DMD And X-chromosome Inactivation Flashcards
A boy with Duchenne muscular dystrophy (DMD) was born to parents with no family history of the disease. The most likely explanation for this occurrence is:
A) A CGG expansion that resulted in the disruption of the promoter of the dystrophin gene
B) Infidelity
C) A point mutation in the dystrophin gene
D) A recombination event in the dystrophin gene that gave rise to a frameshift mutation
E) A translocation that resulted in the disruption of the dystrophin gene
Comment: Best answer is D. DMD is caused by deletion of several exons in about 70% of cases, significantly more often than point mutations. The word deletion was omitted from the correct answer but instead, one mechanism resulting in deletion was described. A deletion of exons that result in frameshift will result in DMD while a deletion not changing reading frame results in BMD (Becker’s). C and E could both be correct answers but both are rarer than the deletion of several exons and therefore not the most likely answer. Regarding infidelity: males with DMD are not expected to become fathers; therefore, infidelity would not be expected to increase the risk of DMD. Additional information: non-paternity happens in only a few percent of all births (in most populations), and at least 1/3 of all cases of DMD has no family history.
The mother of a boy with molecularly proven Duchenne muscular dystrophy has mild muscle weakness and an elevated serum creatine kinase (CK). What most likely accounts for this?
A) Skewed X-inactivation (Lyonization) B) She has testicular feminization syndrome C) She is 45,X D) She is 47,XXX E) She is 47,XXY
Correct answer: Skewed X-inactivation can lead to the situation where a heterozygote female shows symptoms of a disease like DMD, because her X-chromosome with the normal copy was inactivated leaving the mutated DMD allele as the active allele in a large proportion of her cells. This is seen in about 5-10% of all female carriers for DMD. None of the other answers show anything that would fit the mother of this boy.
The following pedigree shows a family segregating for Duchenne Muscular Dystrophy (DMD). Individual II-1 was found to have a deletion of exons-45-48 of the dystrophin gene. Individual II-3 is currently pregnant with a boy. She shows an elevated CK but she tested negative for this mutation. The risk for the fetus III-2 to have DMD is closest to?
A) 0%B) 10%C) 50%D) 75%E) 100%
Comment: Correct answer is that the risk is close to 0% (though not exactly 0%). High level of CK shows that she has some muscular problem, either acquired or inherited. This does not have to be caused by DMD. There is a known DMD mutation in the family explaining the affected children. Person II-3 does not have that mutation. The risk of her fetus to develop DMD is therefore low.
The combination of the above indicates that DMD is not the reason she has increased CK. It would still be appropriate to try to determine what the cause of her CK elevation really is, she might have something else that could be a problem for her fetus. However, those considerations is beyond the scope of this question.
A zygote is formed that contains the following chromosomes that appeared as result of a reciprocal translocation: an X chromosome where the distal part of the q-arm was replaced by the distal part of 5 q, and the rest of 5 carrying the distal part of the q-arm of the X. It is a balanced karyotype 46XX,t(X:5); all other chromosomes were normal. The two X-chromosomes are therefore the normal X (nX) and the translocation X (tX) which contains some part of chromosome 5. At the time this zygote has developed into a newborn girl, what is the most likely X chromosome inactivation pattern?
A) Most cells have tX as the Barr body
B) Most cells have nX as the Barr body
C) About equal proportions of cells have tX and tN as the Barr body
Correct answer: Most cells have nX as the Barr body. Those cells that inactivate the tX chromosome also thereby are inactivating a portion of DNA that should be part of chromosome 5. This means that functionally, there is only one active copy of that part of chromosome 5, so functionally it is a partial monosomy. Remember that monosomy is not tolerated for any chromosome except X (and not even that well for X). Therefore, cells that inactivate nX will do better than those inactivation tX, and the newborn will contain mostly cells inactivating nX.
A 22-year-old woman has a brother with DMD but no other family history. Her husband is healthy and has no family history of any genetic disease. She is pregnant and is asking for advice. She wants to know what the risk is for her to have a child with DMD A) 1/4 B) 1/6 C) 1/8 D) 1/10 E) 1/12
Comments: E is the correct answer. With no other affected people, her brother is an isolated case. That means that his mother only has a 2/3 risk of being a carrier; the balance of the risk is that the brother has a new mutation. With the mother having 2/3 times ½ risk of passing on, the 22-year-old woman has a risk of 1/3 for being a carrier. Multiply that with ½ for passing on, and with another ½ for the child to be a boy, and you get the correct answer of 1/12. (Reminder: we talked at length about that extra ½ during the risk calculation lecture in Fundamentals 1).
Look again at the previous question. If the sister of the affected has an affected son, does that change the risk of her next child, and why?
A) Yes, it means that she has had her bad luck and the risk for the next child is lower than 1/12
B) No, she still has the same carrier risk
C) Yes, it means that she must be a carrier and the risk is increased
Comments: C is the correct answer. The additional affected person demonstrates two things: firstly, the brother was not the result of a new mutation (he is no longer an isolated case) and secondly, that both his mother and his sister must be carriers.
Dystrophin, a 427 kD protein that has been shown to be defective in Duchenne muscular dystrophy, is:
A.An isoenzymic form of muscle actin that loses all function in DMD patients
B.A cytoskeletal protein associated with the muscle fiber membrane
C.A mutated form of troponin C that stimulates the growth of calf muscles
D.Normally converted to myosin by proteolytic cleavage
E.Found in blood complexed with muscle creatine kinase (CK MM)
Comments: B is the correct answer except that it is incomplete. Dystrophin is also expressed in brain tissue.
You are seeing a couple whose son has a severe form of osteogenesis imperfecta, an autosomal dominant trait. The man states that he had previously had a different partner, and that they had had a child who had also been diagnosed with a severe form of osteogenesis imperfecta and who had died soon after birth. What is the BEST explanation for these observations?
a. Pleiotropy
b. Epistasis
c. Variable expressivity
d. Germline mosaicism
Comments: this question is probably best thought of as a cumulative question that is not too closely connected with this particular lecture. D is the correct answer: the man might very well have a group of germline stem cells that are mutated in the collagen gene even though he does not have the mutation in his body cells (somatic cells). This concept was first introduced in the chromosome lecture. Epistasis is usually taught in blood groups. Variable expressivity and pleiotropy are both taught in Mendelian inheritance patterns. Remember that Variable expressivity does not include no symptoms, so the difference between the father and the offspring is not due to variable expressivity.
An inactivated X-chromosome is not expected to be present in which one of the following cells?
A.Brain cells from a female with a balanced X-autosomal translocation
B.Hepatocytes from a normal female
C.Oocytes from a normal female
D.Pulmonary epithelial cells from a female with Down syndrome
E.Skin cells from a male with Klinefelter syndrome
Comments: remember that the X-chromosome is expected to be reactivated in the germline cells before they start gametogenesis, so the X chromosome in the oocyte should not be inactivated.
