Unusual Methods of Inheritance Flashcards

1
Q

What is genetic anticipation and give an example.

A
  • Genetic disease with worsening severity and earlier onset as passed down generations
  • EXAMPLE: Myotonic dystrophy - autosomal dominant - causing progressive muscle deterioration and myotonia
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2
Q

Why does myotonic dystrophy show genetic anticipation? PART 1

A
  • Usually individuals have an expanding CTG trinucleotide which repeats 5-37 times
  • In MD, unstable CTG repeats in regulatory region of DMPK gene which increase with successive generations
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3
Q

Why does myotonic dystrophy show genetic anticipation? PART 2

A
  • Increase in repeats = greater severity
  • Affects regulation of DMPK gene (alters RNA processing and interferes with protein production)
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4
Q

What is fragile X syndrome?

A
  • X-linked dominant disease - more common in males than females
  • Cause long faces and large ears
  • Frequent single genetic cause of autistic spectrum disorder
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5
Q

How does Fragile X syndrome occur? PART 1

A
  • Diseasing causing gene is FMR1 gene on X chromosome, encodes FMRP protein which plays role in brain/synaptic development
  • Unstable CGG trinucleotide repeats
  • 50-200 copies won’t cause syndrome but causes associated disorder
  • 200+ copies causes syndrome
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6
Q

How does Fragile X syndrome occur? PART 2

A
  • Expansion occurs when females with unstable associated condition pass on diseased genes
  • Males with associated condition don’t have affected daughters.
  • Daughters with associated condition likely to have affected offspring.
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7
Q

What is DNA methylation and how does it influence Fragile X syndrome? PART 1

A
  • Attachment of methyl groups to 5’ regions of gene
  • Added to cytosine group, catalysed by DNA methyltransferase
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8
Q

What is DNA methylation and how does it influence Fragile X syndrome? PART 2

A
  • Increases with increased repeats at promoter which reduces binding of transcription factors and gene expression
  • In Fragile X syndrome, methylated trinucleotide repeats at 5’ UTR (promoter) region of FMR1 gene
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9
Q

Describe genomic imprinting.

A
  • For some genes, only one active allele. One of inherited alleles from parents is transcriptionally silenced i.e imprinted
  • Inactivated by methylation
  • IMPRINTING - process of gene silencing
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10
Q

Describe Prader-Will syndrome (PWS)

A
  • Deletion of base pairs from long arm of chromosome 15 (C15)
  • Occurs when C15 deletion inherited from father
  • CLINICAL PRESENTATION: Short stature, obesity, small hands and feet
  • Can also occur when deletion inherited from father, and remaining copy contains maternally imprinted alleles
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11
Q

Describe Angelman Syndrome (AS)

A
  • Deletion of base pairs from long arm of chromosome 15 (C15)
  • Occurs when C15 deletion inherited from mother
  • CLINICAL FEATURES: Seizures and severe intellectual disability
  • Can also occur when deletion inherited from mother, and remaining copy contains paternally imprinted alleles
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12
Q

What is uniparental disomy and how can it cause PWS and AS?

A
  • Both copies of chromosome inherited from one parent
  • PWS = When 2 maternal copies of C15 inherited, no paternal copies
  • Other way round for AS
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13
Q

Describe mitochondrial inheritance and mutations.

A
  • Mutations occur in mtDNA - double stranded circular molecules
  • Maternal inheritance
  • mtDNA encodes proteins involved in oxidative phosphorylation
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14
Q

Why is there a high mtDNA mutation rate?

A
  • Lack of DNA repair mechanisms
  • Damage from free oxygen radicals produced during oxidative phosphorylation
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15
Q

Describe heteroplasmy.

A
  • Each cell contains population of mtDNA molecules - some mitochondria are mutated and some are not
  • mtDNA replicates during cell division and mitochondria sorted randomly amongst daughter cells
  • Varibale expression of mitochondrial disease due to random distribution of mutated and non-mutated mitochondria
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16
Q

Describe genetic abnormalities linked to mitochondrial mutations.

A
  • Mutations affect ATP synthesis
  • Organs with large ATP requirements more affected e.g CNS
  • Example: Leber hereditary optic neuropathy - optic nerve death occurs leading to rapid loss of vision