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PATHO > Lecture 8 + 9: Genetic Diseases > Flashcards

Lecture 8 + 9: Genetic Diseases Flashcards

1
Q

single gene, mendelian traits

A

-inheritance patterns
-penetrance and expressivity
-sources mutations
-effects of mutations on gene function
-how do variants lead to dominant and recessive traits?

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2
Q

cytogenetic disorders

A

-down syndrome

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3
Q

single gene disorders with atypical patterns of inheritance are diseases caused by:

A

-triplet repeat mutations
-mutations in mitochondrial genes
-genomic imprinting

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4
Q

Inheritance patterns of single gene disorders

A

-recessive
-dominant
-autosomal
-sex-linked

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5
Q

autosomal

A

involves chromosomes 1-22

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6
Q

Autosomal recessive trait inheritance

A

-25% noncarrier
-50% carriers
-25% affected

-all children of an affected parent are carriers
-early sge of onset usually
-more uniform symptoms compared to dominant disorders

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7
Q

Inheritance of autosomal dominant trait

A

-50-50 chance of passing trait to child
-NO carriers
-delayed age of onset
-huntington diseases signs appear later in life

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8
Q

Penetrance

A

-% of ppl who have certain mutation show traits associated with defects in the gene
-complete=100%
-incomplete<100%

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9
Q

Expressivity

A

-mutations giving rise to different outcomes in different ppl
-different number, identity, extent (severity)
-range from complete to minimal

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10
Q

Expressitivity is affected by:

A

-other genes
-Exposure to harmful chemicals or
conditions
-Environment
=Age

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11
Q

Types of variants

A

-benign
-likely benign
-pathogenic
-likely pathogenic
-uncertain significance

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12
Q

How do variants occur

A

-inherited
-non-inherited
-new de novo variants

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13
Q

Iherited variants

A

-from parent to child
-in almost every cell of body thru life
- germline variants present in the parent’s germ cells

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14
Q

Non-inherited variants

A

-occur at some time during life
-not every cell
-somatic variants
-not passed down
-can be caused by environment

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15
Q

New de novo variants

A

-found in child but neither parent
-may occur in egg but not be present in other cells or in egg after uniting with sperm
-variants aquired during development can lead to mosaicism

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16
Q

Types of genetic variants

A

-substitutiions (silent, missense, nonsense)
-frameshift (insertion, deletion)

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17
Q

silent mutations

A

-redundant amino acids
-no effect on protein function

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18
Q

missense mutation

A

-wrong nucleotide
-leads to wrong amino acid which will ruin protein

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19
Q

nonsense mutation

A

-wrong nucleotide
-leads to STOP sequence
-terminates protein early

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20
Q

Frameshift mutations (insertions and deletions)

A

-lead to incorrect amino acid sequence down the line

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21
Q

Can pathogenic variants occur in areas other than protein coding sequences?

A
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22
Q

amorphic

A

loss of function

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23
Q

hypomorphic

A

partial loss of function

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24
Q

hypermorphic

A

gain of function

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25
Q

dominant negative

A

-inhibits activity of unmutated protein

26
Q

neomorphic

A

aquisition of new property

27
Q

Cystic Fibrosis (autosomal RECESSIVE)

A

-most common lethal disease of white people
-loss of function mutations in CFTR

28
Q

CFTR variants have different effects on CFTR

A

-ppl fare better with variants with PARTIAL activity instead of complete loss of function
-variants establish dose-response relationship
-mild CF when CFTR alleles have 10-20% function

29
Q

Ivacaftor

A

-increases function of CFTR protein
-works only on specific genotype
-improves clinical symptoms

30
Q

How does loss of function lead to recessive effect?

A

-most times, the unmutated copy of the gene is not able to make up for the loss of expression or activity from the mutate gene
-no dosage compensation

31
Q

What level of expression is required for full activity?

A

slide 25

32
Q

How does loss of function lead to dominanr effect?

