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Molecular Basis Of Disease > Genetics part 2 > Flashcards

Genetics part 2 Flashcards

1
Q

What are the categories of CFTR mutations?

A
  1. Non-sense mutation - G542X - non functional protein - degraded quickly - no protein formed
  2. Delta 508 - deletion of phenylalanine - 70% of patients - protein recognised as misfolded - degraded - no channel in the membernae
  3. Full length channel - lacks the function - substitution of glycine to aspartic acid
  4. Partial activity - less phenotype
  5. Reduced number of transcript
  6. Accelerated turn over
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2
Q

What is Werner mesomelic syndrome?

A
  1. Rare autosomal recessive disease
  2. Premature aging
  3. Hypo- or aplasia of tibia
  4. Problems with hands and feet
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3
Q

What is mutation in gene for Werner mesomelic syndrome?

A

Sonic hedgehog - important gene during development

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4
Q

What is major trafficking network?

A
  1. Birth defect
  2. Tissue regeneration
  3. Stem cell renewal
  4. Cancer growth
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5
Q

What does protein patched inhibit?

A

Smoothened

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6
Q

What happens when sonic hedgehog is bound?

A

It disables the function and smoothened is active

Activate certain transcription factors and these are Gli (glioblastoma)

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7
Q

What is a morphogen?

A

A substance who’s non-uniform distribution governs the pattern of tissue development

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8
Q

What is the function of sonic hedgehog?

A

Determine which of these neurons develop at different location

Has a bigger effect on limb formation

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9
Q

Where is sonic hedgehog located?

A

Chromosome 7

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10
Q

Where is the enhancer sequence located?

A

Different gene lmbr1

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11
Q

What is the prevalence of Huntington disease?

A

4-10 per 100,000

mean age of onset

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12
Q

What is the clinical features of Huntington disease?

A
  1. progressive motor dysfunction (lack of coordination, jerky movements)
  2. Cognitive decline (decline into dementia)
  3. Psychiatric disturbance (mood changes; an early sign)
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13
Q

What happens when the symptoms of HD manifest?

A

Early-subtle psychomotor dysfunction

  1. Jerky movement
  2. Motor impairments
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14
Q

What is the neurobiology of HD?

A
  1. Neural dysfunction and eventually neuronal cell death
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15
Q

What does HD have?

A

Expansion of CAG triplet

few copies of them: between 10-26[healthy amount of copies]

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16
Q

What amount of CAG triplet copies lead indicates disease of HD?

A

> 40 repeats

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17
Q

What does the protein of HD have?

A

post modification translation

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18
Q

What is done to the amino acids of HD?

A
  1. Ubiquitinated
  2. Sumolyated
  3. Phosphorylated
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19
Q

What is the location of the HD protein?

A

Mostly cytoplasmic
Can go into nucleus
Role in vesicle transport
Gene regulation occurs and RNA traffickinf

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20
Q

What does availible evidence suggest about HD disease?

A

Arises predominantly from a gain of toxic function

From abnormal conformation of mutant HTT

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21
Q

What could also lead to disease pathogenesis of HD?

A

Loss of function of HTT

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22
Q

What is X-linked Recessive?

A

Carrier mother
50% chance - affected son
If father affected, all daughters are carries, none of son inherit the X chromosome, get Y chromosome from father

e.g. Haemophilia A - mutation in factor 8

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23
Q

What are the symptoms of Duchene Muscular Dystrophy (DMD)?

A
  1. Muscle wasting disease
  2. Difficult to walk and climb the stairs
  3. Wheelchair confined before 12 years old
  4. Respiratory and cardiac impairment
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24
Q

What is the clinical signs of DMD?

A

Progressive muscle weakness involving all striated skeletal/cardiac muscle

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25
Q

What BMD?

A

Similar symptoms but with variable time course/severity

Some patients are asymptomatic while some become wheelchair confined around 16 years

Can survive into old age

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26
Q

What do both DMD and BMD have?

