Colombia
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In North American 70% of cases of CF are caused by what kind of mutation:
1-frameshift2-missense
3-silent
4-Translocation
5-nonsense
6-RNA splicing
pd: This question belong to MJL1717
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| asmi
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1.frameshift...deletion of 3 bases common
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| usmleasr
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1.frame shift
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| Colombia
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Are you sure?
Because I read that only one AA is changed.
I think the mutation is missense.
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| asmi
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its three base deletion which is most common in CF
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| Colombia
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I agree, but: "Frameshift mutations occur when the number of bases added or deleted is not a multiple of three" BRS pag 66
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| asmi
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defination for frameshift :
Frameshift mutations can revert in a number of ways
i. adding a base to compensate for a deleted base
ii. losing a base to balance an extra one that has been inserted
iii. losing tow more bases if one has been lost, bringing the total lost to 3
iv. gaining extra bases to bring the total number gained to 3
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| krsma
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Kaplan Pathology (p.47)
states that genetically, in CF, the most common mutation is a deletion in amino acid at position 508 (usually phenylalanine).
In this case: 1 aa deleted --> shifts the entire reading frame of a gene --hence "frameshift-mutation"
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| usmleasr
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colombia one thing is for sure.....ans is definitely not other choices ..so we can ans as diagnosis of exclusion..though i am also confused now as it appears as in frame mutation :?
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| Quinn
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USMLE4ME IS RIGHT, CF IS A FRAMESHIFT MUTATION...POSITION 508 WITH 1 AA LOSS....
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| Colombia
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I disagree also.
Deletion is completely diferent of frameshift mutation. The patient MUST to delete bases in a number different that Three to be a frameshift. CF is just a deletion of phenilalanine AA only. The AA before Phenylalanine and after phenylaalanine dot change.
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| asmi
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columbia here is a very informative artical on it...hope its useful .
About 70% of mutations observed in CF patients result from deletion of three base pairs in CFTR's nucleotide sequence. This deletion causes loss of the amino acid phenylalanine located at position 508 in the protein; therefore, this mutation is referred to as delta F508 or F508
http://www.ornl.gov/sci/techresources/Human_Genom...
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| Colombia
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Thanks asmi
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| mjl1717
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This disease with a frequency of 1 in 2000, carrier rate is 1 in 25 (heterozygous for this gene) but most carriers do not know they harbor a lethal allele until they produce an affected child. Chromosome 7
**I cant speak of N. America but world wide the most frequent mutation
found on 70% of all CF chromosomes is- a deletion of three bases that
results in loss of one amino acid phenylalanine (abbreviated F) at
position 508 in the CF protein. This mutation is called delta 508
The delta 508 protein is improperly processed and gets hung up in the
golgi complex rather then migrating to the cell surface.
* Over 200 other CF mutaions have been reported, but each of them
is rare and together they still do not account for all of the remaining
30% of CF chromosomes.
One thing thats so striking about CF is how such a lethal gene is so
common, especially when so few affected individuals reproduce.
Perhaps the mutation rate of this gene is UNUSUALLY HIGH!
* key point for the exam is the protein isolated in 1990, Cystic Fibrosis
Transmembrame Regulator (CFTR) which in simple words may have
2 functions a "gate" and a "gatekeeper" for chloride.
Also Id describe this only as a deletion. Frame shift involves more
change
/
:shock:
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| mjl1717
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Also I agree with "usmleasr" under exam circumstances and the mechanics of the exam frameshift would be the answer via "diagnosis of exclusion."
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| Colombia
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Thanks
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| krsma
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wow, good discussion guys!!!
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| bluestar
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I think none of the answers is right.
:idea: Silent, missense and nonsense mutation all refer to the situation when only a SINGLE nucleotide base is changed,
:idea: frameshift refers to when one or two nucleotides (or their mutiples) are deleted/added, which leads to misreading of all nucleotides downstream. This is not the case with CF, since in CF we only lose a 508 AA and everything else is intact.
The most important thing we may ignore is that all of the above mutations refer to the delete/add of nucleotide BASE, not the Amino Acid. In the case of CF, 508 was deleted, the deletion actually starts from the 3rd base of 507. Fortunately, the isoleucine (Ile) at amino acid position 507 remains unchanged (which is a silent mutation) because both ATC and ATT code for isoleucine and from 509 AA to all the AA downstream all remain unchanged.
Hope this helps.
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| mjl1717
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Bluestar I agree with you its officially considered a small deletion.
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| bluestar
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thanks, mjl1717. BTW, do you have any evidence?
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| mjl1717
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Looking at some old notes from a Northwestern Review Course I noticed the genetics proffessor officially called the loss of phenylalanine in CF an
" In Frame (3bp) deletion"-- :idea:
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| Idiopathic
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Yes this is true. It is an inframe deletion of Phe. Does that make the answer frameshift?
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| mjl1717
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According to my Genetics Text by Mange and Mange page 276-frameshift mutation is defined as addition or deletion of one or more bases.Frameshift mutations
not only alter the codon in which they occur,but may shift the reading frame, the division of DNA message into successive three letter words.
The term point mutaion is often used for both base substitutions or small frameshift mutations since they are not microscopically visible.
This text is completely different from Kaplan-who says fameshift is deletion or addition of one base. There is ambiguity here.
Once again we now what to eliminate--only frameshift is left.
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| rida
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Guys, I actually came across the same kind of questions in board simulator series, wiht cystic fibrosis, and in the explanation this is what it said:
F508 mutation consists of a 3 base deletion. Because codons are three bases long, this mutation effectively represents a deletion of one codon, therefore, one amino acid residue, a phenylalanine at position 508 is missing from the mutant protein. Because exactly one codon is deleted, the reading frame of the ribosome is not thrown off, and the alteration is NOT a frameshift mutation. Other than the one deleted amino acid, the remainder of the polypeptide chain is unchanged.
I think the correct answer is 2, missense mutation..... 
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| Idiopathic
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Goljan agrees...missense by default since:
the reading frame isnt altered.
no stop codon inserted early.
not a silent mutation, since an AA is lost and a phenotypic change results.
translocation and RNA splicing are just gibberish.
One codon is misread (it just isnt there) and that make sit missense.
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