Exam 5: Single Gene Disorders Flashcards Preview

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Flashcards in Exam 5: Single Gene Disorders Deck (67):
1

allele heterogeneity

different mutations in same gene cause different phenotypes; gain or loss of function
Ex: cystic fibrosis - mutations in different domains of same gene have different impact on function of gene production

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anticipation

severity of disease increases when transmitted through a pedigree
frequently observed in triplet expansion mutations

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autosomal recessive

both alleles of gene are defective
Affected children usually have normal parents
Both sexes are equally affected
Consanguinity is often present

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carrier of recessive genetic disease

Person carries only one defective allele - don't suffer from disease but have 50% chance of passing defective allele to child

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coefficient of inbreeding

degree of homozygosity of child
Siblings share 50% of genes, if they have a child, child will be homozygous for 25% of genes
Coefficient for inbreeding for children of siblings is 1/4

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compound heterozygote

2 recessive alleles for same gene, but with those two alleles being different from each other (both alleles mutated but at different locations)

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Recessive inheritence is mostly observed in defects of

Enzymes
Proteins involved in transport and storage

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consanguineous mating

Matings of closely related individuals
Increases risk for development of recessive disease - more likely to carry same recessive mutant allele

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delayed age of onset

disorders appear later in life
People do not know if they are carriers of disease by time they have children - do not know if they are at risk of passing it on

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dominant negative effect

Affects mostly structural proteins
If mutation produces an abnormal protein, mutant protein may compete with wildtype form. If protein is part of large complex, mutant proteins may destabilize
structure
Dominant inheritance

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expressivity

how strong a disease phenotype shows

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gain of function

mutation that alters the proteins activity, can give new function
mutation function different from wildtype - can see effect of mutation no matter how many wildtype versions are present
Seen in signal transduction proteins
Dominant inheritance

13

genetic fitness

chance of person to reproduce
fitness of zero = can't reproduce at all

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haploinsufficiency

half of gene dosage is not sufficient for cell to carry out its function
Many structural proteins needed in quantities too large to be supplied by just one allele
Dominant inheritance

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heteroplasmy

presence of a mixture of more than one type of organellar genome within a cell
cells contain varying fractions of defective mitochondrial DNA molecules

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lifetime risk for single gene genetic disease

2%

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single gene disorders

one or both alleles of one gene is defective

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loss of function

mutation that may reduce the protein's activity

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modifier genes

genes that have small quantitative effects on the level of expression of another gene

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mutation hotspot

a chromosomal region where mutations occur frequently
typically a CG dinucleotide repeat

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null mutation

underlying mutation completely destroys a protein

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penetrance

the extent to which a particular gene or set of genes is expressed in the phenotypes of individuals carrying it, measured by the proportion of carriers showing the characteristic phenotype

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premutation

change in gene that proceeds a mutation; does not alter function of gene
In Huntington's Disease above 40 repeats in triplet expansion, disease develops. Close to 35 repeats may not develop HD, but chance of them producing gametes with pathogenic number of repeats is high
Likely to have several offspring with penetrant new mutations

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pseudoautosomal region of Y

area of Y chromosome that has extensive homology to X chromosome, required for alignment with X-chromosome in meiosis
Only a few genes on Y chromosome

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sex determining region of Y (SRY)

area of Y chromosome that contains the genetic information for male development of an embryo

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recurrence risk

chance of parents having another affected child after having one
risk of having child affected with single-gene disorder remains same because conceptions are statistically independent events

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sweat chloride test

measurement of electric conductivity of skin surface
tests for cystic fibrosis (defect in chloride channel causes sweat to be salty & high electric conductivity)

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two hit model

need to inactivate both alleles for disease to be seen
If a person already lacks one of copies (born with mutated allele) they are very sensitive to mutations in other allele & more likely to develop disease - predisposition

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X-chromosome inactivation

one of female X chromosomes are inactivated early in embryonal development in random, but fixed manner
some cells use maternal and other cells use paternal X chromosome (mosaic)

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Achondroplasia

Defect in bone growth
Autosomal Dominant
New mutations, fitness, dominant negative allele, mutation hotspot

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Cystic Fibrosis (CF)

Defective chloride channel
Autosomal Recessive
Allele heterogeneity, modifier loci

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Duchenne Muscular Dystrophy (DMD)

Defect in dystrophin (necessary for attachment of smooth, cardiac, and skeletal muscle cells to extracellular matrix)
X-recessive
new mutations, large target

33

Ehlers-Danlos Syndrome

Collagen disorder
Autosomal Dominant and Recessive

34

Familial Hypercholesterolemia

Defective LDL receptor
Autosomal Dominant
Allele heterogeneity - heterozygotes have elevated serum levels of lipoproteins (2x) and homozygotes have lipoprotein levels 4x as high (gene dosage)

