When the noose tightened around the GPR101 gene

Having established beyond doubt that the region identified by the American researchers corresponded to a locus of gigantism, the scientists defined a new gigantism syndrome: X-LAG (X-linked acrogigantism). “This is a syndrome that begins in the cradle and which causes the tallest giants”, points out Albert Beckers. “The children are born normally and begin to grow abnormally even before they are one year old. They develop large pituitary adenomas which do not respond well to traditional therapies. They secrete phenomenal quantities of growth hormone as well as prolactin”.  Genetic studies have shown that these “little” giants (who are seen to exhibit gigantism at a very young age) are carriers of the duplication of genes on the X chromosome.  

In parallel, the scientists tasked themselves with determining which of the 11 duplicated genes were responsible for this syndrome. Having reduced the number of genes potentially involved to 4 by cross-checking between the patients, Albert Beckers and his colleagues looked at which of them were expressed in the hypophyseal tumors of patients who had been operated upon. “Three of these genes were quite normally expressed while the fourth was represented respectively between 600 and 100 times more in two distinct tumors. This was undoubtedly the culprit!” reveals the specialist. The gene in question was GPR101 which codes for a receptor whose function is unknown to this day.

A still unknown receptor in the spotlight

Published in The New England Journal of Medicine (4), the results of this study show the duplication of the GPR101 gene which explains the development of the biggest giants in the world. “We cannot prove it, but we would be prepared to bet that Robert Waldow, who measured 2m72, was affected by the X-LAG syndrome”, indicates Albert Beckers.  “What we show in this study, is that the syndrome is related to the duplication of the 4 genes on the X chromosome, that GPR101 is probably the culprit and that this chromosomal aberration is dominant and affects a slightly larger number of women than men. It is also the second genetic cause of FIPA, because it can be transmitted by affected parents to their children”, continues the researcher.

The receptor which is coded by the GPR101 gene is certainly actively involved in the regulation of the growth hormone and its role is directly linked to GHRH – the hormone that releases the growth hormone – and whose receptor is also over-expressed in patients affected by this condition. Up to now, chromosomal aberrations involved in gigantism consisted of the mutation of genes and not the duplication of these same genes. It is therefore a new genetic mechanism that causes growth problems that has been demonstrated in this study. “This work opens up many and varied research avenues”, indicates Albert Beckers. “We have found the gene that codes for a receptor that is unknown to us. We assume that it is used in the growth of the organism but extra research will be necessary to confirm this theory. What is sure is that it is involved in a highly effective biological production of growth hormone! Perhaps this receptor also plays a role in dwarfism…”?

Research which has yet to reveal all its findings…

The theories resulting from the researchers’ discovery are many and are likely to keep scientists who are interested in gigantism busy for a long time. “Whatever happens, we must first find the ligand of this receptor, stimulate it and slow it down in order to observe the consequences of these manipulations and to see if this receptor is involved in other diseases”, continues the endocrinology specialist.

Today, scientists are following different avenues of research to unveil the mystery surrounding giants with a view to one day improving the quality of life of individuals affected by gigantism syndromes. This is because of the fact that, apart from the obvious handicap caused by their great height, giants are subject to a number of conditions and die relatively young.

At the present time, Professor Albert Beckers’ team has three articles which are about to be published and which will reveal new discoveries about the underlying mechanisms of gigantism.  Among the research work conducted by the team from Liege, is the analysis of bone samples taken from the Constantin giant of Mons who measured 2m59…

(4) Gigantism and Acromegaly Due to Xq26 Microduplications and GPR101 Mutation. N Engl J Med. 2014 Dec 18;371(25):2363-74. doi: 10.1056/NEJMoa1408028