Ch 5: Genetic Disorders Flashcards
What are the three categories of human genetic disorders?
Mutations in single gene w/ large effects - highly penetrant, ie sickle cell anemia
Chromosomal Disorders - structural or numerical alteration (ie trisomy 21)
Complex multigenic disorders - disease in which a polymorphism changes the extent to which the likelihood changes with that gene (ie T2DM).
Mutations to what type of cells are transmitted to the progeny and can give rise to inherited diseases?
germ cells
Define mutation
a permanent change in the DNA
A mutation that introduces a stop codon prematurely is best described as what type of mutation?
A. conserved missense mutation
B. Non-conserved missense mutation
C. Nonsense mutation
D. polysense mutation
C. Nonsense mutation - B-thalassemia
A. conserved missense mutation - change in AA that is biochemically similar, function preserves
B. Non-conserved missense mutation - change in AA that is biochemically not similar, function reduced or altered
D. polysense mutation - DFE (dont fuckin exist m8)
How could a mutation in a noncoding sequence influence protein synthesis in a cell?
The mutation could cause problematic splicing, disturbed promoter or enhancer regions which would alter mRNA production
A 27 year old male comes into his providers office for a very expensive, non-existent DNA test to figure out why his shit so busted. Which of the following situations, if found, would count as a frameshift mutation?
A. 3 bp deletion
B. 3 bp insertion
C. 1 bp deletion
D. 6 bp insertion
C. 1 bp deletion
if a multiple of 3 occurs it is not a frameshift becasue the reading frame is maintained p. 139. as far as severity… it seems that yo shit gets busted no matter what’s deleted or inserted
Describe the mechanism of trinucleotide-repeat mutations.
An increase in three nucleotides, usually G’s and C’s. Some examples are Huntington’s or Fragile X
A 24 year old woman presents markedly unhinged. She says her mother and her mother’s siblings were all unhinged and her grandmother was unhinged. What are the odds that her grandchild by her son will be unhinged.
0%
I was trying to hint mitochondrial inheritance and now i realize questions are hard. Allison’s son will be unhinged but his kids won’t be. If this is a dumb question, hit 5 and move on
True or false: all congenital disorders are genetic
False: congenital syphilis
congenital just means born with
Define pleiotropism and give an example.
a single mutation that leads to many end effects - sickle cell anemia
Describe the autosomal dominant pattern of inheritance
disease is manifested in the heterozygous state, can occur in both males and females, and can be passed on by both males and females.
- 1 parent is affected
- 1/2 chance
- effects non-enzymatic proteins and receptors
How does incomplete penetrance affect autosomal dominant disorders?
incomplete penetrance would mean that only portion of the people who carry the mutation will express the mutation. This leads to variable expressivity
Differentiate between loss of function and gain of function mutations in autosomal dominant mutations?
Loss of function occurs when the mutation makes a defective protein or depletes a protein entirely rengering the process non-functional
Gain of function - less common, is characterized by excessive proteinfunction such as the over production of huntingtin in huntington’s disease
Describe the pattern of autosomal recessive inheritance
largest category of mendelian disorders, must have both alleles mutated in order to present with the disorder.
- parents dont show it
- children have 1/4 chance
- if there is low occurrence in gen pop then consanguineous marriage.
Name the most common features of autosomal recessive interitance
- expression is more uniform
- complete penetrance is common
- early onset
- new mutations can occur but are often undiagnosed
- many mutated products are equally matched by functional products
Why does y-linked inheritance not happen?
most mutations on Y chromosome result in infertility
Describe the X-linked pattern of inheritance
predominantly boys due to hemizygosity and inability to compensate with second X chromosome.
Characterize X-linked recessive features
- Passed down by heterozygous mother to son.
- Daughters of affected man are all carriers
What are the four mechanisms categories involved in single-gene disorders?
- Enzyme defects and their consequences
- Defects in membrane receptors and transport systems
- Alterations in the structure, function, or quantity or quantity of nonenzyme proteins
- mutations resulting in unusual reaction to drugs
Explain how an enzyme deficiency or dysfunction would result in accumulation of substrate.
depending on where the block is, the lack of the reaction will cause substrate to accumulate or will shuttle the substrate into parallel pathways with a potential accumulation of a different product.
Describe Marfan syndrome
a disorder of connective tissue, manifested by changes in skeleton, eyes, and cardiovascular system
What causes marfan syndrome and what are the two mechanisms in which the deficiency causes symptoms
results from inherent defect in an extracellular glycoprotein called fibrillin-1. Causes loss of structural support in microfibril rich connective tissues and excessive TGF-B activation
mechanisms
- fibrillin is major component of microfibrils. These are found in aorta, ligaments, and ciliary zone around lens. FBN-1 underlies marfans, FBN-2 underlies contractural arachnodactyly
- loss of fibrillin activates TGF-B which activates metalloproteases and destroys ECM.
Describe the morphology of marfan syndrome
patient is tall, long extremities, lax joints in extremities and fingers, variety of spinal deformities.
Ocular subluxation out and superiorly
Cardiovascular lesions including aneurysm and dissection - most common are mitral valve prolapse and dilation of the ascending aorta.
Treated with B-blockers
Describe ehler-danlos syndromes
comprise a clinically genetically heterogeneous group of disorders that result in some defect in the synthesis or structure of fibrillar collagen.
Which of the EDS follow an autosomal recessive pattern of genetic inheritance.
Kyphoscoliosis (VI) - hypotonia, joint laxity, congenital scoliosis, ocular fragility
Dermatosparaxis (VIIc) - severe skin fragility, cutis laxa bruising
What are the clinical findings of classic (I/II) EDS?
Skin and joint hypermobility, atrophic scars, easy bruising
What is the cause of the kyphoscoliosis (VI ) type of EDS
mutations in genes encoding lysyl hydroxylase - most common form of the autosomal recessive type
what does the vascular form (IV) of EDS result from
deficiencies in type III collagen
What do the arthrochalasia (VIIa,b) and dermatosparaxis type (VIIc) of EDS result from?
defect in the conversion of type I procollagen into collagen.
What is the cause of classic (I) EDS
mutations in type V collagen
Describe familial hypercholesterolemia
an autosomal dominant receptor disease that is a consequence of a mutation in the LDL receptor needed for the absorption of cholesterol
What is the major and immediate source of plasma LDL
IDL