35

Fructose 1,6 bisphosphate deficiency

Fasting hypoglycemia
Autosomal recessive

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Glucose 6-phosphate dehydrogenase deficiency

Sensitivity to H2O2-generating agents and fava beans
X-recessive

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Glycogen storage disorders

Hypoglycemia, accumulation of glycogen
Autosomal recessive

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Huntington Disease (HD)

Neurological disorders
Autosomal dominant
New mutations, triplet expansion, anticipation

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Leber's Hereditary Optic Neuropathy (LHON)

Defect in mitochondrial DNA, leads to deterioration of optic nerve and blindness
mitochondrial defect
Heteroplasmy

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Neurofibromatosis (NF)

Multiple tumors
Autosomal dominant
new mutations, variable expressivity

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Osteogenesis Imperfecta I (OI-I)

Defective type I collagen
Autosomal dominant
Dominant negative alleles, allele heterogeneity

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Phenylketonuria (PKU)

tyrosine metabolism
autosomal recessive
newborn screening

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Sickle cell anemia

Hemolysis
Autosomal recessive

44

Sucrase-Isomaltase deficiency

Sucrose/glucose polymer intolerance
autosomal recessive

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recessive mode of inheritance

loss of a functional copy can be compensated for by multiple regulatory mechanisms; needs loss of both alleles (two mutant alleles, homozygote)

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Dominant inheritance is mostly observed in defects of

structural proteins
proteins involved in growth, differentiation, and development
Receptor and signalling proteins

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Dominant inheritance

one mutant allele is enough to cause disease - heterozygosity

48

X-chromosome mutations

dominant in males - have only one X chromosome
in female, depends on if mutated X homolog is active or inactive and whether neighboring cells with normal copy can take over function of mutant cells
X-linked diseases cannot be passed father to son

49

Mitochondrial disorder inheritance

inherited from mother - does not follow Mendelian rules
many copies of mitochondrial chromosome - induces variable expression

50

Using information from pedigree, one can

make accurate estimate of risk for a person to be a carrier of a recessive disease
Estimate likelyhood couple will have an affected child

51

Linkage analysis

Used to trace inheritance of a marker on chromosome linked to disease alleles

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Consanguineous matings

matings of closely related individuals
increases risk for developing recessive disease - good chance carry same mutant alleles

53

Inborn Errors of Metabolism (IEM)

class of hundreds of autosomal recessive disorders caused by defects in metabolic enzymes
Individually rare, but cumulatively occur 1/300 births
typically screened for at birth
can be acute or chronic

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characteristics of autosomal recessive pedigree

affected children usually have normal parents
both sexes equally affected
consanguinity often present

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characteristics of autosomal dominant pedigree

affected child has at least one affected parent
both sexes equally affected
disease can be transmitted father to son

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incomplete penetrance

people with disease genotype do not develop symptoms
leads to situation where dominant disease seems to "skip" generation

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variable expressivity

not all people with disease genotype will develop same set of symptoms at young age

58

new mutation

occurs spontaneously (not passed on)
would not see disease in parents & recurrence risk would be low

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triplet expansion

trinucleotide repeat expansion
caused by slippage during DNA replication
larger expansion, more likely to cause disease or increase severity of disease

60

Haploinsufficiency vs. Dominant negative

Hap: reduced gene dosage not enough for cell to carry out function (structural proteins needed in too large quantities for only one allele - familial hypercholesterolemia)
Dom: deformed mutant protein competes with wildtype form, may destabilize structure (collagen disorders, Ehlers-Danlos syndrome)

61

OI-1 Type 1

Haploinsufficiency - all collagen made is normal, but amount is reduced by half (one copy of gene not enough) Brittle bones and blue sclerae

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OI-1 Type 2, 3, 4

Dominant negative - missense mutations in some of glycine codons cause abnormal collagen to be produced
range from bone deformities/fractures to brittle bones, black sclerae and death

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Loss of function mutation in RET gene causes

Hirschsprung disease
destroy molecule's ability to respond to stimulus - impairs development of neurons that populate colon

64

Gain of function mutation in RET gene causes

Multiple Endocrine Neoplasia (MEN)
render signaling molecule constitutively active
causes proliferation of neuroendocrine cells

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Characteristics of x-linked mutation pedigree

No father-son transmission
Affected boys usually have unaffected parents
Males are affected more than girls

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X-;linked dominant disease

affected male transmits disease to all of his daughters but none of his sons
affected female transmits to half of her children

67

Mitochondrial inheritance pedigree characteristics

passed from mothers to all of her children
fathers do not transmit disease