A

Mutation on the dystrophin gene

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27
Q

DMD

A

Dystrophin gene is absent/non-functional

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28
Q

BMD

A

Dystrophin gene is partial functional

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29
Q

What is the incidence of DMD?

A

1/4000

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30
Q

What is the incidence of BMD?

A

1/20,000

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31
Q

What is the structure of the Dystrophin gene?

A
  1. Largest gene
  2. Spans 2.7 million base pairs on the x chromosome
  3. short arm p arm
  4. Contains 79 exons
  5. Number of different promoters
  6. In different tissue - different promotoers
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32
Q

Structure of Dystrophin gene (2)

A
  1. 4 major structural domains
  2. N terminal domain - coded by exons 1-8 - actin- binding domain
  3. Central part - coded by exon 8 to 61
  4. 24 repeats which interact mainly with structural protein (actin, microtubules)
  5. 3rd domain coded by exons 62-69 - Cys-rich domain
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33
Q

What does Dystrophin domain bind to?

A

Most important part of dystrophin; the membrane protein B-dystroglycan

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34
Q

What is C terminal domain of Dystrophin coded by?

A

Exon 69-79
Bind to two cytoplasmic protein:

  1. Syntrophin
  2. Dystrobrevin
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35
Q

What is Dystrophin anchored to plasma membrane by?

A

Phospholipid and B-dystroglycan

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36
Q

What is DMD and BMD mutation caused by?

A
  1. Number of mutations caused by deletion
  2. 65% deletion (one or several exons)
  3. 10% duplications of exons
  4. 15% of single point mutations
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37
Q

What does deletion and insertion either do?

A

Conserve the reading frame or not - Difference between DMD and BMD

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38
Q

Conservation of Reading frame

A

BMD

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39
Q

Doesn’t conserve Reading frame?

A

DMD

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40
Q

What does in-frame mutation lead to?

A

Less severe BMD disease

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41
Q

What is primary defect in BMD and DMD caused by?

A

Dystrophin scaffolding network

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42
Q

What is the consequence of disruption of dystrophin scaffolding network?

A

Transmission of forces from cytosol to extracellular matrix is impaired

Frequent ruptures of plasma membrane during contractions

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43
Q

What does disruption of dystrophin scaffolding network lead to?

A
  1. Increase influxes of calcium - activate calcium-dependent proteases
  2. Leads to cell death
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44
Q

What is muscles of dystrophin protein eventually replaced by?

A
  1. Connective and adipose tissue
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45
Q

What is modelling of 3 exons?

A
  1. Exon 1 - ATG codon, number of CGG codons and carries on
  2. Exon 1 - finishes on codon CGG
  3. Exon 2 starts with next codon CGG
  4. Exon 2 finishes with 2 nucleotides on one codon and the remaining nucleotide of the codon is in exon 3
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46
Q

Deletion of exon 2

A
  1. 3 exons
  2. ATG and codons are made up of CGG repeated a number of times
  3. Put in open reading frame reader
  4. ATG - codes for methionine
  5. CGG - codes for arginine
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47
Q

Duplication of exon 1

A
  1. Exon 1 will finish with 3 nucleotide of a codon CGG
  2. Duplication - protein will be much longer
  3. Methionine starts and then all arginine
  4. Peptide sequence hasn’t changed but it becomes longer
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48
Q

What does BMD mutation have?

A

Less severe phenotype

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49
Q

What is De-novo mutation?