A

-osteogenesis imperfecta
-point mutations
-gain of function

33
Q

Osteogenesis imperfecta

A

-defects in collagen production
-most abundant protein in body
-collagen trimer
-loss of proa1
-dominant negative effect caused by point mutations

34
Q

collagen trimer

A

-2 subunits of a1
-1 subunit of a2

35
Q

Autosomal dominant caused by gain of function

A

-LDL receptor levels regulated by PCSK9 which

36
Q

PCSK9

A

-binds LDL on cell surface
-internalized with LDLR
-direct LDLR to lysosome
-LDLR completely degraded
-reduces number of LDLRs on cell

37
Q

PCSK9 gain of function effect:

A

-increase affinity for LDL-R
-enhance sorting of LDL-R to lysosome

38
Q

Autosomal dominant caused by loss of function

A

-familial hypercholesterolemia (FH)
-most often caused by mutations in the LDLR
->3000 pathogenic variants

39
Q

Inheritance of X-linked recessive

A

-50% chance of passing gene
-only males are affected
-affected males pass gene to daughter but not to sons
-female can be affected if father has trait and mother is a carrier (rare)

40
Q

X-linked genetic diseases

A

-hemophilia A and B:
-joint bleeding, muscle hematoma, soft tissue bleeding

41
Q

hemophilia A

A

-factor VIII
-inversion and small deletion mutations

42
Q

hemophilia B

A

-factor IX
-missense mutations
-more common

43
Q

Disease caused by triplet repeat mutations

A

-Fragile X syndrome
-some genes contain repeats of 3 nucleotides
-longer repeats disrupt gene function
-~40 diseasees all associated with neurodegradations

44
Q

Fragile X syndrome

A

-mental retardation
-FRM1 gene on X chromosome gets silenced
-expanded CGG sequence
-methylation

45
Q

Diseases Caused by mutations in mitochondrial genes are RARE

A

-mutations in mitochondrial genes are transmitted to progeny by DAUGHTERS, but not sons
-affect organs that depend most on oxidative phosphorylation (muscle, heart, brain)

46
Q

mitochondria

A

-separate genome
-multiple copies per cell
-are inherited only from MOTHER

47
Q

Cytogenetic disorders

A

-chromosonal abnormalities
-frequent
-change in chromosome number or structure
-can affevt autosomes or sex chromosomes
-disorders characterized by a change in autosome number are more severe (more genes involved) than single gene disorders

48
Q

Common chromosomal abnormalities

A

-translocation
-isochromosome
-deletion
-inversions
-ring chromosome

49
Q

translocation

A

-transfer of part of one chromosome to another chromosome

50
Q

isochromosome

A

-centromere divides horizontally rather than vertically
-results in 2 short arms and 2 long arms only

51
Q

Deletion (chromosome)

A

-loss of a portion of a
chromosome

52
Q

Inversions (chromosome)

A

-2 intersitial breaks
-segment reunites but is flipped

53
Q

Ring chromosome

A

-variant of deletion
-after loss of segments from each end, arms unite to make a ring

54
Q

Karotype

A

chromosome map

55
Q

Chromosome nondisjunction

A

??slide 40

56
Q

Genetic diseases with abnormal chromosome numbers

A

-down syndrome (trisomy 21)
-turner syndrome (monosomy X)

57
Q

genetic imprinting

A

-parent of origin transmission
-some reegions of DNA inactivated (silenced) in copy received from mother or father
-maternal/paternal
-occurs in ovum or sperm
-transmitted to all somatic cells from zygote
-if a gene that is turned off in the maternal copy is mutated in the paternal copy, genes in that region will not be expressed
-complex inheritance patterns

58
Q

Diseases involving genomic imprinting

A

-Prader-Willi syndrome
-Angelman syndrome

59
Q

angelman syndrome (from mother)

A

-region of chromosome 15 deleted
-from mother
-mental retardation
-ataxic gait
-seizures
-inappropriate laghter

60
Q

Prader-Willi syndrome

A

-deletion of region of chromosome 15
-from father
-mental retardation
-short stature
-hypotonia
-obesity
-small hands and feet
-hypogonadism

PATHO (31 decks)

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