5.1 - Modes of inheritance Flashcards
1
Q
Dominant autosomal disorders
A
- a characteristic is dominant if it manifests in a heterozygote (i.e. two different alleles at a locus)
- single gene / allele disease
- disease passed down to offspring with multiple generations affected - vertical transmission
- affected person usually has an affected parent
- each child of an affected person has a 1 in 2 chance of being affected
- may arise de novo (new mutation) - possible mosaicism
- males and females are equally affected and equally likely to pass on the condition - vertical pedigree pattern
2
Q
Why are brown eyes dominant over blue eyes?
A
- the gene responsible for eye colour is OCA-2 which controls amount of melanin in melanocytes
- if you have allele for brown eyes, you get an active form of OCA-2 which means your melanocytes get melanin in them to make the eye brown
- if you have allele for blue eyes, you get an inactive form of OCA-2, so no melanin goes into melanocytes and the eye is blue
- if you get a copy of each, the active OCA-2 from the brown allele will mean the melanocyte gets melanin
3
Q
Dominant autosomal disorders tend to be:
A
- gain-of-function - gene now makes a protein with a new function e.g. constitutively active, aggregates, longer lifespan, new location = increasing their effect
- dominant negative effect - the mutated form interferes with the activity of proteins it binds e.g. dimers or multimers which reduces activity
- insufficient - mutant in one gene results in 1/2 the amount of a protein that is not enough for normal function (rare)
4
Q
Huntington’s disease - autosomal dominant
A
- 1/20000 in UK
- symptoms usually start 30-50 years of age
- difficulty concentrating, depression, stumbling, involuntary jerking, problems swallowing
- mutation - results from expansion CAG (glutamine) repeat huntingtin
- result - abnormal intracellular Huntington protein aggregate gains a pathological function and is toxic to neurons resulting in cell death
5
Q
Osteogenesis imperfecta - autosomal dominant
A
- brittle bone disease - 1/15000
- group of genetic disorders mainly affecting bones
- bones break easily
- mild to severe
- hearing loss, breathing problems, short height, blue tinge to whites of eyes
Mutations: - type I - insufficient quantities of collagen
- type II, III and IV - mutation of collagen results in an abnormal protein that has an altered structure and interferes with the function of the normal protein
- result - weakening connective tissue particularly bone
6
Q
Autosomal recessive disorders
A
- recessive - two copies of the abnormal (non-working) gene must be present in order for the disease / trait to develop
- tend to be ‘loss of function’ mutations e.g. deletions
- parents and children of affected people are normally unaffected
- one or more siblings affected - each subsequent sibling has a 1 in 4 chance of being affected (two heterozygous parents)
- males and females equally affected
- horizontal pedigree pattern - across generations rather than down generations
- carriers - lost a single copy of a gene but the normal one is sufficient to maintain normal function
7
Q
Consanguinity
A
- consanguineous marriages elevate the risk of autosomal recessive diseases
- if the family has multiple consanguineous marriages, affected individuals may be seen in several generations
- the rarer the disease (lower disease gene frequency), the higher the risk of autosomal recessive disease
8
Q
Cystic fibrosis - autosomal recessive
A
- 1/3000 newborns
- failure to thrive
- defective chloride ion channel results in impaired airway defence
- prone to respiratory infections
- digestive issues e.g. meconium ileus
- largest cohort of chronically ill patients
- mutations - various mutations in gene encoding chloride ion channel (CFTR gene on chromosome 7)
- result - defective chloride ion channel, loss of function, works less well, degraded faster or present in inadequate amounts
9
Q
Sex chromosomes
A
- consist of an X and a Y chromosome
- determine the sex
- X-chromosome 1000-1300 genes (~850 protein coding)
- Y-chromosome 150 genes (50-70 protein coding) - smaller
10
Q
X-linked disorders - recessive
A
- affects mainly males - effectively dominant for them - they only 1 X chromosome so if it is mutated then there is no other X chromosome to provide normal unmutated gene
- females can be carriers and affected males are linked through females
- affected boys may have affected uncles
- females who are homozygous for the mutation (two copies) have the disorder
- parents and children of affected people are most commonly unaffected
- brothers of affected son have a 1 in 2 risk of having disorder, sisters have a 1 in 2 risk of being a carrier
- all daughters of a man with an X-linked disorder will be carriers as men only have one X chromosome - all sons will be healthy as inherit the Y from the father
- examples - haemophilia (more frequent/severe bleeds, factors VIII or IX)
- in some cases female carriers exhibit subtle signs of the disease e.g. Fabry’s Disease
11
Q
X-linked disorders - dominant
A
- similar to autosomal dominant pattern (seen in both sexes)
- BUT all daughters and no sons of an affected father are affected
- condition often milder and more variable in females than in males
- some disease only present in females as males not viable
Example: X-linked hypophosphatemia
- PHEX gene mutation
- over production FGF21 - inhibits kidney phosphate resorption
- kidneys cannot retain phosphate
- results in vitamin D resistance - rickets
12
Q
Y-linked disorders
A
- affects only males
- all sons of an affected father
- vertical pedigree pattern
Example: Retinitis Pigmentosa Y-linked
- mutation in RPY gene
- cells of retina produce a defective protein
13
Q
Mitochondria
A
- specialised organelle of eukaryotic cells
- share an evolutionary past with bacteria - endosymbiosis
- have their own DNA
- majority of mitochondrial proteins encoded by nuclear genes
- mutations in these genes cause most mitochondrial disease
- some diseases caused by mutations in mitochondrial DNA
14
Q
Mitochondrial inherited disorders
A
- disease caused by mutations in mitochondrial DNA
- all mitochondria inherited from mother - maternally inherited
- all children of an affected woman may be affected
- children of affected men are never affected
- vertical pedigree pattern
- mitochondrial conditions are typically extremely variable even within a family
15
Q
Mitochondrial disease variability - heteroplasmy
A
- mitochondria have multiple copies of their genome - some normal, some mutant (heteroplasmy)
- only express disease effects above a threshold of mutated copies
- when mitochondria replicate via binary fission, they can lose/gain mutated genes - results in variability of number of mitochondria affected by disease whenever cells and mitochondria divide
- many mitochondria in each cell, which undergoes random segregation
- severity of symptoms vary with number of affected mitochondria, and develop once threshold reached - develop with age due to accumulation of mutant mitochondria
- not all mitochondrial disease caused by mutations in mitochondrial DNA - most are caused by mutations in cell genome and have mendalian or sex chromosome linked inheritance
