W5LECT - Autosomal inheritance - Autosomal dominant inheritance Flashcards
What are the features of monogenic diseases
- Inheritance follows the Mendelian rules (except mitochondrial inheritance)
- One gene is in the background of a given disease or trait
- „Major – high” impact genes
- Rare diseases
- Minor environmental may influence
- Pedigree analysis informative
- ~8000 human traits/diseases
What are the features of rare diseases?
- Prevalence: < 1:2000
- Number of affected individuals varies significantly by disease
- On average, a person carries 6-8 genetic abnormalities
- Life expectancy is significantly reduced
- 80% of rare diseases are due to genetic causes
- They affect 3-4% of births
- Onset of the rare diseases are different
- Most cases are incurable
- Delays in making the right diagnosis
What are the 3 examples of monogenic diseases?
- Huntington disease (AD)
- Osteogenesis imperfecta (AD)
- Familial hypercholesterolaemia (Aa) - AD
What are the 2 examples of chromosomal diseases?
- Prader-Willi syndrome (deletion)
- Down syndrome (Trisomy)
What are the 4 examples of Multifactorial (complex) diseases?
- Schizophrenia
- Type 2 diabetes
- Bipolar disorder
- Breast carcinoma
What are the differences between Dominant vs Recessive traits?
What are the consequences of dominant phenotype?
- Gain of function mutation:
- Protein with new function or with constant activity is coded - Loss of function mutation in case of dose sensitive genes
- Haploinsufficiency
- Dominant negative effect: mutant gene product pevents the function of the normal gene product
what is the consequence of recessive phenotype?
̵ Loss of function mutation:
gene product having less or no function or there is no gene product
(half dose of the gene product is enough → not dose sensitive genes)
What does this picture illustrate?
Dominant negative effect
Describe the Significance of loss of function mutation
- Abnormal phenotype, Product not enough for the function
=> Haploinsufficiency
Besides genetic background, what can influence the phenotype?
Monogenic inheritance can be influenced by several factors other than genotype
- Environment
- Epigenetic factors
- Modified genes
Describe Diseases/traits inhereited autosomal dominant way
1/ ~4500 known dominant traits
2/ Average incidence of disease: 0.1-3/1000 live births
3/ Tissues commonly affected
- Skeletal system, connective tissue - Nervous system
4/ Genes of receptor-, structural- and regulatory proteins or protoonkogenes are usually mutated
What are Characteristics of autosomal dominant (AD) inheritance?
1/ Disease/trait is expressed in heterozygote (Aa) and homozygote dominant (AA) form
2/ The severity and frequency are the same in both sexes
3/ Phenotype of homozygotes is more severe than heterozygotes
4/ Vertical pedigree pattern
5/ Variable penetrance and expressivity
6/ Affected persons have at least one affected parent (except for new mutations)
7/ There is a paternal age effect for new mutations.
What are the features of Achondroplasia?
- Mutation in FGFR3 (fibroblast-growth factor receptor 3) gene
- Disproportionate dwarfism
- Longitudinal growth of tubular bones is affected
- Limbs are affected
- Forehead is dominant,
middle part of the face is less developed
What does Dependence of new mutations on paternal age mean?
- Probability of new mutations higher for fathers aged over 35
- New mutation develops during spermatogenesis
Why do we have Dependence of new mutations on paternal age?
In female.
- Arrest in meiosis I, in diplotene
(5. month of embryonic development)
- Chrs held together by chiasmata for 10-50 years
- Less effective meiotical check point
- Lack of elimination of abnormal oocytes
In male,
- Production of sperms: 60-65 days
- Effective meiotical check point
- Elimination of abnormal
spermatocytes
- Spermatogona continuously divide
What are the features of Primordial germ cell mosaicism?
- New mutation can occur during the mitotic divisions of germ cells (e.g. spermatogonia)
- The father carrying a germline mutation is phenotypically healthy
- His offspring mcan be affected
Penetrance
1. What is Penetrance?
Percent of the manifestation in individuals with a disease-causing variant
Penetrance
2. What are the 2 types of penetrance? Their characteristics?
- Complete penetrance: everyone carrying a disease-causing variant will develop the disease
- Incomplete or reduced penetrance: not everyone with a disease causing variant will develop disease
What type of protein is FGFR3 protein?
a receptor tyrosine kinase
What are the major sites of FGFR3?
- Ig-like loops
- Transmembrane domain
- Tyrosine kinase domains
Why do we say that FGFR3 with major sites of mutation?
