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MFM > Single Gene Disorders: Autosomal Dominant and Recessive Inheritance > Flashcards

Single Gene Disorders: Autosomal Dominant and Recessive Inheritance Flashcards

1
Q

4 types of point mutations

A
  1. missense - codon codes for different AA
  2. nonsense - premature stop codon
  3. insertion - frameshift
  4. deletion - frameshift
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2
Q

what is a gain of function mutation

A

oncogene - mutation results in production of a protein that has increased activity in an unregulated manner

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3
Q

what is a loss of function mutation

A

tumor suppressor - mutation results in lack of protein or synthesis of protein that is nonfunctional

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4
Q

what is genotype

A

specific allele that an individual has at locus within genome

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5
Q

what is phenotype

A

physical manifestation of the genotype

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6
Q

how to determine if disease is autosomal dominant?

A
  1. no skips in generations, successive generations are affected vertically
  2. both males and females affected equally
  3. disease is transmitted to subsequent generations by both males and females
  4. CAN include father to son transmission
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7
Q

which diseases display autosomal dominant inheritance pattern?

A
  1. von willebrand
  2. von hippel lindau
  3. ALS
  4. retinoblastoma
  5. multiple endocrine neoplasia
  6. tuberous sclerosis
  7. hereditary spherocytosis
  8. huntingtons disease
  9. marfan’s syndrome
  10. ehlers danlos syndrome
  11. neurofibromatosis type 1 and 2
  12. familial adenomatous polyposis
  13. achondroplasia
  14. acute intermittent porphyria
  15. familial hypercholesterolemia
  16. inherited cancer syndromes
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8
Q

what is the most common form of dwarfism?

A

achondroplasia

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9
Q

what causes achondroplasia

A

Gly380Arg mutation in FGF receptor gene FGFR3

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10
Q

what does FGFR3 gene encode for?

A

receptor tyrosine kinase receptor that is responsible for controlling bone growth and differentiation

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11
Q

what does the mutation in Gly380Arg result in?

A

gain of function mutation leading to constitutively active receptor, and inhibiting chondrocyte proliferation

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12
Q

symptoms of achondroplasia?

A
  1. short limbs
  2. long and narrow trunk
  3. macrocephaly with prominent forehead
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13
Q

what is the most important thing to remember with achondroplasia?

A

individuals homozygous (aa) for Gly380Arg mutation are NOT VIABLE, therefore, a person with achondroplasia is Heterozygous (Aa) , and therefore 1/3 of children will be normal with heterogenic parents (bc 4th child not considered viable)

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14
Q

what causes marfan syndrome?

A

mutation in fibrillin-1 gene (FBN-1)

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15
Q

what does the mutation in FBN-1 lead to?

A

abnormal TGF-beta signaling, since normally fibrillin-1 sequesters TGF-beta to inhibit its signaling

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16
Q

symptoms of marfan syndrome?

A
  1. aortic root dissection or aneurysm
  2. ectopic lentis (abnormal lens position)
  3. tall stature, abnormally long arms
  4. arachnodactyly (spider fingers) with joint hypermobility
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17
Q

what is marfan syndrome an example of?

A

pleiotropy, where the disruption of the one gene leads to multiple seemingly unrelated effects

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18
Q

what is neurofibromatosis caused by?

A

mutation in NF1 gene

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19
Q

symptoms of neurofibromatosis ?

A
  1. irregular pigmented skin aka cafe au lait spots
  2. multiple benign fleshy tumors (neurofibromas)
  3. benign tumors on the iris (lisch nodules/hamartomas)
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20
Q

what is neurofibromatosis an example of ?

A

variable expressivity, where the degree of severity of a mutation varies greatly among individuals with the same mutation i.e. parent with mild case can have child with severe case even though they have the same mutation

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21
Q

what is familial hypercholesterolemia?

A

high levels of LDL in the blood due to mutation in gene encoding LDL receptor (LDLR)

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22
Q

what does mutation in the LDLR result in?

A

prevents liver cells from removing LDL from blood, leading to high levels of LDL in the blood

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23
Q

describe heterozygous familial hypercholesterolemia ?

A

reduction in LDL receptor function and develop CVD by 30-40 years of age (less severe)

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24
Q

describe homozygous familial hypercholesterolemia?

A

childhood onset of cardiovascular disease and development of xanthomas (accumulation of lipid under skin)

25
Q

what is retinoblastoma?

A

mutations in RB1 that predisposes individuals to cancer of retina

26
Q

what does RB1 do?

A

tumor suppressor gene that encodes for a protein involved in control of the cell cycle

27
Q

what is retinoblastoma an example of?

