19.03.05 AD - haploinsufficiency Flashcards
Are most autosomal genes dosage sensitive?
No. For most genes the second allele is sufficient for normal (or sub-clinical) function.
What is haploinsufficiency?
A situation in which the total level of a gene product (a particular protein) produced by the cell is about half of the normal level and that is not sufficient to permit the cell to function normally.
What genes are more likely to be haploinsufficient?
Ones where all mutation types (missense, nonsense, gene deletion etc.) produce the same phenotype. This suggests LOF as opposed to GOF, and an AD inheritance pattern is observed (affected males and females have an equal probability of passing on the trait to offspring, both male and female offspring has a 50% chance of inheriting the mutant allele).
Can genes on sex chromosomes show haploinsufficiency?
No
Types of genes showing haploinsufficiency:
1) Highly expressed genes
Genes which need to produce large quantities of product, and a single gene copy can’t meet this demand.
Types of genes showing haploinsufficiency:
2) Dosage-sensitive genes
- genes that are part of a signalling system that depend on partial occupancy or competition for a receptor
- genes that co-operate in interactions
- gene products that compete to determine a developmental switch
- These are all measured against something else in the cell, so relative ratios are more important that absolute amounts
- Therefore gene products that act in their own often don’t show dosage effects
Types of genes showing haploinsufficiency:
3) Imprinted genes
- Only 1 allele is expressed due to imprinting
- Mutations on the expressed allele will be dominant
Can diseases that show AD inheritance due to haploinsufficiency also have AR forms?
Yes. Some diseases can be caused by complete loss of one allele, or 50% reduction in both alleles.
- Expression of the single allele or both allele will show variation in penetrance and expression, probably due to external factors (such as expression of other genes, environment, age etc).
What happens if you inherit 2 domiant alleles?
This can result in lethality or more severe forms of the disease.
E.g. - Het mutations in PROC cause protein K deficiency. and increased risk for DVT’s in their 20’s, however HOM/compound HET carriers develop neonatal purpura fulminans with necrosis of the skin, which is life threatening.
Are haploinsufficient genes often found in segmentally duplicated regions?
No. These regions are prone to mutations via NAHR. This suggests a mechanism is in place to try to main the correct dosage of these genes.
Hypertrophic cardiomyopathy (HCM) - example of haploinsufficiency in a single gene disorder
- Clinical features - Left-ventricular hypertrophy (LVH) in the absence of predisposing cardiac/cardiovascular conditions (common symptoms are hypertension, palpitations, progressive heart failure and heart congestions). Sudden cardiac death in early adulthood is major cause of mortality.
- Characteristic histopathological disruption of heart myocytes and abnormal ECG.
Onset = most common late adolescence
Prevalence = 1/500 - Genetics = 50-75% of people with HCM have a mutation (so positive prediction value is high). 20 genes have been implicated, all are involved in the structure and function of the sarcomere in the heart. 70-80% of mutations are in MYH7 and MYBPC3. 10% are in TNNT2 and TNNI3. Clinical sensitivity of this four gene panel is ~50%.
- MYBPC3 is haploinsufficient. Truncated protein doesn’t get incorporated into HCM cardiac tissue, and full length protein shows lower levels.
- Thought is that multiple genes in the same pathway may be involved (that must work together) so mutations in a range of genes can cause similar phenotype.
Alagille syndrome type 1 (JAG1; Jagged 1 and NOTCH2)
- example of haploinsufficiency in a single gene disorder
- Clinical features - multi-system phenotype involving heart, liver, eye and skeletal defects. Often get lack of bile ducts, cardiac abnormalities and typical facies.
- Detect JAG1 mutations in 89% of patients. 7% of patients have whole gene del/dups (this includes 20p12 microdeletion). NOTCH2 mutations found in 1-2%.
- No genotype/phenotype correlation and penetrance is reduced (lots of carriers are sub-clinical)
- High de novo rate (50-70% of cases are de novo).
- JAG1 is a ligand of the NOTCH1 receptor, which (when activated) is involved in transcriptional activation of various factors involved in cell differentiation and morphogenesis.
Cleidocranial dystosis (RUNX2) - example of haploinsufficiency in a single gene disorder
- involves missing or partial collarbones, soft bones and fontanelle (skull closure) and restricted growth.
- Caused RUNX2 mutations
- Key transcription factor involved in development of osteoblasts - so critical for skeletal development.
Aniridia (PAX6)
- example of haploinsufficiency in a single gene disorder
- Lack of irises (alongside associated eye defects) causing severe defects in vision.
- PAX6 is a control gene involved in eye development.
- HOM loss of PAX6 can cause complete lack of eye formation and is fatal in mice.
GLUT1 deficiency syndrome (SLC2A1)
- example of haploinsufficiency in a single gene disorder
- SLC2A1 is involved in transport of glucose across the BBB.
- Mutations in SLC2A1 cause GLUT1DS1 - neurological condition where you get low CSF:blood glucose ratio and seizures.
- Treatment is a ketogenic diet - replacing carbohydrates with protein & fat
