13 Dec New Genetic Loci for Gigantism and Acromegaly Identified
MedicalResearch.com Interview with:
Dr. Constantine A. Stratakis, M.D., D.Sc
National Institutes of Health, Clinical Research Center
Bethesda, MD 20892-1862
Medical Research: What is the background for this study? What are the main findings?
Dr. Stratakis: We have been working for years on the genetics of pituitary tumors in association with other conditions. A few years ago (attached), we studied for the first time a series of pediatric giants that we sequenced for then known genes. We found a few MEN1 and AIP mutations but all mutations were present in older kids with gigantism. This left out the youngest among the giants without any genetic defect. This was the first time I realized that I was dealing with a different disease. We started looking for additional genetic defects and when we found the Xq26 microduplications in 3 kindreds. We contacted the custodians of the largest series in the world – Dr. Beckers in Liege. He screened his cases, once we gave him the coordinates, and boom – it was there…
The most significant thing here is that this is a new disease really: the early pediatric gigantism is almost exclusively due to Xq26 microduplications unless it is part of a family with another syndrome (AIP, MEN1, Carney complex). If there is no family history and you are dealing with a toddler with gigantism, based in these data, there is a more than 80% chance of having an Xq26 defect. This is pretty amazing!
In addition, assuming that GPR101 is the responsible gene (which needs to be confirmed with additional studies) this identifies a new molecular pathway of increasing growth hormone secretion, most likely due to upregulation of GHRH – all of this needs to be confirmed in further human and animal studies.
The Xq26 genomic micro-arrangements (which contain the GPR101, but also 3 other genes) is the big news here…
Medical Research: What should clinicians and patients take away from your report?
Dr. Stratakis: Well, first, clearly, we have a powerful genetic screening test for a new overgrowth condition.
Second, GPR101 should be straightforward to study for inhibitors and/or agonists, like other GPCRs.
Third, a better understanding of what regulates growth hormone secretion may offer insight in additional molecular mechanisms regulating pituitary function and development.
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. Stratakis: As above, animal studies will clarify the gene and the molecular pathway; very important to do these quickly. A larger series of acromegalics need to be screened for GPR101 sequence defects and each has to be tested for its function.
This is the difficulty of identifying a new gene with an unknown function.
Citation:
Gigantism and Acromegaly Due to Xq26 Microduplications and GPR101 Mutation
December 3, 2014DOI: 10.1056/NEJMoa1408028
Last Updated on December 13, 2014 by Marie Benz MD FAAD