They might be giants: Understanding a childhood genetic defect

2014

Challenge

A small number of genes have been identified as being involved in early childhood overgrowth, also known as gigantism, but the molecular explanation for the genetic condition remained unclear, and treatments aimed at alleviating the disorder were often ineffective.

Advance

IRP researchers led by Constantine A. Stratakis, M.D., D.(med)Sci., took a new approach to the problem and looked at copy-number variants in the genome of patients with gigantism, rather than sequencing individual genes. The group discovered that a single defect on the X-chromosome was responsible for most cases of gigantism in early childhood, through the subsequent over-expression of growth hormone.

Impact

Having demonstrated that an identifiable genetic defect on the X-chromosome is responsible for the majority of cases of early-onset gigantism, clinicians can now use the test for more accurate identification and treatment. One of the genes responsible for overgrowth, GPR101, is a new target for understanding growth hormone secretion and its effects on growth. Its discovery may lead to new treatments for gigantism and new research on the regulation of growth in young children. 

Publications

Trivellin G, Daly AF, Faucz FR, Yuan B, Rostomyan L, Larco DO, Schernthaner-Reiter MH, Szarek E, Leal LF, Caberg JH, Castermans E, Villa C, Dimopoulos A, Chittiboina P, Xekouki P, Shah N, Metzger D, Lysy PA, Ferrante E, Strebkova N, Mazerkina N, Zatelli MC, Lodish M, Horvath A, de Alexandre RB, Manning AD, Levy I, Keil MF, Sierra Mde L, Palmeira L, Coppieters W, Georges M, Naves LA, Jamar M, Bours V, Wu TJ, Choong CS, Bertherat J, Chanson P, Kamenický P, Farrell WE, Barlier A, Quezado M, Bjelobaba I, Stojilkovic SS, Wess J, Costanzi S, Liu P, Lupski JR, Beckers A, & CA Stratakis. (2014). Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. N Engl J Med. 371(25), 2363-74.