Single gene disorders Flashcards
Recessive inheritance is mostly observed in defects of what?
Enzymes
Proteins involved in transport and storage
Dominant inheritance is mostly observed in defects of what?
Structural proteins
Proteins involved in growth
Receptor and signalling proteins
What is haploinsufficiency?
When half of gene cannot carry out cell function (explanation of dominant mode of inheritance)
What is the dominant negative effect?
When mutational protein competes with normal form, or destabilizes a structure composed of normal and mutated (explanation of dominant mode of inheritance)
What is the gain of function explanation for dominant inheritance?
Change in the function of the mutated protein compared to normal (signal proteins usually)
What is the lack of back up explanation of dominant inheritance?
Like two-hit model of CA
What is the psuedoanasomal region of Y?
Part of the Y chromosome that is similar to X
True or false: the X chromosomes in females are both expressed simultaneously by each cell
False–each cell expresses one, but varies between cells
What is the coefficient of inbreeding?
Describes the degree of homozygosity of a child
What is the most prevalent IEM?
PKU–defect in F hydroxylase
What recessive disease (that we discussed) is characterized by a defective Cl transporter?
Cystic fibrosis
Why is the sweat of someone with cystic fibrosis salty/more electrically conductive?
Loss of Cl transporter and effects on Na transporter
What are the two major types of cystic fibrosis discussed?
Pancreatic sufficient
Pancreatic insufficient
What are two possible explanations as to why there is heterogenity in cystic fibrosis?
- Different allele mutations
2. Modification of other proteins (different ion channel may take over)
Why aren’t patient found with homozygous dominant alleles of a disease?
This is usually fatal
also less probable
What is the term that describes when someone who has a mutated genotype does not express the phenotype?
incomplete penetrance
What accounts for the “skip” in generations seen in inherited diseases?
incomplete penetrance
What is the term that describes how strong a phenotype shows?
Expressivity
NF1 has highly variable expressivity. What does this mean?
The symptoms expressed by individuals with the disorder vary widely
NF1 has complete penetrance. What does this mean?
ALL individuals with NF1 will express some sort of symptoms at some point
Why is examining the parents crucial in determining if their next child (after having one who is affected) will be affected with a disease?
To determine whether the parents are carriers with overlooked symptoms, or if the mutation in the child is new.
True or false: if a parent has an inherited disease, but has only mild expression of it, then his/her affected offspring will also have mild expression
False
What is the cause of Huntington’s disease?
Triplet expansion of a CAG triplet leading to the expansion of polyglutamine stretches
What is the number of CAG repeats in a normal individual? In someone with huntingons?
9-35 is normal
>40 huntingtons
What is a premutation?
A propensity to transmit a mutation to one’s offspring without carrying the disease–Huntington’s is the classic example (note this is NOT a recessive gene)
What is the term describing the increasing severity of a disease as it is transmitted through a pedigree?
Anticipation
What is the gene that is the cause of Achomdroplasia?
FGFR3
What is FGFR3?
A Y-kinase that inhibits chondrocyte proliferation
What is a mutational hotspot?
An area where new mutations form readily
Why are older male sperm more likely to produced offspring with genetic mutations?
Higher chance of developing spontaneous mutations since they are produced from cells that have had a longer time to mutate
What are the two ways collagen defects can develop
- Problem with the primary structure of collagen
2. Problem with the enzymes that make collagen
The dominant form of Ehlers-Danlos syndrome is due to what?
Mutation in collagen
The recessive form of Ehlers-Danlos syndrome is due to what?
Mutation in enzymes that process collagen
Familial hypercholestremia is a recessive or dominant disorder?
Dominant
How does Familial hypercholestremia demonstrate the gene dosage effect?
Homozygotes have 4x higher LDL levels–heterozygotes have only x2
What are the surface regions that LDL receptors are found in?
coated pits
What is the protein that LDL receptor binds to?
Apoprotein B
The LDL receptors are internalized and are turned into what structure?
Lysosomes
What happens to the LDL receptor when it is in the lysosome?
Bud off into vesicles to be recycled back to cell surface
What is the action of acyl-coa:cholesteryl acyltransferase?
Esterifies excess cholesterol that is released by the LDL receptor lysosomes
Why is it notable that the LDL receptor is a heavily glycosylated protein?
Room for error in glycosylation
What is the RET gene’s function?
Receptor and signalling molecule in development
What are the two types of mutation that the RET protein can undergo?
gain-of-function (increased signal)
Loss-of-function (loss of signal)
A LOF in the RET protein leads to what disease?
Hirschsprung disease (impairment of neuron development)
A GOF in the RET portein leads to what disease?
Multiple endocrine neoplasia (proliferation of neuroendocrine cells)
Why are both Hirschsprung disease and MEN dominant diseases?
Hapaloinsufficiency
What is Duchenne muscular dystrophy?
Defect in the dystrophin gene
What does dystrophin do?
it is a protein that is essential for attachment of muscle cells to the ECM
What type of inheritance is DMD?
X-linked recessive
True or false: the mutational rate of mitochondrial DNA is much lower than the nuclear DNA
False
What is heteroplasmy?
cells contain varying fractions of defective mtDNA (due to the fact that there is >1000 mtDNA in a cell)
What is LHON?
Mutation in the ND1 gene the encodes complex I of the ETC
What is a compound heterozygote?
When an individual has two mutant alleles
What is allele heterogeneity?
different mutations in the same gene causing different phenotypes
What is locus heterogeneity?
Mutations in different genes cause the same phenotype
What are modifier genes?
Genes specific to an individual that modify a mutated gene’s effects
What is pleiotrophy?
A mutation that causes multiple phenotypes–not all carriers of same mutation display the same phenotype
What type of mutations do ova contribute?
non-disjunction
What type of mutations do sperm contribute?
Replication errors
