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Genetics and genomes > W6LECT - Autosomal inheritence II. Autosomal recessive inheritance > Flashcards

W6LECT - Autosomal inheritence II. Autosomal recessive inheritance Flashcards

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Biology 101 flashcards
1
Q

What are the features of Diagnostic odyssey?

A
  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
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2
Q

What are the features of Diagnostic odyssey?

A
  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
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3
Q

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

A
  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
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4
Q

What is enzymopathy?

A

Mutations affecting an enzyme

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5
Q

What is hemoglobinopathy?

A

mutations of hemoglobin

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6
Q

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

A
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7
Q

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

A
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8
Q

What is the Genotype causing autosomal recessive diseases?

A

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

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9
Q

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

A
  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
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10
Q

Incidence of monogenic diseases
2. Describe Founder effect

A
  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
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11
Q

What are the features of Enzymopathies?

A
  • 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
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12
Q

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

A

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

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13
Q

What are the features of Phenylketonuria (PKU)?

A
  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
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14
Q

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

A
  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
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15
Q

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

A
  1. Light hair, skin and eyes
  2. Eczema
  3. Microchephaly
  4. Jerking movements
  5. Mental retardation
  6. Mood disturbance
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16
Q

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

A
  1. Light hair, skin and eyes
  2. Eczema
  3. Microchephaly
  4. Jerking movements
  5. Mental retardation
  6. Mood disturbance
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17
Q

Phenylketonuria (PKU)
3. Explain Accumulaten of phenylalanine

A

-

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18
Q

Describe Allele heterogeneity

A

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

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19
Q

Describe Allele heterogeneity

A

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

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20
Q

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

A
  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
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21
Q

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

A

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

22
Q

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

A

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

23
Q

Describe Mutation in CFTR gene

A
  • > 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)
24
Q

How does CFTR mutation affect Male infertility?

A
  • CFTR mutation essential
  • All homozygotes and complex heterozygotes have azoospermia
25
Q

How does CFTR mutation affect Pancreatic dysfunction?

A
  1. Less frequent
  2. Correlation with the type of CFTR mutation
  3. Other genes are also important
26
Q

How does CFTR mutation affect Pulmonary dysfunction?

A
  1. Wide range of phenotypic variability
  2. Not exclusively explained by CFTR mutation
  3. Environment is also important
27
Q

Describe Incidence of cystic fibrosis?

A
  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)
28
Q

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

A
  1. 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
29
Q

Describe Newborn screening for cystic fibrosis

A
  • 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
30
Q

What are the features of SMA – spinal muscular atrophy

A
  1. Mutation in SMN1 gene
  2. SMN (survival of motor neuron) proteion is affected
  3. progressive, selective destruction of α-motor neurons
31
Q

What are the symptoms of SMA – spinal muscular atrophy?

A

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

32
Q

Describe SMN1 and SMN2 genes?

A

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

33
Q

What are Consequences of SMN1 mutation?

A

Functional protein → normal phenotype

34
Q

What are Consequences of SMN2 mutation?

A

Mostly non-functional SMN
protein

35
Q

Describe Newborn screening for SMA

A
  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
36
Q

Describe Significance of newborn screening

A
37
Q

Describe Hemoglobinopathies

A
  • 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
38
Q

Hemoglobinopathies
-> What are the types of mutations?

A
  1. Affecting the structure: sickle cell anaemia
  2. Decreasing the synthesis of globin genes: thalassemias
  3. Causing hereditary persistence of fetal hemoglobin
39
Q

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

A
  1. Missense mutation in β-globin gene
  2. Hemoglobin S
    ̶ Rigid structure
    ̶ Sickling phenomenon
    → blocking capillaries
    → degradation red blood cells
40
Q

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

A
  • ”Sickle cell crisis”
  • Ischaemia
  • Pain
  • Spleen and kidney damage
  • Haemolytic anaemia
41
Q

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

A

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

42
Q

Sickle cell disease
- Glu6Val substitution causing ___

A

alteration in beta-globin

43
Q

Sickle cell disease
- Glu6Val substitution causing ___

A

alteration in beta-globin

44
Q

How can HbS allele protects against malaria infection?

A

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

45
Q

What are the features of Thalassemia?

A
  • 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
46
Q

What are the symptoms of Thalassemia?

A
  1. Hemolytic anaemia
  2. Jaundice, enlarged spleen
  3. Abnormal bone development
  4. Iron accumulation
47
Q

Describe Prevalence of thalassemias

A
  1. ’Thalassa’ means ’Sea’
  2. Common in the Mediterranean, Middle East, Africa
  3. Heterozygotes have a selection advantage over malaria
48
Q

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

A
  1. Precipitation of hemoglobin
  2. Inadequate oxygen transport
49
Q

What are the features of α-thalassemia?

A
  • More common type
  • Causing problem in fetus and in adults
  • Mutation in α1 and/or α2 globin genes
  • Deletion is the most common mutation
50
Q

What are the features of β-thalassemia?

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

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