A
  1. Parent doesn’t show mutation but the patient does
  2. 30% of cases
  3. Patients have duplication s of A which is not in either parents
  4. Leads to DMD - out of frame
  5. From this point onward, amino acid sequence will be different
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50
Q

Haemophilia A (factor VIII mutations)

A
  • Bleeding disorder that slows blood clotting
  • Clotting cascade: inactive pro-enzymes, activated in turn
  • Intrinsic, extrinsic and common pathway
  • In a trauma, clotting factors get sequentially activated
  • Molecules: proteases, cleave next molecule to activate it
  • Trauma → activation of factor 7 → activation of factor 10 → prothrombin to thrombin → convert fibrinogen to fibrins
  • Formation of cross-linked fibrin clots
  • Mutations in factor 8 leads to defective clotting
  • There’s also intrinsic pathway activated by serine proteases
  • Activation of factor 12 → activation of factor 11,9,10 and then goes through the common pathway
  • Von willibrand factor → role in the initial clot
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51
Q

What can different mutations cause?

A

Different severities - expressivity

Have a mutation but see different activities

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52
Q

What can Haemophila A be?

A
  1. Severe (<1% activity)
  2. Moderate (1-5% activity)
  3. Mild (5-30% activity)
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53
Q

What is two different missense mutation?

A
  1. Nucleotide 65 - GT - arginine to isoleucine
    (10-15% of activity which lead to mild phenotype)
  2. G-C subtitution - Arginine to threonine
    (1% activity - severe outcome)
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54
Q

What can lead to mutation in the same genome?

A

Expressivity of the clinical outcome

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55
Q

Inversion, severe phenotype

A
  1. No trancription of the full gene
  2. Region in the intron of factor 8 -intron 1
  3. Very similar sequence to another region - located 14,000 base pairs away
  4. Recombination between these 2 homologous areas
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56
Q

What is the net effect of Inversion?

A

Exon 1 pointing in one direction and exon 2 and other genes pointing in the other direction

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57
Q

What is adjacent to exon 1?

A
  1. Promoter

2. Non-functional and will be a severe phenotype

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58
Q

What can you do to restore factor levels?

A
  1. Intravenous recombinant or plasma factor 8

2. Desmopressin

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59
Q

X-linked dominant

A
  1. MLS
  2. Affected father, all affected daughters
  3. None of the son gets affected because Y chromosome goes to son
  4. 50% chance of inheriting this disease
  5. All affected males wouldn’t exist
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60
Q

What are examples of X-linked dominant disorder?

A
  1. Some forms of retinitis pigmentosa (degenerative eye disease)
  2. Chondrodysplasia Punctata (disorder of cartilage and bone development)
  3. Microphtalmia with linear skin defects syndrome (MLS)
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61
Q

What is MLS?

A
  1. Rare X-linked dominant condition
  2. Unilateral or bilateral microphtalmia (small eye balls)
  3. Linear skin defects - hyper-pigmented areas
  4. It only affects the females
  5. Lethal in males
  6. Caused by de-novo mutations
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62
Q

What is problem with MLS?

A
  • Problems in identifying which genes are involves
  • Deletions which delete multiple genes
  • Regions indicated by 2 yellow zigzag lines are deleted – junctions of the sequence
  • Use flanking primers – PCR this area – around 4000 base pair fragments
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63
Q

What is the mutation of MLS?

A
  1. Point mutation on gene holocytochrome C
  2. The first mutation - MS1 makes a stop codon C to T = TGA is a stop codon
  3. The second mutation - M32 a conversion of arginine to cysteine
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64
Q

What has a function of the ETC?

A

Holocytochrome C-type Synthase (HCCS)

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65
Q

What is the function of HCCS?

A
  1. Function in oxidative phosphorylation found in mitochondria between 2 membranes
  2. Attaches a haem group to cytochrome C
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66
Q

What is cytochrome C involved in?

A
  1. Oxidative phosphorylation
  2. Shuffles electrons between complex 3 and 4
  3. form a complex apoptotic-protease activating factor 1
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67
Q

What is used to label mitochondria?

A

Fluorescent molecule

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68
Q

What is the function of Mitochondria?

