Here’s a great question about the inheritance pattern of retinoblastoma. I love this type of question, because it forces you to really think about something you would normally just accept.
Q. I don’t get why the mutant RB gene in familial retinoblastoma is said to be inherited in an autosomal dominant fashion! Simply inheriting the mutant RB gene is not enough to give you the disease…so how can they call it dominant? Isn’t that the definition of dominant – you inherit one allele and it “dominates” the other one, giving you the phenotype associated with that allele? And why do some sources say that the RB gene is inherited in an autosomal dominant fashion, but expressed as an autosomal recessive trait on a cellular level? That makes no sense to me.
A. Before we get to the answer, let’s take a look at what some reputable sources say about autosomal dominant inheritance of the RB gene.
Here is what Robbins says:
“Approximately 60% of retinoblastomas are sporadic, and the remaining are familial, with the predisposition to develop the tumor being transmitted as an autosomal dominant trait.”
“In familial cases [of retinoblastoma], children inherit one defective copy of the RB gene in the germ line (one hit); the other copy is normal. Retinoblastoma develops when the normal RB allele is mutated in retinoblasts as a result of spontaneous somatic mutation (second hit). Because only a single somatic mutation is required for loss of RB function in retinoblastoma families, familial retinoblastoma is inherited as an autosomal dominant trait.”
“At this point we should clarify some terminology. A child carrying an inherited mutant RB allele in all somatic cells is perfectly normal (except for the increased risk of developing cancer). Because such a child is heterozygous at the RB locus, this implies that heterozygosity for the RB gene does not affect cell behavior. Cancer develops when the cell becomes homozygous for the mutant allele or, put another way, when the cell loses heterozygosity for the normal RB gene (a condition known as LOH, for loss of heterozygosity).”
Here’s something from the Division of Reproductive and Medical Genetics at the National Naval Medical Center regarding a concept known as “reduced penetrance:”
An individual who has the genotype for a disease may not exhibit the disease phenotype at all, even though he or she can transmit the disease gene to the next generation.
Retinoblastoma, an autosomal dominant malignant eye tumor, is a good example of reduced penetrance. Many carriers of the RB susceptibility gene do not have the disease.
Finally, here’s something from the book Ocular Pathology by Myron Yanoff:
A. If both chromosomal 13q14 regions are normal, no retinoblastoma will develop.
B. If one of the two 13 chromosomes has a 13q14 deletion, duplication, or point mutation (a heterozygous condition), a retinoblastoma still will not result.
C. If both 13 chromosomes have a 13q14 deletion, duplication, or point mutation (a homozygous condition), retinoblastoma results.
D. Therefore, retinoblastoma is inherited as an autosomal recessive trait at the cellular level; nevertheless, retinoblastoma behaves clinically as if it has an autosomal dominant inheritance pattern with 90% penetrance [in other words, if a person inherits one “bad” RB gene, the chances are 90 in 100 that they will develop retinoblastoma].
So, to answer your question, the “bad” RB gene is said to be inherited in an autosomal dominant fashion because:
1. Everyone who inherits a mutated RB gene “expresses” it, in a way. Everyone who inherits the gene has 1) a loss of RB function (they don’t make as much RB protein as normal people) and 2) an increased risk of getting the disease. True, not everyone with the mutant gene gets the disease, but everyone with the mutant gene gets the predisposition to get the disease. So you can safely say that the mutant RB gene follows an autosomal dominant pattern of inheritance because everyone who inherits the gene expresses a particular trait (the trait in this case consists of decreased RB function and an increased risk of developing retinoblastoma).
2. In the classic autosomal dominant disease inheritance pattern, everyone who inherits the “bad” gene gets the disease in question. Makes sense. However, there is this concept called “reduced penetrance” which says that for some genes/diseases, not everyone who inherits the “bad” gene will get the disease in question. Most will, but some won’t. Even the people that don’t get the disease, however, are able to pass the gene on to the next generation, which is a feature of autosomal dominant genes in general. In the case of retinoblastoma, penetrance is about 90% – meaning that if you inherit the mutated RB gene, you have about a 90% chance of getting retinoblastoma.
As for this notion that the mutant RB gene acts as an autosomal recessive gene at the cellular level, that makes some sense too, because just inheriting that one gene alone is not enough to get the disease; you have to mutate the other copy as well. So in that sense, it is “recessive.”
I think the most important thing in this whole discussion is that you realize that if you inherit the mutant RB gene, your chances of getting the disease go way up, but in order to actually express the disease, you need to acquire a mutation in the other allele (which virtually all people who inherit that bad RB gene do!).
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- AG said Thanks Kristine, very helpful!
- Frank MD said Succinctly explained. Excellent! Thank you so much!!
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- Carol said Thanks…. Well explained
- Ulyses Yakovlevich said This looks like an awesome tool for future Pathologists to learn from :).
- Chief said Amazing explanation. No other website teaches this interesting and important medical lesson. Not eve...
- Dr.Kisor Kumar Pal said Very helpful and practical discussion.I learned a lot.
- Cheri said Thank you ! I’m a traveler in Pathology/Histology
- Dr. Syed Mahbub Baksh said During my residency years, I have read only two books: Robbins Pathology and Henry’s Clinical...
- Theresa said Thanks for breaking this down in a simple way to understand it. Well done.