- Missense mutations
- Several different mutations within the gene
- Allele heterogeneity: different variants of the same gene result in similar symptoms/diseases
- Achondroplasia (ACH) and its more severe form (SADDAN)
- Hypochondroplasia (HYP)
- Thanatophoric dysplasia type I and II (TDI and TDII)
What is the mechanism of Normal FGFR3?
- Ligand-dependent activation of an inhibitory signaling pathway
- Proliferation and differentiation of chondrocytes along with matrix synthesis and bone growth
What is the mechanism of Mutant FGFR3?
- There is mutation in transmembrane domain
- Activation of the inhibitory RAS–MAPK pathway that is both ligand (FGF) dependent and independent
- Inhibition of chondrocyte proliferation and differentiation, leading to imparied matrix synthesis and bone growth
What are the 4 features of Marfan syndrome – Arachnodactyly?
- Mutation in FBN1 gene coding fibrillin 1 protein
- Connective tissue defect
- Relative high frequency of new mutations – paternal age effect
- Pleitropic disease: mutation of a single gene controlling multiple phenotypic traits.
What are the symptoms of Pleiotropy?
Variable expressivity is typical in Marfan syndrome
=> T/F?
True
Variable expressivity is typical in Marfan syndrome
=> What is Variable expressivity?
severity of symptoms varies from person to person with same genotype (variant)
What is the difference between Complete expressivity and Variable expressivity ?
- Complete expressivity: everyone with the same variant and the same severity of symptoms
- Variable expressivity: different symptoms or different severity of symptoms in individuals with the same genotype
If there is Mutation of fibrillin 1, what will happen?
Haploinsufficiency or Dominant Negative may occur
Mutation of fibrillin 1
=> What are the mutations in DNA and Protein that can cause Haploinsufficiency?
- DNA
- Most commonly nonsense, frameshift, splice site mutations or gene deletions - Protein: Not made, unstable or degraded
Mutation of fibrillin 1
=> What are the mutations in DNA and Protein that can cause Dominant Negative?
- DNA
- Most commonly missense
- In-frame indel mutations - Protein: stable abnormal protein
What are the 5 features of Osteogenesis imperfecta?
- Type I collagene affected
- Connective tissue defect
- Pleiotropic disease
- Variable expressivity
- Reduced penetrancia
What are the genes that code for type I collagen?
- COL1A1 gene -> Collagen α1 chain
- COL1A2 gene -> collagen α2 chain
=> Create Collagen I triplehelix
=> Formation of cross-links → collagen fibril
What is locus heterogeneity?
the mutations of several different genes result in the same or in very similar phenotype
Give an example of allele heterogeneity
Different mutations in the COL1A1 gene cause different severity of symptoms → allele heterogeneity
What are the 5 features of Familial hypercholesterolaemia?
- LDLR gene coding LDL receptort is mutated
- Elevated serum LDL levels
- Early onset of cardiovascular disease (CAD)
− myocardial infarction
− vascular diseases of brain and peripherial blood vessels - Heterozygote form is relatively common (1:250)
- Other symptoms: Cholesterol deposits throughout the body = xanthomas
Describe Mutations in LDLR gene
- Several different mutations are known (> 1500)
- Missense
- Nonsense
- Splicing site mutation
- Deletion (in frame and frameshift) - Depending on the site of the mutation, different functions of the LDL receptor are lost
What is the Effect of mutations on the amount and function of the LDL receptor?
- No synthesis
- Decreased Modification and transport
- No/insufficient ligand-binding
- No/insufficient internalization
- No/insufficient recirculation
What are the features of Huntington disease?
- Mutation in HTT gene coding for huntingtin
- Trinucleotide repeat disease
- Late onset disorder: starts in age 35-44
- Anticipation: The disease is expressed in gradually more severe levels and earlier in the offspring generations
- Complex disease of locomotor, cognitive and psychiatric symptoms
Why do we say that Huntington disease is a trinucleotide repeat disease?
- CAG triplet repeats
- CAG codes for glutamine amino acid
- High number of CAG repeats → polyglutamine protein
What is the mechanism of normal Huntingtin protein ?
Normal huntingtin promoting the assembly of transcriptional complex
→ transcription
What is the mechanism of Polyglutamine hungtintin?
Polyglutamine hungtintin inhibiting the formation of transcriptional complex
→ no transcrition
Poliglutamine huntingtin protein forms aggregates
What is Anticipation? (Huntington disease)
- The disease is expressed in gradually more severe levels and earlier in the later generations
- Related to CAG repeat number
- Expansion of repeat number from generation to generation
What is the consequence of Replication slippage?
„Replication slippage”
→ repeat expansion
→ anticipation
