W6LECT - Autosomal inheritence II. Autosomal recessive inheritance

Question 1

What are the features of Diagnostic odyssey?

Answer 1

1. People living with rare disease often have long journeys towards diagnosis
2. It can take 1, 2,5, 10, 15 or even 45years
3. Unnecessery test and inadequate treatment
4. Considerable physical and mental suffering

Question 2

What are the features of Diagnostic odyssey?

Answer 2

1. People living with rare disease often have long journeys towards diagnosis
2. It can take 1, 2,5, 10, 15 or even 45years
3. Unnecessery test and inadequate treatment
4. Considerable physical and mental suffering

Question 3

What are the 5 Characteristics of autosomal recessive (AR) inheritance?

Answer 3

1. Disease/trait is expressed only in homozygote recessive (aa) form
2. Parents of the affected person are heterozygotes (Aa) not expressing the trait
3. Consanguinity of parents is frequent
4. Horizontal pedigree
5. Mutations affecting an enzyme = enzymopathy
6. Mutations of hemoglobin = hemoglobinopathy

Question 4

What is enzymopathy?

Answer 4

Mutations affecting an enzyme

Question 5

What is hemoglobinopathy?

Answer 5

mutations of hemoglobin

Question 6

What are the Factors, that cause differences in the manifestation of a genotype in an expected phenotype?

Answer 6

Question 7

What are the Factors, that cause differences in the manifestation of a genotype in an expected phenotype?

Answer 7

Question 8

What is the Genotype causing autosomal recessive diseases?

Answer 8

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

Question 9

Frequency of autosomal recessive diseases
1. What are the features of Heterozygote advantage?

Answer 9

1. Heterozygote genotype has a higher relative fitness to either homozygous genotype
2. 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

Question 10

Incidence of monogenic diseases
2. Describe Founder effect

Answer 10

1. Small group separated from the population
2. Genetic variations in founders are spread → genetic isolation
3. Frequency of recessive alleles differs from high population frequency

Question 11

What are the features of Enzymopathies?

Answer 11

• 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

Question 12

What are the characteristics of Diseases of phenylalanine – tyrosine metabolic pathway

Answer 12

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

Question 13

What are the features of Phenylketonuria (PKU)?

Answer 13

1. Mutation in PAH gene
2. Deficient phenylalanin
   hydroxylase
3. High phenylalanine (Phe) serum level
4. Neurological symptoms can be prevented with a phenylalanine free diet

Question 14

Phenylketonuria (PKU)
1. What are the features of Phenylketonuria (PKU)?

Answer 14

1. Mutation in PAH gene
2. Deficient phenylalanin
   hydroxylase
3. High phenylalanine (Phe) serum level
4. Neurological symptoms can be prevented with a phenylalanine free diet

Question 15

Phenylketonuria (PKU)
2. What are the symptoms of Phenylketonuria (PKU)?

Answer 15

1. Light hair, skin and eyes
2. Eczema
3. Microchephaly
4. Jerking movements
5. Mental retardation
6. Mood disturbance

Question 16

Phenylketonuria (PKU)
2. What are the symptoms of Phenylketonuria (PKU)?

Answer 16

1. Light hair, skin and eyes
2. Eczema
3. Microchephaly
4. Jerking movements
5. Mental retardation
6. Mood disturbance

Question 17

Phenylketonuria (PKU)
3. Explain Accumulaten of phenylalanine

Answer 17

-

Question 18

Describe Allele heterogeneity

Answer 18

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

Question 19

Describe Allele heterogeneity

Answer 19

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

Question 20

Cystic fibrosis
1. What are the 5 features of Cystic fibrosis?

Answer 20

1. CFTR gene affected
2. Cystic fibrosis transmembrane conductance regulator protein
   = Cl- channel
3. Ducts of the exocrine glands becomes blocked
4. Secretion of dense mucus
5. Recurrent infections

Question 21

Cystic fibrosis
2. What are the characteristics of CFTR gene?

Answer 21

Cl- ion channel
- ABC transporter
- 2 x 6 transmembrane domain, ATP-binding domain
(NBD1 és NBD2)
- Cl- ion release from the cell

Question 22

What is the Role of Cl- channel in the airway epithelium?

Answer 22

Mutant CFTR
-> Abnormal or missing chloride channel
-> Cl- ion secretion ↓
-> Na+ ion reabsorption ↑
-> Water reabsorption ↑
-> Thick, sticky mucus
-> Infection, Inflammation, Bronchus blocking

Question 23

Describe Mutation in CFTR gene

Answer 23

• > 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)

Question 24

How does CFTR mutation affect Male infertility?

