Single Gene Disorders

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35 Terms

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define Mendelian disorders

genetic disease where one gene is involved and its mutation causes disease

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APOE4 allele

Increases risk of sporadic AD. 25% of people have 1 copy (increases risk 2x), 2 to 3% have 2 copies (increases risk 12 to 15x)

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Why is it important to identify genes responsible for hereditary conditions/disorders?

May allow disrupted biological processes to be understood ā†’ treatment/cures/gene therapy. Also allows diagnosis prior to symptoms eg BRCA1 identification

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example autosomal dominant disorders and their prevalence

familial hypercholesterolaemia (1/500) and Huntingtonā€™s (1/15,000)

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example autosomal recessive disorders and their prevalence

cystic fibrosis (1/2000 caucasians) and Tay Sachs (1/3000 American Jews)

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X linked Mendelian disorders and their prevalence

Duchenne muscular dystrophy (1/7000) and hemophilia (1/10,000)

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How is approach to identifying affected gene decided on?

Based on what is already known about gene/disease. Whatever approach is chosen, DNA samples from patient, family, population and healthy controls are needed

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20th century gene identification techniques used

chromosomal damage and positional cloning

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gene identification 21st century

patient genome/exome sequenced and causative mutations searched for

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visible chromosomal damage/cytogenetic rearrangements

hypothesised to be responsible for disrupting/deleting gene - marker for gene location

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Duchenne muscular dystrophy (DMD)

presents in boys around 3-5 years old. Patients show progressive muscle weakness/atrophy and sarcopenia

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DMD gene identification

Initially identified by chromosomal damage. Xp21 completely sequenced in 1987

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dystrophin

  • mutated DMD protein

  • 3685 amino acids long

  • anchors moving muscle to solid ECM

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When was positional cloning used?

when no visible evidence of chromosomal damage

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positional cloning step 1

  • large multigenerational families w/ extensive disorder history identified

  • pedigree analysis

  • linkage analysis w/ genetic markers

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positional cloning step 2

identify overlapping DNA clones from the chromosomal locus

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positional cloning step 3

identify genes found in the affected chromosomal locus and determine exons and introns

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positional cloning step 4

analysed to determine if mutation(s) are in patient samples and not in healthy family members

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what happens in Huntingtonā€™s

Neurons in basal ganglia and deep cortical layers (responsible for motor control) killed ā†’ dementia, psychosis, chorea and premature death

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Who did the HD collaborative research group study?

Venezuelan village with very high (1/50) HD rate - founder effect

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How was the HD gene cloned?

  • RFLP polymorphic markers - 8th, G8, showed linkage - region 4p16.3

  • 4 candidate genes in region characterised

  • repeat expansion in IT15 found ā†’ Huntingtin cloned

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trinucleotide repeat expansion mutations

polymorphic repeats of a specific trinucleotide sequence. Unstable in meiosis so number of repeats changes between generation due to incorrect melting and reannealing of DNA followed by incorrect repair

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observations in HD families

number of repeats increases over generations and thus severity increases and age of onset is earlier

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HTT gene repeats

  • trinucleotide repeat CAG variation ā†’ changes in glutamine (Q) expression

  • normal HTT 11 - 34 repeats (median 19)

  • Disease HTT has 37 to 86 repeats (median 45)

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Huntingtons gain in function

increased inflammatory response, mitochondrial oxidative stress, apoptosis and transcriptional misregulation ā†’ cell death

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HTT gene function

unknown - proteins healthy and disease gene binds have roles in transcription, vesicle transport and cytoskeleton/synapse

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current targets of disease gene research

very rare mutants/variants that cause specific conditions being targeted now that genome sequencing is more accessible

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Describe the process of modern Sanger chain termination

primer, DNA polymerase, dNTPs and small amounts of fluorescently labelled ddNTPs added. Primer extension, chain termination and product recovery take place followed by electrophoresis

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How does Sanger sequencing work?

Fluorescent dyes emit light at different wavelengths, different base emission during electrophoresis

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what does whole genome sequencing rely on?

Next generation sequencing aka high throughput sequencing

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issues with WGS

  • massive data production/storage

  • analysis of assembly of reads into a genome

  • differentiating disease mutation vs benign polymorphism vs benign rare variant

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Huntingtons treatment

Has no cure or treatment to stop/slow down neurodegeneration but can take drugs to relieve symptoms

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medicines to treat chorea caused by Huntingtons

tetrabenazine, antipsychotics eg haloperidol which suppress movement as side effect, amantadine

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drugs to treat mental health issues associated with Huntingtons

antidepressants eg citalopram, antipsychotics eg olanzapine

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non-drug treatments for Huntingtons

psychotherapy, speech therapy, physical and occupational therapy