X-linked acrogigantism (X-LAG) is a recently described form of familial or sporadic pituitary gigantism characterized by very early onset GH and IGF-1 excess, accelerated growth velocity, gigantism and/or acromegaloid features. Germline or somatic microduplications of the Xq26.3 chromosomal region, invariably involving the GPR101 gene, constitute the genetic defect leading to X-LAG. GPR101 encodes a class A G protein-coupled receptor that activates the 3',5'-cyclic adenosine monophosphate signaling pathway. Highly expressed in the central nervous system, the main physiological function and ligand of GPR101 remain unknown, but it seems to play a role in the normal development of the GHRH-GH axis. Early recognition of X-LAG cases is imperative because these patients require clinical management that differs from that of other patients with acromegaly or gigantism. Medical treatment with pegvisomant seems to be the best approach, since X-LAG tumors are resistant to the treatment with somatostatin analogues and dopamine agonists; surgical cure requires near-total hypophysectomy. Currently, the efforts of our research focus on the identification of GPR101 ligands; in addition, the long-term follow-up of X-LAG patients is of extreme interest as this is expected to lead to better understanding of GPR101 effects on human pathophysiology.
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Chromatin conformation capture in the clinic: 4C-seq/HiC distinguishes pathogenic from neutral duplications at the GPR101 locus.
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Andalusian Center for Developmental Biology (CABD), Junta de Andalucia - Universidad Pablo de Olavide (UPO) - Consejo Superior de Investigaciones Cientificas (CSIC), Seville, Spain.
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- - X-linked acrogigantism (X-LAG) is a serious genetic condition caused by duplications on chromosome X that affect the GPR101 gene, leading to excessive growth due to misexpression of this gene in the pituitary gland.
- - The researchers used advanced genomic techniques, specifically 4C/HiC-seq, to examine the impact of GPR101 duplications on the functional structure of the genome in families with these duplications, finding that some did not create harmful changes.
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The Genetic Pathophysiology and Clinical Management of the TADopathy, X-Linked Acrogigantism.
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Department of Endocrinology, Centre Hospitalier Universitaire (CHU) de Liège, University of Liège, Domaine Universitaire Sart Tilman, 4000 Liège, Belgium.
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- - Pituitary gigantism is a rare condition caused by excess growth hormone, occurring before growth plates close, and nearly 50% of cases have a genetic basis, including X-linked acrogigantism (X-LAG), which particularly affects infants and can lead to extreme height.
- - X-LAG is associated with chromosome duplications that disrupt normal gene regulation, resulting in overproduction of growth hormone and prolactin, with approximately 40 known cases identified in the past decade, often transmitted from mothers to sons.
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Department of Endocrinology, Centre Hospitalier Universitaire de Liège, University of Liège, Liège, Belgium.
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- * The duplication modifies the normal gene arrangement, leading to increased hormone production and causing gigantism due to a new regulatory domain (neo-TAD) that disrupts typical genetic control.
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Basal interaction of the orphan receptor GPR101 with arrestins leads to constitutive internalization.
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Laboratory of Molecular Pharmacology, GIGA-Molecular Biology of Diseases, University of Liege, Liege, Belgium; Laboratory of Medicinal Chemistry, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege, Liege, Belgium. Electronic address:
GPR101 is an orphan G protein-coupled receptor that promotes growth hormone secretion in the pituitary. The microduplication of the GPR101 gene has been linked with the X-linked acrogigantism, or X-LAG, syndrome. This disease is characterized by excessive growth hormone secretion and abnormal rapid growth beginning early in life.
View Article and Find Full Text PDFGPR101: Modeling a constitutively active receptor linked to X-linked acrogigantism.
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FORTH, Heraklion, Greece; ELPEN Research Institute, Athens, Greece.
GPR101 is a G protein-coupled receptor (GPCR) implicated in a rare form of genetic gigantism known as X-linked acrogigantism, or X-LAG. In particular, X-LAG patients harbor microduplications in the long arm of the X-chromosome that invariably include the GPR101 gene. Duplications of the GPR101 gene lead to the formation of a new chromatin domain that causes over-expression of the receptor in the pituitary tumors of the patients.
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