W6LECT - Autosomal inheritence II. Autosomal recessive inheritance Flashcards
What are the features of Diagnostic odyssey?
- People living with rare disease often have long journeys towards diagnosis
- It can take 1, 2,5, 10, 15 or even 45years
- Unnecessery test and inadequate treatment
- Considerable physical and mental suffering
What are the features of Diagnostic odyssey?
- People living with rare disease often have long journeys towards diagnosis
- It can take 1, 2,5, 10, 15 or even 45years
- Unnecessery test and inadequate treatment
- Considerable physical and mental suffering
What are the 5 Characteristics of autosomal recessive (AR) inheritance?
- Disease/trait is expressed only in homozygote recessive (aa) form
- Parents of the affected person are heterozygotes (Aa) not expressing the trait
- Consanguinity of parents is frequent
- Horizontal pedigree
- Mutations affecting an enzyme = enzymopathy
- Mutations of hemoglobin = hemoglobinopathy
What is enzymopathy?
Mutations affecting an enzyme
What is hemoglobinopathy?
mutations of hemoglobin
What are the Factors, that cause differences in the manifestation of a genotype in an expected phenotype?
What are the Factors, that cause differences in the manifestation of a genotype in an expected phenotype?
What is the Genotype causing autosomal recessive diseases?
1/ Several mutations in a gene can be responsible for a given disease/trait
2/ Compound heterozygote: a person who carries two different mutant alleles of a gene
Frequency of autosomal recessive diseases
1. What are the features of Heterozygote advantage?
- Heterozygote genotype has a higher relative fitness to either homozygous genotype
- Due to environmental factors
- Environmental factor + homozygote normal (AA) → worse survival due to environmental factors
- Environmental factor + heterozygote (Aa) → higher survival, heterozygous genotype counteracts with environmental factors
- Environmental factor + homozygote mutant (aa) → poor survival due to recessive disease
Incidence of monogenic diseases
2. Describe Founder effect
- Small group separated from the population
- Genetic variations in founders are spread → genetic isolation
- Frequency of recessive alleles differs from high population frequency
What are the features of Enzymopathies?
- Diseases involving enzymes
- Enzymes are usually synthesised in higher quantities than required
Enyzyme defficiency:
̶ Accumulation of substrate
̶ Abnormal product - Soluble substrate: freely distributed, symptoms can develop anywhere
- Fixed substrate/product: the specific tissue/organ where the molecule is present will be affected
- A defect in one enzyme can affect the function of several enzymes
What are the characteristics of Diseases of phenylalanine – tyrosine metabolic pathway
1/ A defect in a particular enzyme also affects the subsequent reaction steps
2/ Some symptoms are common in different diseases
3/ e.g. disturbed melanin synthesis in phenylketonuria and albinism
What are the features of Phenylketonuria (PKU)?
- Mutation in PAH gene
- Deficient phenylalanin
hydroxylase - High phenylalanine (Phe) serum level
- Neurological symptoms can be prevented with a phenylalanine free diet
Phenylketonuria (PKU)
1. What are the features of Phenylketonuria (PKU)?
- Mutation in PAH gene
- Deficient phenylalanin
hydroxylase - High phenylalanine (Phe) serum level
- Neurological symptoms can be prevented with a phenylalanine free diet
Phenylketonuria (PKU)
2. What are the symptoms of Phenylketonuria (PKU)?
- Light hair, skin and eyes
- Eczema
- Microchephaly
- Jerking movements
- Mental retardation
- Mood disturbance
Phenylketonuria (PKU)
2. What are the symptoms of Phenylketonuria (PKU)?
- Light hair, skin and eyes
- Eczema
- Microchephaly
- Jerking movements
- Mental retardation
- Mood disturbance
Phenylketonuria (PKU)
3. Explain Accumulaten of phenylalanine
-
Describe Allele heterogeneity
1/ > 400 mutation in PAH gene
2/ Affected individuals are compound heterozygotes
3/ Different allele frequencies in different populations
4/ Complete PAH enzyme deficiency → classic PKU
5/ Reduced PAH activity → milder symptoms
Describe Allele heterogeneity
1/ > 400 mutation in PAH gene
2/ Affected individuals are compound heterozygotes
3/ Different allele frequencies in different populations
4/ Complete PAH enzyme deficiency → classic PKU
5/ Reduced PAH activity → milder symptoms
Cystic fibrosis
1. What are the 5 features of Cystic fibrosis?
- CFTR gene affected
- Cystic fibrosis transmembrane conductance regulator protein
= Cl- channel - Ducts of the exocrine glands becomes blocked
- Secretion of dense mucus
- Recurrent infections
Cystic fibrosis
2. What are the characteristics of CFTR gene?
Cl- ion channel
- ABC transporter
- 2 x 6 transmembrane domain, ATP-binding domain
(NBD1 és NBD2)
- Cl- ion release from the cell
What is the Role of Cl- channel in the airway epithelium?
Mutant CFTR
-> Abnormal or missing chloride channel
-> Cl- ion secretion ↓
-> Na+ ion reabsorption ↑
-> Water reabsorption ↑
-> Thick, sticky mucus
-> Infection, Inflammation, Bronchus blocking
Describe Mutation in CFTR gene
- > 1800 different mutations → several, different allele in a population
- Frequency of carriers: 1:25
- Most common: ΔF508 = deletion of phenylalanine in position 508
(deletion of a triplet)
How does CFTR mutation affect Male infertility?
