DLA 12 Flashcards
What is the difference between an allele and a locus
Locus - location of a gene
allele - one of the alternative forms of a gene that occur at a locus
What is Recurrence risk?
Probability that the offspring of a couple will express the genetic disorder.
What is a Consultand?
The person who approaches a physician or geneticist
for a consultation.
Who/what is a Proband?
The affected individual in the family who gains the
attention of the physician due to a genetic condition
What is a pedigree?
diagrammatic representation of the family history
Autosomal dominant disorders
manifest in the heterozygote
Affected children receive the disease-causing allele from an affected parent
Skipped generations NOT common (Vertical inheritance)
Males and females are typically affected with equal frequency
It is very rare to find a homozygote that contains a mutation for a autosomal dominant disorder, but it is still possible. what is the disease?
familial hypercholesterolemia (FHC) due to LDLR deficiency
very rare
Autosomal recessive disorders?
A person will show the trait (disorder) only when two disease alleles of the same gene are present
AR disorders typically occur when a disease allele is inherited from both parents
Homozygosity by descent?
increases the risk that an autosomal recessive disorder will be uncovered
What is suggestive of of autosomal dominant inheritance?
The pedigree shows vertical inheritance
The second child of a couple has cystic fibrosis, an autosomal recessive disorder that is extremely highly penetrant, and easily detected in infancy. What is the likelihood that the first child of this couple is a carrier?
67 % (2/3)
Several different genetic (molecular) mechanisms
exist that can explain AD inheritance?
- Haploinsufficiency
- Gain of function
- Dominant negative
- Loss of heterozygosity
What is the purpose of the LDL receptor? what disease happen when that receptor is nonfunctional?
The LDL receptor (LDLR) is found on the hepatocyte
LDL receptor binds to LDL particles to clear them from the blood
Familial hypercholesterolemia is the result when this receptor does not work
What are the clinical symptoms of familial hypercholesterolemia (FHC)?
have 2x the level of circulating LDL, and high circulating cholesterol
Xanthomas may form. Yellowish deposition of cholesterol near elbows, ankles, wrists, palpebral areas
Is FHC a dominant or recessive disorder?
Dominant
What else can cause FHC?
Hypercholesterolemia can be caused by variants in other genes in a Mendelian fashion.
So a person could have FHC and have two functional copies of the LDLR gene. Mutation is elsewhere!
What is an example of locus heterogeneity?
The development of FHC even though their are two functional copies of the LDLR gene. The mutation is else where.
Haploinsufficiency of an enzyme?
very rare!!
So in most cases, a person who is heterozygous for a loss of function mutation in just about ANY enzyme would not have phenotype (no disease). only one functional copy of that gene is needed
What disease is an exception to the rule that only one functional copy of an enzymatic gene is needed?
Acute intermittent porphyria
Due to the demand of heme, both alleles must be functional
What are the symptoms of AIP or acute intermittent porphria?
Intermittent symptoms of anxiety, nausea, pain, constipation, diarrhea
What are the two examples of a mutation leading to a gain in function?
- Mutation leads to the gene doing more than what it normally does
- the mutation leads the gene having a new function
Explain why Achondroplasia occurs?
A specific DNA base pair change causes the encoded protein to function in an unregulated manner.
FGFR3 gene encodes a receptor protein tyrosine kinase
Normally FGFR3 protein signals to bone growth plates during development to begin ossification
If FGFR3 signals in an unregulated manner, premature ossification of bone growth plates occurs, and person
developes disproportionate short stature
What is the specific mutation that leads to Achondroplasia?
Leads to the Glycine 380 Arginine amino acid substitution (Gly380Arg)
very little allelic heterogeneity
Huntington’s disease?
Huntington disease is caused by an expansion of an unstable triplet of bases in an exon of the huntingtin gene (HTT)
Leads to an expanded tract of glutamine amino acids in the encoded protein
Causes new function(s) of the gene (unknown), that leads to death of neurons
Marfan syndrome?
mutation of the FBN1 gene which encodes a connective tissue protein called fibrillin-1
What are two types of FBN1 mutations that cause marfan syndrome?
Mutations that lead to less fibrillin-1 protein – so this would be a FBN1 loss of function gene, and the AD inheritance would be explained by haploinsufficiency
A mutation that allow the fibrillin protein to be made in
normal amounts, but what is made will interact inappropriately with the normally formed fibrillin-1 (from the other allele) and also other connective tissue proteins (dominant negative)
Osteogenisis imperfecta (brittle bone disease)
Caused by mutation of COL1A1 or COL1A2
caused by collagen defects
OI can be explained by either haploinsufficiency or dominant negative models of autosomal dominance
Dominant negative
A special case of gain of function
Dominant negative Vs haploinsufficiency
When considering Marfan syndrome, and OI, (in most cases) the disorder is likely to be more severe when caused by the dominant negative variant
Neurofibromatosis
Caused by inheritance of one pathogenic NF1 allele from a gamete.
What is the function of the NF1 gene?
The NF1 protein suppresses cellular proliferation
So loss of NF1 leads to formation of benign tumors
(neurofibromas), and also increased risk for other cancer types
Neurofibromas?
usually noncancerous (benign) tumors that are often located on or just under the skin
A 5-year-old girl is diagnosed with neurofibromatosis and she and her family are treated accordingly. Which of the following is this child most likely at increased risk for as she ages?
cancer!
A 5-year-old girl is brought to the physician for follow-up examination because of facial dysmorphology and hypertelorism. Genetic testing shows that she has a pathogenic variant in the ALX4 gene which encodes a transcriptional regulator. The mutation which is not found in either parent, causes the gene to not be expressed. Which of the following best explains the inheritance of this disorder?
Haploinsufficiency
Galactosemia
Caused by homozygous loss of function in one of 3 different enzymes responsible for metabolism of galactose
Treatment for galactosemia is, of course, restriction of milk sugar from the die
Phenylketonuria: PKU
Inheritance of 2 loss of function alleles of the enzyme phenylalanine hydroxylase (PAH gene)
Buildup of Phe is toxic, causes irreversible brain damage
treatment: don’t eat phenylalanine
What is PKU the inability to do?
inability to convert phenylalanine to tyrosine
Homocystinuria
The high levels of circulating homocysteine interact with connective tissue and also cause neurological manifestations
Autosomal recessive
Inborn error of metabolism
Sickle cell disease (SCD) mutation
Caused by a mutation in the gene for beta-globin
Causes a Glu6Val change in the encoded protein
Causes hemoglobin to polymerize
SCD is considered recessive or dominant?
autosomal recessive
What lab technique can differentiate between sickle-cell trait, sickle-cell anemia, and normal?
electrophoresis!
What is Pseudo-dominant?
Apparent autosomal dominant inheritance when a
heterozygote & homozygote for an autosomal recessive disorder have affected children
easily mistaken as dominant from a simple pedigree
What factors increase the risk of autosomal recessive traits?
- Consanguinity
- Heterozygote advantage
- Genetic isolation
- Assortative mating
Example of co-dominance?
blood group types
AB
What is incomplete dominance?
Phenotype is intermediate between the parents
combination of two traits
red + white = pink
