a frame shift and so active dystophin is produced al be it a shorter form this protein retains some of the activity of the longer form.
This phenomenon is a common occurance with different gene phenotypes associated with different mutations.
Unstable mutations and trinucleotide repeat disorders
The underlying cause of all these diseases is a trinucleotide repeat expansion. This is a mutation in which a region of three repeated nucleotides in the genome increases in number during DNA replication. If there are fewer than 27 repeats in the genome, these tend to be stable and the function of the protein remains normal. As the number of repeats increases, it reaches a thresehold 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. These types of disease are characterised by an earlier onset of disease and the greater severity of symptoms in each succeding generation, as the number of repeats increases.
Example of trinucleotide repeat disorder
Huntingdons disease and so CAG repeat