- CFTR mutation essential
- All homozygotes and complex heterozygotes have azoospermia
How does CFTR mutation affect Pancreatic dysfunction?
- Less frequent
- Correlation with the type of CFTR mutation
- Other genes are also important
How does CFTR mutation affect Pulmonary dysfunction?
- Wide range of phenotypic variability
- Not exclusively explained by CFTR mutation
- Environment is also important
Describe Incidence of cystic fibrosis?
- Relatively common in Caucasian populations
- Most common mutation: ΔF508
- Affected individuals are usually homozygotes for ΔF508, or compound heterozygotes (ΔF508/other allele)
Cystic fibrosis carrier has selection advantage over cholera infection
=> Explain
- High prevalence of heterozygotes correlates to cholera epidemics
- AA die in cholera infection
- aa die in cystic fibrosis
- Aa have milder symptoms of cholera infection → survive
Describe Newborn screening for cystic fibrosis
- Incidence in Caucasians throughout the world of between 0.25 to 5 per 10,000 live births
- A few drops of blood from a heel prick
- Levels of immunoreactive trypsinogen (IRT)
- If the IRT is high, the second test (sweat chloride test or DNA test) is done
What are the features of SMA – spinal muscular atrophy
- Mutation in SMN1 gene
- SMN (survival of motor neuron) proteion is affected
- progressive, selective destruction of α-motor neurons
What are the symptoms of SMA – spinal muscular atrophy?
− Progressive muscle wasting
− Standing, sitting difficult
− Difficulty breathing and swallowing
− Finally paralysis
− Limb and spine deformities
Describe SMN1 and SMN2 genes?
1/ SMN1
- Functional SMN protein encoded by the SMN1 gene
=> Normal amount and function of SMN protein
2/ SMN2
- Silent genecopy
- Instabile protein is synthesized
=> Arising protein is truncated and degrades quickly
What are Consequences of SMN1 mutation?
Functional protein → normal phenotype
What are Consequences of SMN2 mutation?
Mostly non-functional SMN
protein
Describe Newborn screening for SMA
- Incidence of 1 in 6,000 to 10,000 live births
- Three, approved disease-modifying treatment options for SMA in Europe
- Genetic test (qRT-PCR) identifies a homozygous SMN1 exon 7 deletion
- SMA newborn screening pilot trials show that pre-symptomatic treatment results in age-appropriate motor development
Describe Significance of newborn screening
Describe Hemoglobinopathies
- Disorders of hemoglobins
- Most common monogenic diseases
- Structure of hemoglobin
+) Adult hemoglobin = hemoglobin A (HbA): 2 alpha- and 2 beta chain
+) two identical α-globin genes (α1 and α2) + β-globin genes - Most of them inherited autosomal recessive way
- Types of mutations:
+) Affecting the structure: sickle cell anaemia
+) Decreasing the synthesis of globin genes: thalassemias
+) Causing hereditary persistence of fetal hemoglobin
Hemoglobinopathies
-> What are the types of mutations?
- Affecting the structure: sickle cell anaemia
- Decreasing the synthesis of globin genes: thalassemias
- Causing hereditary persistence of fetal hemoglobin
Sickle cell disease
1. What are the features of Sickle cell disease
- Missense mutation in β-globin gene
- Hemoglobin S
̶ Rigid structure
̶ Sickling phenomenon
→ blocking capillaries
→ degradation red blood cells
Sickle cell disease
2. What are the symptoms of Sickle cell disease?
- ”Sickle cell crisis”
- Ischaemia
- Pain
- Spleen and kidney damage
- Haemolytic anaemia
Sickle cell disease
- What is Missense mutation of beta-globin gene?
GAG codon changing to GTG → glutamate (Glu) being substituted by valine (Val) at position 6
Sickle cell disease
- Glu6Val substitution causing ___
alteration in beta-globin
Sickle cell disease
- Glu6Val substitution causing ___
alteration in beta-globin
How can HbS allele protects against malaria infection?
1/ Heterozygotes for HbS allele have a selection advantage over malaria
2/ HbS allele frequency correlates with malaria infection
3/ Short half life of HbS- containing RBC
4/ Faster clearence than malaria spreading cycle
5/ No or mild form of malaria in heterozygotes
What are the features of Thalassemia?
- Most common human single-gene disorders
- Loss of function mutation
+) α-globin genes → α-thalassemia
+) β-globin gene → β-thalassemia - Relative excess of one of the globin chain → precipitation → red blood cell destruction
What are the symptoms of Thalassemia?
- Hemolytic anaemia
- Jaundice, enlarged spleen
- Abnormal bone development
- Iron accumulation
Describe Prevalence of thalassemias
- ’Thalassa’ means ’Sea’
- Common in the Mediterranean, Middle East, Africa
- Heterozygotes have a selection advantage over malaria
What are the consequences of α-and β-thalassemia?
- Precipitation of hemoglobin
- Inadequate oxygen transport
What are the features of α-thalassemia?
- More common type
- Causing problem in fetus and in adults
- Mutation in α1 and/or α2 globin genes
- Deletion is the most common mutation
What are the features of β-thalassemia?
- Symptoms only appear after birth
- Several different mutation (missense mutation typical)