A
  1. Energy production
  2. Apoptosis
  3. Urea cycle removing a nitrogen waste products
  4. Reactive oxygen species
69
Q

Energy production

A
  1. Citric acid cycle
  2. Oxidative phosphoylation
    [protein gradient is formed]
  3. Shuffling of protons from inner membrane space to matrix - Generation of ATP
70
Q

Apoptosis

A
  1. Extrinsic pathways - different receptors and ligands - trigger cell death
  2. Activation of caspases
  3. Caspases activates other receptors - cell death
    • Second pathways – run via mitochondria (cytochrome C)
      • When cytochrome C leaks out of the mitochondria – apoptosome formed and activates caspases 9
71
Q

What are molecules that prevent apoptosis [anti-apoptotic molecule]?

A
  1. Bcl2

2. Bcl-x

72
Q

When does apoptosis occur?

A

During development

73
Q

What is the consequence of without apoptosis ?

A

Webbed fingers and toes

74
Q

Urea cycle removing nitrogen waste product?

A

Part of the cycle is within mitochondria

  1. Ammonium + carbonate [+ATP] –> Carbamoyl phosphate
  2. Orthenine + carbamoyl phosphate –> Citrulline
  3. Citrulline shuttles outside of mitochondria via aspartate to get fumurate
  4. Fumurate enters krebs cycle
75
Q

What is Reactive oxygen species?

A
  1. Produced by oxidative phosphorylation
    - Oxygen molecule with extra electron
    - Highly reactive
    - Dangerous for cells because can cause mutations
76
Q

What are examples of the many enzymes that get rid of ROS?

A
  1. Cupper zinc
  2. Superoxide dismutase
  3. Manganese superoxide dismutase
77
Q

What can peroxide be detoxified by?

A

Glutathione peroxidase

78
Q

Mutation in the superoxide dismutase

A

Motor neuron disease
located on chromosome 21
These enzymes take free radicals and turn them into hydrogen peroxide

79
Q

What is certain amount of ROS essential for?

A

Homeostasis and normal growth and metabolism

80
Q

If ROS is too little

A

Problem with host defences

81
Q

If ROS is too much

A

cell death

82
Q

Mitochondrial DNA

A
  1. Located in the matrix
  2. 16 and 1/2 kb in size
  3. 100-1000 copies per cell
  4. 37 ribosomal RNA genes
  5. 22 tRNA and 13 proteins involved in oxidative phosphorylation
83
Q

What are mutations in Mitochondrial DNA?

A
  1. Mutations are homoplastic (all mtDNA have mutated)

2. Mutations are Heteroplastic ( a proportion of mtDNA have copies of mutated or other proportion as wild type)

84
Q

What are a lot of mutations?

A
  1. Substitutions which affect genes
85
Q

Where are 50% of the mutations?

A

tRNA genes

86
Q

What is the onset and severity of mutations dependent on?

A
  1. Threshold effect - % of mutated vs. wild type mtDNA
  2. % of the mutated DNA can change in the cell
  3. During mitosis - mitotic segregation - mitochondria randomly segregrated
  4. Clonal expansion - amplifcation of mutated mtDNA
  5. mtDNA bottleneck - precise mechanism unknown
87
Q

What are most mutations?

A
  1. Recessive
  2. 60-90% of mutated mtDNA
  3. Dominant mutations - <25% with mtDNA
88
Q

What clinical information is used to figure out if mutation causes disease?

A
  1. Histochemical
  2. Biochemical
  3. Molecular testing
89
Q

What is Cybrids?

A
  1. Fusion of enucleated human cells + immortalised human cells
90
Q

What are the models used to look at disease?

A
  1. Yeast model
  2. Mouse model
  3. Stem models
91
Q

Yeast model

A

Homology between yeast and humans

Introduction of mutation: ballistic method

92
Q

Mouse model

A

IPS model of humans with mitochondrial disease

93
Q

Stem models

A

Take cells from patients who have mitochondrial disease and reprogram them

94
Q

What is an example of mitochondrial disease?

