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Growth and Development > Genetic disorders > Flashcards

Genetic disorders Flashcards

1
Q

What is an epigenetic trait?

A

A stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence (in vitro fertilisation)

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2
Q

Basis of epigenetics

A

Cells have identical DNA but diff terminal phenotypes
Non-genetic cellular memory - records developmental and environmental cues (stimulus may only occur once but is remembered for lifetime)

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3
Q

What could epigenetics explain?

A

Not always possible to identify genetic determinants which fully explain heritability of complex traits
Inability to pinpoint causative genetic effects in complex diseases

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4
Q

3 characteristics of epigenetics

A

Heritable
Self-perpetuating
Reversible

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5
Q

What can epigenetics affect?

A

DNA methylation
Histone modification
Nucleosome location
Non-coding RNA (miRNA)

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6
Q

Methylation epigenetics

A

Twin studies shown methylation can be affected by environment
Low levels of nutrients or toxins can affect enzymes that methylate DNA
Some genetic variants make people more susceptible to environmental factors that alter DNA methylation

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7
Q

Genes vs epigenetics

A

Genes are blueprint for creating proteins while epigenetics determines how genes are read
As well as passing on genes we pass on molecular switching & info about how genes should be expressed

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8
Q

Amy Cuddy expt

A

2 gps for 2 mins, either high power or low power position

  • 86% HP opted to gamble, only 60% of LP
  • testosterone: HP 8% increase, LP 10% decrease
  • Stress hormone cortisol: HP 25% decrease, LP 15% increase
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9
Q

Most common trans epigenetic signal

A

Transcription factor
-activates its own transcription factor so epigenetic state is self-sustaining
Small RNAs can be trans signal

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10
Q

Epigenetic cis signals

A

Cis signals are physiclaly associated with DNA e.g. DNA methylation or changes in histones

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11
Q

DNA methylation and disease

A
  • Methylation used to silence genes by blocking binding of other proteins thus interfering with transcription (e.g. transcription factors)
  • Abnoraml methylation demonstrated in Fragile X syndrome, may play role in some autoimmune disorders e.g. lupus or neurophychiatric disorders e.g. autism
  • Cancer cells have abnormally low levels of methylation i.e. genes activated inappropriately or if excessive methylation some genes may be switched off (control cell division)
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12
Q

Zebularine in Human Liver Cancer

A

An integrated genomic and pharmacoepigenomic approach predicts therapeutic response of Zebularine in human liver cancer

  • Zebularine = DNA methylation inhibitor
  • Pxs are responders or non-responders
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13
Q

Genes and tooth development

A

Teeth develop in highly controlled & coordinated way
-interaction between cells of different embryonic origins
Teeth develop diff shapes depending on exact position in mouth and combination of genes expressed in area
Genetic pathways control tooth initiation and patterning
Growth factors control expression of genes early in tooth development but at later stages this control may be reversed
-examples: diff animals diff teeth and ‘small white pearls’ (odontoma)

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14
Q

PAX9

A

Mutation of PAX9 associated with oligodontia

-oligodontia: rare genetic disorder in which more than 6 teeth are absent

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15
Q

GREMLIN2

A

GREM2 is strong BMP antagonist - regulates BMPs in embryogenesis and tissue development

  • isolated tooth agenesis, microdontia, short tooth roots, taurodontism, sparse & slow growing hair, dry & itchy skin
  • other tooth related genes not involved
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16
Q

MicroRNAs in tooth development

A

Discrete miRNA expressed in molars compared with incisors

Diff in those expressed in epithelium compared with mesenchyme

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17
Q

Why do mammals only have one row of teeth? What controls this?

