Individuals with PWS typically have incomplete sexual development, but, paradoxically, often begin to exhibit signs of puberty much earlier than expected. The incidence of bone fide ‘precocious puberty’ in PWS is not entirely clear, but it is evident that normal onset and progression of puberty is frequently disrupted.
The reason for this aspect of PWS just became much more clear in a paper published in the New England Journal of Medicine last week [Abreu et al Central Precocious Puberty Caused by Mutations in the Imprinted Gene MKRN3]. As so often happens in science, the answer came from an unexpected angle, an entirely different line of study in families exhibiting an inherited form of precocious puberty.
In the study, the authors identified 15 families in which precocious puberty clearly had an inherited component. They then used an unbiased method to identify the gene mutations that were responsible for this early onset of puberty. Using advanced ‘next generation’ DNA sequencing techniques, they sequenced all of the genes of these family members (that’s more than 20,000 genes per person) and identified those genes that harbored mutations. One gene that was mutated in several families was MKRN3, which happens to be one of the PWS-region genes.
The PWS region on chromosome 15 is complex and includes several genes that encode proteins (including NECDIN, MAGEL2 and MKRN3) as well as small and large RNAs that don’t make produce proteins but likely function to regulate other genes. The genetic evidence suggests that loss of the sequences making the regulatory RNAs (in particular the SNORD116 snoRNAs) is responsible for the major features of PWS. However, the nearby protein encoding genes, including MKRN3, are deleted or silenced as well. The data from Abrue and colleagues indicates that it is the loss of MKRN3 in PWS that can cause puberty to start at an inappropriately young age.
How MKRN3 works is not fully clear, but it is normally made at high levels in the brain throughout early development, and is thought to act as a brake, preventing the onset of puberty. In the normal situation, MKRN3 protein levels drop at about the same time that expression of other proteins important in promoting sexual development start ramping up. Thus, the break is released, the gas pedal is engaged, and puberty ensues. In PWS, the break is missing and thus some of the features of puberty get underway before they should. This study does not immediately lead to any change in how an endocrinologist would treat or not treat a person with PWS who is showing signs of early puberty, but it does provide some satisfaction in having a better understanding of why this occurs. Because MKRN3 is also expressed outside the brain, the study also suggests that there may be subtle changes in cells elsewhere in the body as a result of MKRN3 loss in PWS. But there are some notable differences between those with loss of MRKN3 only (as described in the current study) and those with PWS - whereas individuals with PWS usually never fully progress through puberty and are only rarely fertile, those with MKRN3 mutations do end up completing puberty and are fertile, although they may have short stature. Thus, the other genes and regulatory RNAs in the PWS region are also likely to be contributing to the disruption of normal sexual development in PWS.
Interestingly, in what seems, for now, to be an odd coincidence, some of the children in the current study with precocious puberty and MKRN3 mutations also had esotropia (a.k.a, strabismus or crossed eyes). Because crossed eyes not uncommon in the general population, additional studies will have to be done to determine if it is loss of MKRN3 function that causes this problem. However, it would be consistent again with PWS, where esotropia is very common.
In summary, this study provides an explanation of the early occurrence of some features of puberty in PWS (including body hair and advanced bone age) that parents and doctors have noted for some time. It establishes that PWS presents with a constellation of symptoms, in part, because there are several genes involved, each of which may contribute to different aspects of the phenotype. Finally, it reminds us that even as a disease-specific organization, we need to recognize the importance of being supportive of all biomedical research– one never knows where the next important insight into PWS will come from.