Exam 5: Single Gene Disorders Flashcards
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
anticipation
severity of disease increases when transmitted through a pedigree
frequently observed in triplet expansion mutations
autosomal recessive
both alleles of gene are defective
Affected children usually have normal parents
Both sexes are equally affected
Consanguinity is often present
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
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
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)
Recessive inheritence is mostly observed in defects of
Enzymes
Proteins involved in transport and storage
consanguineous mating
Matings of closely related individuals
Increases risk for development of recessive disease - more likely to carry same recessive mutant allele
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
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
expressivity
how strong a disease phenotype shows
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
genetic fitness
chance of person to reproduce
fitness of zero = can’t reproduce at all
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
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
lifetime risk for single gene genetic disease
2%
single gene disorders
one or both alleles of one gene is defective
loss of function
mutation that may reduce the protein’s activity
modifier genes
genes that have small quantitative effects on the level of expression of another gene
mutation hotspot
a chromosomal region where mutations occur frequently
typically a CG dinucleotide repeat
null mutation
underlying mutation completely destroys a protein
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
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
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
sex determining region of Y (SRY)
area of Y chromosome that contains the genetic information for male development of an embryo
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
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)
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
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)
Achondroplasia
Defect in bone growth
Autosomal Dominant
New mutations, fitness, dominant negative allele, mutation hotspot
Cystic Fibrosis (CF)
Defective chloride channel
Autosomal Recessive
Allele heterogeneity, modifier loci
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
Ehlers-Danlos Syndrome
Collagen disorder
Autosomal Dominant and Recessive
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)
Fructose 1,6 bisphosphate deficiency
Fasting hypoglycemia
Autosomal recessive
Glucose 6-phosphate dehydrogenase deficiency
Sensitivity to H2O2-generating agents and fava beans
X-recessive
Glycogen storage disorders
Hypoglycemia, accumulation of glycogen
Autosomal recessive
Huntington Disease (HD)
Neurological disorders
Autosomal dominant
New mutations, triplet expansion, anticipation
Leber’s Hereditary Optic Neuropathy (LHON)
Defect in mitochondrial DNA, leads to deterioration of optic nerve and blindness
mitochondrial defect
Heteroplasmy
Neurofibromatosis (NF)
Multiple tumors
Autosomal dominant
new mutations, variable expressivity
Osteogenesis Imperfecta I (OI-I)
Defective type I collagen
Autosomal dominant
Dominant negative alleles, allele heterogeneity
Phenylketonuria (PKU)
tyrosine metabolism
autosomal recessive
newborn screening
Sickle cell anemia
Hemolysis
Autosomal recessive
Sucrase-Isomaltase deficiency
Sucrose/glucose polymer intolerance
autosomal recessive
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)
Dominant inheritance is mostly observed in defects of
structural proteins
proteins involved in growth, differentiation, and development
Receptor and signalling proteins
Dominant inheritance
one mutant allele is enough to cause disease - heterozygosity
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
Mitochondrial disorder inheritance
inherited from mother - does not follow Mendelian rules
many copies of mitochondrial chromosome - induces variable expression
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
Linkage analysis
Used to trace inheritance of a marker on chromosome linked to disease alleles
Consanguineous matings
matings of closely related individuals
increases risk for developing recessive disease - good chance carry same mutant alleles
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
characteristics of autosomal recessive pedigree
affected children usually have normal parents
both sexes equally affected
consanguinity often present
characteristics of autosomal dominant pedigree
affected child has at least one affected parent
both sexes equally affected
disease can be transmitted father to son
incomplete penetrance
people with disease genotype do not develop symptoms
leads to situation where dominant disease seems to “skip” generation
variable expressivity
not all people with disease genotype will develop same set of symptoms at young age
new mutation
occurs spontaneously (not passed on) would not see disease in parents & recurrence risk would be low
triplet expansion
trinucleotide repeat expansion
caused by slippage during DNA replication
larger expansion, more likely to cause disease or increase severity of disease
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)
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
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
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
Gain of function mutation in RET gene causes
Multiple Endocrine Neoplasia (MEN)
render signaling molecule constitutively active
causes proliferation of neuroendocrine cells
Characteristics of x-linked mutation pedigree
No father-son transmission
Affected boys usually have unaffected parents
Males are affected more than girls
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
Mitochondrial inheritance pedigree characteristics
passed from mothers to all of her children
fathers do not transmit disease