A

Antagonistic actions of Msx1 and Osr2 pattern

This also plays a role in cleft palate development

18
Q

Cleft susceptibility genes

A

BMP2 and BMP 4
MSX1
Number of genes found close together on chromosome 6
-if not expressed at right time there will be problem with development

19
Q

AXIN2

A

Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectoral cancer

20
Q

Genes and disease

A 
Riegers syndrome 
Wolf-Hirschhorn
Williams
Kabuki
Ectodermal dysplasia
Holopreosencephaly
21
Q

Riegers syndrome

A

Hypodontia with malformation of anterior camber of eye, one form caused by mutations in homeobox transcription factor PITX2

22
Q

Wolf-Hirschhorn syndrome

A

Short arm of chromosome 4, transcription factor MSX1

23
Q

Williams syndrome

A

Mutation in elastin gene

24
Q

Ectodermal dysplasia

A

150 clinically distinct hereditary syndromes, defects in morphogenesis of ectodermal structures e.g. teeth, nails, hair, skin

25
Q

Holoprosencephaly

A

Abnormalities in forebrain cleavage and midface development

26
Q

What is the most common chronic disease worldwide?

A

Dental caries

27
Q

GWAS

A

Examine genome-wide set of genetic variants in diff individuals to see if any variant is associated with a trait

28
Q

Genes and dental caries

A

Taste genes associated with dental caries

29
Q

Amelogenesis Imperfecta

A

Group of developmental conditions which affect structure and clinical appearance of enamel
Can be isolated or as part of syndrome

30
Q

AMELX

A

Alteration of conserved alternative splicing in AMELX causes enamel defects
-exon 4 is almost always spliced out but here a silent mutation in exon 4 means it is included in the mRNA transcript for amelogenin

31
Q

Gene therapy saliva example

A

Salivary glands target sites for gene therapeutics

Overexpression of transgene product = ‘overflow’ exits via constitutive into bloodstream

32
Q

Advanages of salivary glands

A
  • well-encapsulated, limiting undesirable spread of vector
  • luminal membranes of epithelial cells easy to access relatively non-invasively
  • ductal access uses limited fluid volume not diluted following delivery (low vector doses)
  • well differentiated & slowly dividing
  • make > protein for export
  • single SG not crucial for life and can be removed
33
Q

Protein secretion pathways from salivary glands

A

Predominant leading to saliva (musocal; across apical membrane)
Constitutive leading mainly towards interstitium and bloodstream (serosal; across basolateral membrane)
Overexpression of transgene product = ‘overflow’ exits via constitutive into bloodstream

34
Q

How many cases of oral cancer per year in USA

A

35-40,000

35
Q

5 year survival rate oral cancer USA

A

53% 1975-1977 to 60% 1996-2004

36
Q

Treatment for oral cancer

A

Radiation therapy, side-effects overcome by

  • hyberbaric oxygen
  • chemoprevention
  • surgical gland transfer
  • intensity-modulated RT
37
Q

hAQP1

A

Human aquaporin-1 encodes water channel that facilitates rapid transmembrane water movement in response to osmotic gradient

38
Q

hAQP1 to restore salivary flow

A

In absence of acinar cells due to RT NaCl is not reabsorbed in isotonic primary salivary fluid
Duct cells could generate osmotic gradient (lumen > insterstitium) that water could follow
Transfer of the hAQP-1 cDNA into surviving duct epithelial cells would provide this pathway
–> increased fluid secretion from irradiated gland

39
Q

Treating renal anaemia in swine model

A

Delivery of human erythropoietin gene to parotid glands through Stensen’s duct
> hEPO conc in parotid saliva and serum
Kidney damage not completely reversed but gene transduction of hEPO via parotid is promising potetial alternative therapy for renal anaemia

40
Q

Stem cells and teeth

A

Adult human gingival epithelial cell as source for whole-tooth bioengineering

  • epithelial cells injected into mesenchyme tissue, cultured for 5 days, transplanted into kidney capsules of adult mice
  • 6 weeks later kidneys removed and examined for ‘human’ tissue
41
Q

What are exosomes

A

Durable, cell-specific lipid microvesicles
Can migrate through vasculature
Reside in biofluids e.g. urine, blood, breast milk, bronchial lavage fluid, CSF, saliva
True functions unknown, suggested could range from immune response regulators to tumour invasion promoters

42
Q

Exosomes as salivary biomarkers

A

Tumour-derived exosomes could function as shuttle between distal tumour and oral cavity - discriminatory salivary biomarkers

Growth and Development (23 decks)

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