We recently showed that Xq26.3 microduplications are associated with early childhood-onset gigantism, a condition we named X-linked acrogigantism (X-LAG). Patients with X-LAG present with mixed GH/PRL secreting pituitary macroadenomas and/or hyperplasia. The original smallest region of overlap for the microduplications included 4 coding genes, of which only one, an orphan G protein-coupled receptor named GPR101, was highly expressed in tumors. A single patient with GPR101 microduplication only was recently reported: this proves that GPR101 overexpression alone may cause gigantism. GPR101 was found to be expressed at very low levels or was not expressed in almost all adult human tissues examined, with the exception of specific regions of the brain, including the nucleus accumbens. High expression of GPR101 was observed in the human fetal pituitary but not in adult pituitary tissue and in pituitary tumors other than those with Xq26.3 defect. In contrast to human tissues, adult pituitaries of both rhesus monkey and rat expressed GPR101. However, the pituitary cell type expressing this receptor differs: gonadotrophs in monkeys and somatotrophs in rats express GPR101. In the developing zebrafish embryo, GPR101 showed a bimodal expression pattern: expression levels progressively waning during the first cell divisions (presumably representing maternal transcripts) and then gradually rising with the appearance of the first somites. Beginning at 48 h post-fertilization a strong and brain-specific staining including part of the hypothalamus and pituitary was seen. These studies show that GPR101 is likely to be a significant regulator of growth; the brain is the major site of GPR101 expression across different species, although divergent species-specific expression patterns are evident, especially concerning the pituitary. Differences among species might reflect their different growth, development and maturation patterns. It is also interesting to note that the highest GPR101 expression levels in adult human tissues were observed in the nucleus accumbens, which plays an important role as the reward center, hinting that GPR101 might also be involved in the regulation of food seeking behaviors, in addition to growth and/or puberty.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology