An image of a 43-year-old woman with Hajdu-Cheney syndrome. Image from J Radiol Case Rep. 2014 Sep 30;8(9):1-8 .
In medical research, we sometimes discover things from abnormal cases, and that is precisely the case of a recent study in Molecular Cell (1). In this paper, the authors report that a mutation in a putative gene for the Hajdu-Cheney syndrome can be utilized for developing a new treatment target for osteoporosis. That’s exciting!
Hajdu-Cheney syndrome (HCS), also called “acro-osteolysis” (i.e., breakdown of bone tissue), is a very rare genetic disease, with only 50 cases or so being reported in the world. People with HCS have prominent characteristics such as short stature and developmental delay, short and broad digits, facial dysmorphism, and polycystic kidkeys. Mutations at the NOTCH2 gene have been known to be associated with HCS. This gene codes for protein that is involved in bone maintenance. Moreover, HCS patients are associated with osteoporosis and fractures, tooth abnormalities and periodontal disease. That is why HDS has been a “research target” for osteoporosis researchers for some time.
In a recent paper, a group of investigators from Japan used the HCS model in mice to show that bone loss (in mice) could be reversed. The investigators discovered that a mutation in the NOTCH2 gene together with a protein called FBW7 are involved in the maintenance of bone. The experiment was elegant: they first knocked out the gene for FBW7 in the bone, and the mice became osteoporotic much like HCS; they then used a medication (zoledronic acid) to block osteoclas formation and the result was a reverse of bone loss.
I guess the implication from these results is that (a) zoledronic acid can be used to treat osteoporosis in patients with HCS, and (b) the NOTCH2 and FBW7 system may be a new target for developing new therapies for the treatment of osteoporosis and bone loss in the elderly.
In medical research, outliers are interesting cases because they may point to new discoveries. In Siddharta Mukherjee’s The laws of medicine (2), he notes that normality teaches us rules, but ‘outliers’ teach us laws, and this is quite true for the HCS story.
OTCH2 Hajdu-Cheney Mutations Escape SCFFBW7-Dependent Proteolysis to Promote Osteoporosis
(2) Mukherjee S. The laws of medicine: field notes from an uncertain science. TED Books, 2015.