as we mentioned before, we are connected with experts in cat genetics and bone disorders, who back us up on all the expertise we don’t have. With their help we think we have a very good chance of finding BUB’s mutation once we get her genome sequence.
It also has the big advantage that we can ask them basically anything. And so we did, when we asked Prof. Uwe Kornak from the Charité University Hospital about LilBUB, types of osteopetrosis and the diffences between mutations in animals and humans. Read on……
Q: What was your first thought when we asked you to help us with LilBUB?
Uwe Kornak: Wow – this is the second famous feline I know about after Fritz the Cat!
Q: Are there human diseases that BUB’s appearance reminds you of?
UK: Yes. The combination of high bone mineral density and her unusual face reminds me of Raine syndrome. Another overlap is with a disease called dysosteoclerosis. Both are extremely rare diseases causing a very high bone mass, which we can also see in LilBUB’s X-rays.
The very bright staining of BUB’s bones in the x-rays in comparison to those of another cat are a clear sign of high bone mineral density.
Q: How many types of osteopetrosis are there and how do they differ from one another?
UK: The term osteopetrosis is used for inherited disorders that cause increased bone mineral density due to reduced or absent function of osteoclasts. Osteoclasts certain cells found in the bones that constantly resorb and remodel the bone throughout life. If these cells are not functioning properly, the bone grows too thick.
There are are different types of osteopetrosis which are classified by the way they are inherited (dominant & recessive forms*). Then, the recessive forms are further subdivided into groups that are osteoclast-rich and -poor.
Q: Which of these types of osteopetrosis could LilBUB have?
UK: That is very difficult to say, especially if we don’t know which kind of mutation causes the phenotype. For example: The dysosteosclerosis that BUB reminded me of, seems to be due to altered osteoclast function, so it would be an osteopetrosis just like defined above. The Raine syndrome, on the other hand, is due to a different, complex mechanism that probably doesn’t directly affect osteoclasts and isn’t an osteopetrosis. Therefore, although LilBUB’s bones are opaque and have an abnormal shape it cannot be said with certainty that it suffers from an osteopetrosis in the strict sense.
Q: What kind of difference does the type of osteopetrosis make for the patient?
UK: All types of osteopetroses begin between early infancy and childhood. The congenital forms are usually very dramatic and life-threatening. Children have reduced growth and multiple complications also involving the central nervous system**. Juvenile forms are milder and very rarely entail a reduced life expectancy.
Q: Is it unusual that similar mutations have different effects in humans and animals?
UK: Not at all. This is a rather common finding – especially in the milder heritable disorders. A famous example is the a mutation in the gene Connexin26. Humans with mutations in this gene are deaf, but apart from that completely healthy. However, mice with mutations in Connexin26 do not exist, because the embryos do not develop due to a pivotal role of the mouse Connexin26 gene in the placenta.
Q: If you would have to predict what gene/mutation could cause BUB’s special features, what would your guess be?
UK: Phew. That’s a tricky question. My best guess would be that the phenotype is the result of an alteration of a specific function of the secretory pathway, but in genetics we are often surprised by completely unexpected results. So even if I give you this hypothesis, I wouldn’t bet it.
*Usually autosomal inheritance, rarely also X-chromosomal inheritance occurs. [For all to whom this is unclear, we can address this in a seperate post – Daniel]
** The severe congenital osteopetroses are usually inherited in an autosomal recessive mode, the milder juvenile osteopetroses autosomal dominant