A
  1. Leigh syndrome
95
Q

What is Leigh syndrome?

A
  1. Death within a few years
  2. Severe failure of oxidative metabolism
  3. Progressive loss of mental and movement abilities
  4. Mutation in complex 5 and 1 gene - oxidative phosphorylation will be affected
96
Q

What is the symptom of the Leigh syndrome?

A

Progressive neurodegenerative condition affects brainstem and cerebellum

97
Q

What does Lactic acidosis lead to?

A 
Seizures
Vomitting
Migraine like headache 
cognitive impairment 
Stroke-like episodes
98
Q

what does Leigh syndrome affect?

A

Parieto-occipital region of brain

Visual field defect

99
Q

Where does mutation of proteins of oxidative phoshorylation occur?

A

Complex 1 and 3

100
Q

What does >80% of patients with MELAS have?

A

m.3243A > G mutation in the mT-TL1 gene (tRNA)

101
Q

What is Imprinting?

A

Paternal of origin-specific expression

102
Q

What does imprinting require?

A

Male pro nucleus

Female pro nucleus

103
Q

What is normal development of mouse embryos?

A

Both maternal and paternal genomes

104
Q

What is genetic imprinting?

A

Phenommenon by which certain genes are expressed in a parent of origin specific manner

105
Q

What is Prader-Willi syndrome?

A

Gene is expressed from maternal inherited chromosome

Two chromosome 15 are intact but both inherited from the other

No paternal chromosomes

106
Q

What is Angelman syndrome?

A
  1. UBE3A responsible for Angelman syndrome
  2. Maternally expressed chromosome - inherit from mother
  3. When it goes through maternal line - problem
  4. If you inherit faulty gene from mother than from pateranlly inherited - theres no expression
107
Q

Why do we have the imprinted genes?

A
  1. The kinship theory

2. Co-adaptation theory

108
Q

What is the kinship theory?

A
  1. Conflict between maternal/paternal genes
  2. Animals mostly not humans
  3. A female can have children with multiple men and her contribution is equal between offspring
  4. To have many offspring, it is worthwhile to reduce foetal demand on maternal resources
  5. For a man, who may only have a % of children with a female, it is worthwhile that their offspring grow as big and strong as possible to give them a better chance to survive
109
Q

What is Co-adaptation theory ?

A
  1. Interplay of imprinted genes

2. Ensure optimal foetal development - looking for mother

110
Q

What does mouse studies show?

A

> 80% of imprinted genes cluster together

111
Q

What shows uniparental expression?

A

Same chromosomes thats inherited

112
Q

What is regulation of expression of imprinted genes done by?

A

Methylation

Control these regions

113
Q

What is Imprinting control regions (ICR)?

A

The grouping of imprinted genes within clusters allows them to share common regulatory elements, such as non-coding RNAs and differentially methylated regions (DMRs). When these regulatory elements control the imprinting of one or more genes, they are known as imprinting control regions

114
Q

When can you get expression of this gene?

A

Promoter is unmethylated, Transcription factors can bind

115
Q

When can transcription factor not bind?

A

When the promoter is heavily methylated

116
Q

What are 2 models of imprinted genes?

A
  1. lncRNA

2. Insulator model

117
Q

Where is ICR expressed?

A

Paternal chromosome
Expression of non-coding RNA:

  1. nespas
  2. ncrna
118
Q

What happens in the maternal locus of chromosome?