A

reduced/incomplete penetrance, because is actually a genotypically recessive disease but phenotypically dominant – not all people that inherit RB1 mutation develop Rb, 10% of people with inherited mutation don’t develop Rb

28
Q

autosomal dominant inherited diseases

A
  1. von hippel lindau
  2. von willebrand
  3. ALS
  4. Rb
  5. MEN
  6. tuberous sclerosis
  7. hereditary spherocytosis
  8. huntington disease
  9. marfan
  10. ehler’s danlos
  11. neurofibromatosis 1 and 2
  12. familial adenomatous polyposis
  13. achondroplasia
  14. acute intermittent porphyria
  15. familial hypercholesterolemia
  16. inherited cancer syndromes
29
Q

how to determine if autosomal recessive inheritance pattern?

A
  1. can occur in one generation with multiple affected siblings horizontally – aka doesn’t occur in every generation (not successive)
  2. affects males and females equally
  3. transmitted by phenotypically healthy parents to affected offspring
  4. occurs in higher frequency from consanguineous mating
30
Q

why are there more recessive conditions than dominant?

A

dominant conditions affect individuals in such a way that they cannot reproduce

31
Q

which diseases display autosomal recessive inheritance pattern?

A
  1. cystic fibrosis
  2. albinism
  3. thalassemia
  4. sickle cell anemia
  5. maple syrup urine disease (MSUD)
  6. glycogen storage disease
  7. tay sachs disease
  8. PKU
32
Q

what is one of the most common genetic diseases?

A

cystic fibrosis (1/3500 live births)

33
Q

what causes CF?

A

mutation in cystic fibrosis transmembrane conductance regulator

34
Q

what does CFTR do

A

member of ATP-binding cassette transporter family found in plasma membrane, brings Cl out of the cell and can also regulate HCO3; is important in pH buffering system

35
Q

what regulates CFTR?

A

ATP binding and phosphorylation by protein kinase A

36
Q

what is CF an example of?

A

allelic heterogeneity, where there are over 1800 different mutations in the CFTR gene, and the severity is determined by the type of mutation present

37
Q

class I CF

A

no CFTR synthesis at all

38
Q

class II CF

A

CFTR trafficking defect

39
Q

class III CF

A

dysregulation of CFTR (diminished ATP binding and hydrolysis)

40
Q

class IV CF

A

defective Cl conductance or channel gating

41
Q

class V CF

A

reduced CFTR transcription and synthesis

42
Q

what is Tay Sachs disease?

A

deficiency in hexosaminidase A, an enzyme normally found in lysosomes and breaks down gangliosides in the brain

43
Q

what does deficiency in Hexosaminidase A lead to?

A

accumulation of gangliosides in neurons, leading to neuronal cell death

44
Q

when does infantile tay sachs begin?

A

neurological deterioration begins around 3-6months and continues to progress until death at 2-4 yo

45
Q

common clinical finding in Tay Sachs?

A

cherry red spot on retina and neurological deterioration

46
Q

how can cancer syndromes exhibit autosomal dominanr inheritance pattern?

A

inherit one mutated copy of the allele, but the chance that the other allele will undergo a mutation in that persons lifetime is very high – genotypically recessive, phenotypically dominant

47
Q

explain the dominant negative effect of p53

A

because p53 forms a tetramer in its active form, it can have a mutant acting as a “dominant negative” where the mutant sequesters the wild type and takes up all the wild type so that WT can’t work

48
Q

describe “dominant genotype and dominant phenotype”

A

the dominant negative combines with WT to prevent WT function, so the mutation in the other allele is not needed

49
Q

describe recessive genotype and dominant phenotype

A

point mutation in one allele leads to loss of function/silencing/loss of gene, and the mutation doesn’t associate with WT protein. requires a mutation or loss of the other allele to lose total function

50
Q

describe how beta thalassemia can either be dominant OR recessive

A

some mutations lead to expression of mRNA that encodes unstable beta globin chains that act in a dominant negative effect, masking normal alleles (heterozygotes). follows dominant inheritance pattern bc the mutant binds with WT chain and makes it obsolete.

51
Q

relationship between autosomal recessive and loss of function

A

most loss of function or null mutations (no stable protein made) follow autosomal recessive inheritance

52
Q

how do new mutations happen?

A

they can be transmitted from unaffected parent to affected offspring if the mutation occurs in the germ line. therefore, no family history, but may be present in subsequent generations

53
Q

example of variable expression

A
  1. environmental influences
  2. allelic heterogeneity
  3. heteroplasmy
54
Q

example of incomplete penetrance?

A

retinoblastoma

55
Q

example of pleiotropy?

A

marfan syndrome

56
Q

example of locus heterogeneity?

A

osteogenesis imperfecta

57
Q

example of delayed age of onset and anticipation

A

huntington disease and fragile X syndrome

58
Q

example of imprinting

A

prader wili and angelman syndrome

MFM (39 decks)

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