Phenotypic Variability Flashcards
Phenotypic variability
the variation of gene expression in the same disease in different individuals
ie. individuals with the same genetic disease may not have the same symptoms/presentations (phenotype)
5 categories that cause phenotypic variability
environment - expression of a gene is modified by environmental factors
sex - expression of a gene varies by sex
modifiers - expression of a gene is directly affected by presence of another gene
mutation - different mutation subtypes of same disease
unstable - trinucleotide repeat disorders
How is confusion with classifying disease less
Through reclassification of disease using subtypes e.g. osteogenesis imperfecta (OI) has 9 subtypes now. For OI there are mutations caused by mutations in collagen genes and those caused by mutations in other genes- even for types I to IV which all have mutations in same gene have variability in phenotype
Effect of environment on multiple endocrine neoplasia type 1 (MEN1)
It’s a disease that increases carrier’s chance of developing adenomas in endocrine tissue. Caused by tumour suppressor gene MEN1 mutation
Condition is autosomal dominant but not all with mutation will develop same adenoma type or at same time because second event has to occur to promote tumour formation- some develop many tumours at young age and some don’t until very late in life- exact cause is unknown but there is clearly environmental impact on the course of the disease
Effect on environment on heridatary haemochromastosis
Autosomal recessive disease caused by mutation in human homeostatic iron regulator protein (HFE) which affects the way in which dietary iron is absorbed leading to excess iron absorption leading to build up of iron in various organs causing organ damage
Only 10% of people with the disease have clinically relevant iron accumulation- the dietary load of iron can vary considerably and lower intake levels are associated with improved disease prognosis
Effect of sex on hereditary haemochromatosis
Has difference in time course in males and females- in men it starts developing between ages 40 and 60 but for women it doesn’t develop until many years after menopause
Thought to be due to women losing significant blood amount in menstruation which helps prevent iron build up in other tissues
In people who are homozygous for the causative mutation, symptoms appear 14% of men vs 4% of women. Men also tend to have more severe phenotypes
Effect on sex in congenital long QT syndrome
Rare cardiac disorder caused by mutations in KCNQ1 and KCNH2
Can result in ventricular arrhythmias and cause sudden death
Females are more likely to have it generally, possibly due to ascertainment bias since diagnostic criteria is based on QTc and women have a longer one on average but studies that account for this show women have higher risk of inheriting the mutation than males and mothers are more prone to passing it on than fathers
Exact reason not found but thought to be due to positive selection of mutated allele due to a reproductive advantage arising during gametogenesis, fertilisation, implantation or post-implantation linked to changes in potassium ion fluxes through the mutant channels
Effect on gene on eye color
autosomal dominant trait
There are a number of other genes that interact with OCA-2 to alter eye colour
The type of OCA-2 you inherit is responsible for 80% of eye colour, rest by other genes
Second most important gene is HERC-2 which controls OCA-2 activity 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:
Effect on gene in cystic fibrosis modifiers
Number of different gene variations that interact with CF mutation to change the disease phenotype e.g. immunoglobulin Fc-gamma receptor II which if you have the variant, can increase your chance of developing P. aeruginosa infection by 4x
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 modify cystic fibrosis.
Patients with the same homozygous delF508 mutation can be classified as having either severe or mild lung disease. TGFB1, the gene encoding transforming growth factor beta-1, variants are associated with with the phenotype of severe lung disease.
Effect on gene in Von Hippel-Lindau syndrome modifiers
VHL is a dominantly inherited familial cancer syndrome predisposing to variety of malignant and benign neoplasms like retinal, cerebellar, renal cell carcinoma, pancreatic tumours, spinal hemangioblastoma, pheochromocytoma
Variation in cyclin D1 alters VHL phenotype- the number of retinal angiomas is much higher in individuals with the G allele rather than AA homozygotes- having 1/more G alleles is associated with earlier diagnosis of CNS hemangioblastoma by 2x
Muscular dystrophy
Both Duchenne and Becker muscular dystrophy are caused by mutations in dystrophin gene which is largest human gene
Both diseases are similar in distribution of muscle wasting and weakness but Becker is more mild phenotype with 12 years age of onset- some patients have no symptoms until later in life
Loss of ambulation varies from adolescence onward with death between 40-50 years
This is opposed to DMD which is more severe and has diagnosis at 4.6 years and death at 17
Reason for differences in disease progression is type of mutation- both are deletions in dystrophin gene but in DMD the mutation is a frame shift deletion so no active dystrophin is produced but with BMD the mutation isn’t frame shift so active dystrophin is produced albeit a shorter form which retains some activity of the longer form
Unstable mutations
Some diseases exist called trinucleotide repeat disorders which are caused by trinucleotide repeat expansion- a mutation where 3 repeated nucleotides in genome increases in number during DNA replication
If <27 repeats in a genome these tend to be stable and protein function is normal but as number of repeats increases above the threshold, the repeats become unstable during DNA replication and number of repeats increases which changes protein function
Greater number of repeats results in a more severe phenotype
These types of disease are characterised by earlier onset of disease and greater severity of symptoms in each succeeding generation as number of repeats increases
Huntingtons
CAG repeat which codes for glutamine creating a polyglutamine tract
<27 repeats leads to stable region and normal phenotype
27-35 repeats leads to intermediate phenotype with some minor effects but that DNA region is no longer stable and number of repeats can increase
36-39 repeats leads to characteristic phenotype but not all carriers are affected by the disease
40+ repeats leads to Huntingtons in all carriers