A
  1. ICR methylated

2. Dont get expresssion

119
Q

lncrna

A

transcribed from unmethylated ICRs

  • They can interfere with transcription of other genes by:
  • Active transcription of lncRNA silences genes on the same DNA strand
  • . The lncRNA itself can silence promoters of nearby genes
120
Q

Insulator model

A

chromosome 11
Two-3 genes:
1. Insulin growth factor 2 and H19

  1. ICR unmethylated: CTCF factor sends for protein CCTC binding factor
  2. Binds and expression of H19
  3. Enhancers will normally enhance the expression of 2 genes (ifg2 and isn2)
    - When the CTCF protein is bound In the unmethayled ICR it cannot enhance expression of the two genes
    - A zinc-finger protein CCTC binding factor (CTCF) binds to the active ICR, and forms an insulator.
    - It blocks access of the downstream enhancer to Igf2, and silences therefore this gene.
    - On the Paternal locus, the ICR is inactive, CTCF doesn’t bind, and you get expression from Igf2
121
Q

What happens in Imprinting disorder?

A
  1. 65-75% - maternal deletion of this region - inherit part of this chromosome - no expression of UBE3A
  2. Paternal UPD (Uniparental disomy) - 2 paternally inherited chromosomes
122
Q

What is the % of UBE3A mutation?

123
Q

What is Hyperphagia -excessive eating?

A
  1. This syndrome is on the same chromosome as Angelman syndrome
  2. The mutation that are causing these are similar to Angelman syndrome
124
Q

What is Bone Marrow failure?

A

When your bone marrow is unable to keep with the body’s need for healthy blood cells

125
Q

What is Hypocellular marrow?

A

Reduced number of cells in the marrow

126
Q

What is defective in bone marrow?

A

Don’t make enough white cells, red cells and platelets

127
Q

What are 3 main haemopotietic lineages?

A
  1. Infection
  2. Tenacity to bleed
  3. Anaemia
128
Q

Define syndrome

A

A group of symptoms which consistently occur together

129
Q

What is Bone marrow failure syndrome?

A

Consistent but variable extra-haematopoietic signs and symptoms

130
Q

What is the classification of bone marrow failure (BMF)?

A
  1. Idiopathic

2. Caused by drug/infection

131
Q

What is Idiopathic

A
  1. Commonly used in medicine
  2. Unknown origin
  3. Unknown aetiology (70-80%)
132
Q

What is an example of a drug for BMF?

A

Chloramphenicol

133
Q

What are the most common inherited bone marrow failure syndrome?

A
  1. Fanconi anemia
  2. Schwackman-Diamond syndrome
  3. Dyskeratosis congenita (DC)
134
Q

What is the clinical heterogeneity in Dyskeratosis congeita?

A
  1. Nail dystrophy
  2. Leucoplakia
  3. Skin pigmentation abnormalities
  4. X-linked recessive trait
135
Q

What are the clinical and genetic aspect of DC?

A

Heterogenous

136
Q

What is associated with distinct clinical manifestation?

A

Different patterns of inheritance

137
Q

What are clinical representation characterised by?

A
  1. Pulmonary fibrosis
  2. Hematologic
  3. Solid malignancies
138
Q

What is a recently common blood disorder of Dyskeratosis congenita?

A
  1. Myelodysplasia

2. Leukaemia

139
Q

What doesn’t have clinical symptoms?

A

Aplastic anaemia

140
Q

What is a severe form of Dyskeratosis congenita?

A
  1. Hoyeraal-Hreidarsson syndrome
141
Q

What are the features of Hoyeraal-Hreidarsson syndrome?

A
  1. Cerebellar hypoplasia
  2. Microencephaly
  3. Developmental delay and prenatal growth retardation
142
Q

What are the 3 types of inheritance that are found in DC?

A
  1. X-linked
  2. Autosomal dominant
  3. Autosomal recessive
143
Q

What are examples of gene names of DC?

A
  1. DKC1
  2. TERT
  3. TERC
  4. TINF2
  5. TREL1
144
Q

What are telomerase?

A
  1. Ends of chromosome - piece of DNA caps and protects chromosome
  2. enzyme the lengthens the telomere
145
Q

When does telomerase shorten?

A

As cells divide and we age

146
Q

What is the consequence of shortening of telomerase?

A
  1. Cell senescence/Apoptosis - Cell death
147
Q

What are the function of telomerase?

