Familial Adenomatous Polyposis Genetics: How is it dominant?

[whatdidigetinto]

Can someone please explain to me how this is considered dominant? We are inheriting one mutated APC gene (which is a tumor suppressor gene), so we have the other healthy APC allele still available, so how is it considered dominant???

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[preDoGuy24]

Can someone please explain to me how this is considered dominant? We are inheriting one mutated APC gene (which is a tumor suppressor gene), so we have the other healthy APC allele still available, so how is it considered dominant???

I was thinking that it might have to do with the rate of cell division occuring in the colon, with the with having inherited one dysfunctional APC, the chances of another mutation/damaged APC gene are so high that it might as well be a dominant inheritance pattern.

http://www.ncbi.nlm.nih.gov/books/NBK7570/

"In FAP, about 1 epithelial cell in 10^6 develops into a polyp, a rate consistent with loss of the second APC allele being the determining event"

Kinda goes along with that.

 

[Phloston]

Important concept to get under your belt.

Just because a disease requires two mutations doesn't mean it's AR.

It's AD because it's essentially guaranteed to show up in the next generation.

 

[whatdidigetinto]

Ah now I get it. Do you happen to have any source?

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[Morsetlis]

"The principal cause of mortality is colorectal cancer, which develops in all patients unless they are treated. The mean age at which colorectal cancer develops in patients with classic FAP is 39 years. Patients with adenomatous polyposis itself often are asymptomatic. "

http://emedicine.medscape.com/article/175377-overview#showall

 

[whatdidigetinto]

"The principal cause of mortality is colorectal cancer, which develops in all patients unless they are treated. The mean age at which colorectal cancer develops in patients with classic FAP is 39 years. Patients with adenomatous polyposis itself often are asymptomatic. "

http://emedicine.medscape.com/article/175377-overview#showall

What I meant was a reference which explains this type of inheritance. As in it is a recessive trait but a germ line mutation is rendering it dominant.

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[burningheat]

look up two hit hypothesis... this is very similar to Rb mutations

 

[MLT2MT2DO]

look up two hit hypothesis... this is very similar to Rb mutations

^^

I can't imagine walking into the test center not knowing about the two hit hypothesis. Pretty sure it was Pathoma that did a solid job of covering this

 

[CassieBagley]

to the best of my knowledge:
A gene is considered dominant if inheritance of only 1 copy leads to the phenotypical disease (assuming 100% penetrance). Classic AD diseases include Marfan's and Hereditary Spherocytosis. In those 2 examples, only a single mutated gene is inherited, but that gene happens to exert a "dominant effect" when mutated, meaning it alters normal tissue proteins (Fibrillin & Spectrin/Ankyrin, respectively). FAP is considered AD as well, even though the single mutated gene which is inherited is only a tumor suppressor which does NOT exert a "dominant" effect. Mutated tumor suppressor genes will still require the presence of either an oncogene or a random mutation to produce a tumor. The latter case, a random mutation (aka second hit) occurs with such high frequency in patients with FAP, that it is for all intents and purposes, an AD disease. You inherit that one single mutated tumor suppressor and you WILL have a 2nd hit, and you WILL have the full disease. As oppose to Marfans and Spherocytosis where only 1 gene remain mutated, FAP will have mutations to the APC genes on both of the 5th chromosomes. As stated previously, this is due to the 2 hit hypothesis.

 

[Suncrusher]

What I meant was a reference which explains this type of inheritance. As in it is a recessive trait but a germ line mutation is rendering it dominant.

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you sound like you already understand it. The key is to differentiate whether the question stem is asking whether the protein is dominant or recessive at the gene level (e.g. protooncogene vs. tumor suppressor, or a gene where one mutated allele is enough to cause the disease phenotype vs. a gene where one normal allele produces enough normal protein to maintain the wild-type) or whether the disease is inherited in a dominant or recessive pattern. There are diseases involving recessive genes that are inherited in a dominant pattern: one mutated allele is inherited in a germline mutation and the organism is born with a normal phenotype, but since the organism can't go it's entire life without acquiring a mutation in the normal allele in at least one of its cells, the organism is virtually guaranteed to develop the disease eventually and the disease will display a dominant pattern of inheritance on a pedigree.

edit: CassieBagley did a good job of explaining it, now that I've read all the replies ; )