Answer 24

• CFTR mutation essential
• All homozygotes and complex heterozygotes have azoospermia

Question 25

How does CFTR mutation affect Pancreatic dysfunction?

Answer 25

1. Less frequent 2. Correlation with the type of CFTR mutation 3. Other genes are also important

Question 26

How does CFTR mutation affect Pulmonary dysfunction?

Answer 26

1. Wide range of phenotypic variability 2. Not exclusively explained by CFTR mutation 3. Environment is also important

Question 27

Describe Incidence of cystic fibrosis?

Answer 27

1. Relatively common in Caucasian populations 2. Most common mutation: ΔF508 3. Affected individuals are usually homozygotes for ΔF508, or compound heterozygotes (ΔF508/other allele)

Question 28

Cystic fibrosis carrier has selection advantage over cholera infection => Explain

Answer 28

1. High prevalence of heterozygotes correlates to cholera epidemics 2. - AA die in cholera infection - aa die in cystic fibrosis - Aa have milder symptoms of cholera infection → survive

Question 29

Describe Newborn screening for cystic fibrosis

Answer 29

- 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

Question 30

What are the features of SMA – spinal muscular atrophy

Answer 30

1. Mutation in SMN1 gene 2. SMN (survival of motor neuron) proteion is affected 3. progressive, selective destruction of α-motor neurons

Question 31

What are the symptoms of SMA – spinal muscular atrophy?

Answer 31

− Progressive muscle wasting − Standing, sitting difficult − Difficulty breathing and swallowing − Finally paralysis − Limb and spine deformities

Question 32

Describe SMN1 and SMN2 genes?

Answer 32

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

Question 33

What are Consequences of SMN1 mutation?

Answer 33

Functional protein → normal phenotype

Question 34

What are Consequences of SMN2 mutation?

Answer 34

Mostly non-functional SMN protein

Question 35

Describe Newborn screening for SMA

Answer 35

1. Incidence of 1 in 6,000 to 10,000 live births 2. Three, approved disease-modifying treatment options for SMA in Europe 3. Genetic test (qRT-PCR) identifies a homozygous SMN1 exon 7 deletion 4. SMA newborn screening pilot trials show that pre-symptomatic treatment results in age-appropriate motor development

Question 36

Describe Significance of newborn screening

Answer 36

Question 37

Describe Hemoglobinopathies

Answer 37

- 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

Question 38

Hemoglobinopathies -> What are the types of mutations?

Answer 38

1. Affecting the structure: sickle cell anaemia 2. Decreasing the synthesis of globin genes: thalassemias 3. Causing hereditary persistence of fetal hemoglobin

Question 39

Sickle cell disease 1. What are the features of Sickle cell disease

Answer 39

1. Missense mutation in β-globin gene 2. Hemoglobin S ̶ Rigid structure ̶ Sickling phenomenon → blocking capillaries → degradation red blood cells

Question 40

Sickle cell disease 2. What are the symptoms of Sickle cell disease?

Answer 40

- ”Sickle cell crisis” - Ischaemia - Pain - Spleen and kidney damage - Haemolytic anaemia

Question 41

Sickle cell disease - What is Missense mutation of beta-globin gene?

Answer 41

GAG codon changing to GTG → glutamate (Glu) being substituted by valine (Val) at position 6

Question 42

Sickle cell disease - Glu6Val substitution causing ___

Answer 42

alteration in beta-globin

Question 43

Sickle cell disease - Glu6Val substitution causing ___

Answer 43

alteration in beta-globin

Question 44

How can HbS allele protects against malaria infection?

Answer 44

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

Question 45

What are the features of Thalassemia?

Answer 45

- 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

Question 46

What are the symptoms of Thalassemia?

Answer 46

1. Hemolytic anaemia 2. Jaundice, enlarged spleen 3. Abnormal bone development 4. Iron accumulation

Question 47

Describe Prevalence of thalassemias

Answer 47

1. ’Thalassa’ means ’Sea’ 2. Common in the Mediterranean, Middle East, Africa 3. Heterozygotes have a selection advantage over malaria

Question 48

What are the consequences of α-and β-thalassemia?

Answer 48

1. Precipitation of hemoglobin 2. Inadequate oxygen transport

Question 49

What are the features of α-thalassemia?

Answer 49

- More common type - Causing problem in fetus and in adults - Mutation in α1 and/or α2 globin genes - Deletion is the most common mutation

Question 50

What are the features of β-thalassemia?

Answer 50

- Symptoms only appear after birth - Several different mutation (missense mutation typical)