A
  1. Protect the chromosome end
  2. Distinguish from double strand breaks
  3. Acts as a buffer - protect coding sequences
148
Q

What is the structure of telomeres?

A
  1. 5-10,000 base pairs of TTAGGTTAGG - repeat DNA sequence
  2. Protected by proteins Shelterin
  3. It has an extraordinary end – the strand comes around and kind of sticks itself back into the chromosomes to protect the end as it is fragile
  4. T loop creates the D loop by insertion
149
Q

What are the cap of telomeres?

A
  1. T loop

2. D loop

150
Q

What is complexes involved in telomere due to?

A

Genetic cloning of T and D loop

151
Q

Telomerase

A

extends the end of telomere

  • Made of proteins, collection of proteins and RNA molecule
  • The RNA molecule acts as a template for reverse transcriptase [enzyme that copy RNA into DNA]
152
Q

What are Shelterin?

A

Specialised protein that cap all along the length about 5-10kb of telomere

Distinguish from normal chromatin

Protect telomere along length

153
Q

What is accessory protein?

A

Resolve telomere structure during replication

154
Q

What was mutated in the gene DKC1?

A

X-linked recessive family

155
Q

Where are dominant family mutated in?

A
  1. TIN2
  2. TERT
  3. TERC
156
Q

Where was Recessive family mutated in?

157
Q

What was found all in the same pathway all in telomerase?

A
  1. DKC1
  2. TERC
  3. TERT
158
Q

Where is disease causing variants caused in?

A
  1. TERT
  2. DKC1
  3. TERC
159
Q

TERC

A
  1. Telomerase RNA component
  2. Autosomal dominant
  3. DC
    BMF
    Pulmonary fibrosis
160
Q

TERT

A

Telomerase reverse transcriptase

  1. Autosomal dominant
  2. DC
    BMF
    Pulmonary fibrosis
  3. Autosomal recessive (rare, severe)
  4. DC
    Hoyeeral Hreidarsson syndrome
161
Q

What is variable penetrance?

A
  1. the variable impact of a disease-causing variant
  2. Often seen in late-onset autosomal dominant genetic disease
  3. Due to environmental effects, as well as complex genetics
162
Q

What is disease anticpation?

A
  • It is the same genetic trait coming through the family but it is worsening as It goes down the grandchildren’s down and down the generation
  • It is classic in the famous disease called Huntington disease
  • This is due to the fact that telomeres being passed on successive generations are shortening
163
Q

What is TIN2?

A

Disease causing variants in the shelterin component

It is in the shelterin complex

164
Q

What does shelterin protect?

A

Telomeres from DNA repair mechanisms

165
Q

What is the gene of TIN2?

A

TINF2

always De-novo

166
Q

What is RTEL1?

A

Disease causing variants in a telomere associated helicase

167
Q

What is RTEL1 required in?

A

Telomere replication

Autosomal recessive inheritance

Severe early onset disease

168
Q

What is RTEL1 associated with?

A
  • Immunodeficiency
  • Microcephaly
  • Cerebellar hypoplasia
  • Growth retardation
  • Developmental delay
169
Q

Helicase function and stalled replication

A
  • In mitosis, S phase – copying all of our DNA – 2 daughter cells, cells are dividing
  • Replication fork comes along and copies the genome
  • A replication fork moves towards the telomere and when it encounters T loop and D loop – it has a problem with it and resolve it and that’s where RTEL operates
  • RTEL operates as a helicase [unwinding enzymes] that will
  • resolve this structure along with other proteins and allows replication to continue toward the telomere end – it won’t be able to replicate the end and hence the shortening through cell division
  • When RTEL1 is dysfunctional – the replication remains stalled
  • It is rescued by additional proteins and cut it away so the replication can go to the end – creation of T loops and telomere shortening

Molecular Basis Of Disease (7 decks)

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