title: Screening for GPR101 defects in pediatric pituitary corticotropinomas.
abstract: Cushing disease (CD) in children is caused by adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas. Germline or somatic mutations in genes such as MEN1, CDKIs, AIP, and USP8 have been identified in pediatric CD, but the genetic defects in a significant percentage of cases are still unknown. We investigated the orphan G protein-coupled receptor GPR101, a gene known to be involved in somatotropinomas, for its possible involvement in corticotropinomas. We performed GPR101 sequencing, expression analyses by RT-qPCR and immunostaining, and functional studies (cell proliferation, pituitary hormones secretion, and cAMP measurement) in a series of patients with sporadic CD secondary to ACTH-secreting adenomas in whom we had peripheral and tumor DNA (N=36). No increased GPR101 expression was observed in tumors compared to normal pituitary (NP) tissues, nor did we find a correlation between GPR101 and ACTH expression levels. Sequence analysis revealed a very rare germline heterozygous GPR101 variant (p.G31S) in one patient with CD. Overexpression of the p.G31S variant did not lead to increased growth and proliferation, although modest effects on cAMP signaling were seen. GPR101 is not overexpressed in ACTH-secreting tumors compared to NPs. A rare germline GPR101 variant was found in one patient with CD but in vitro studies did not support a consistent pathogenic effect. GPR101 is unlikely to be involved in the pathogenesis of CD.
authors.affiliation: G Trivellin, Section Endocrinology and Genetics, NICHD, National Institutes of Health, Bethesda, 20892, United States.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Trivellin
authors.affiliation: R Correa, Section Endocrinology and Genetics, NICHD, National Institutes of Health, Bethesda, United States.
authors.forename: Ricardo R
authors.initials: RR
authors.lastname: Correa
authors.affiliation: M Batsis, Section Endocrinology and Genetics, NICHD, National Institutes of Health, Bethesda, United States.
authors.forename: Maria
authors.initials: M
authors.lastname: Batsis
authors.affiliation: F Faucz, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, 20892, United States.
authors.forename: Fabio R
authors.initials: FR
authors.lastname: Faucz
authors.affiliation: P Chittiboina, Surgical Neurology Branch, National Institute for Neurological Diseases and Stroke, National Institutes of Health, Bethesda, 20892, United States.
authors.forename: Prashant
authors.initials: P
authors.lastname: Chittiboina
authors.affiliation: I Bjelobaba, Section on Cellular Signaling, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States.
authors.forename: Ivana
authors.initials: I
authors.lastname: Bjelobaba
authors.affiliation: D Larco, Department of Obstretics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, United States.
authors.forename: Darwin O
authors.initials: DO
authors.lastname: Larco
authors.affiliation: M Quezado, Laboratory of Pathology, National Cancer Institute, Bethesda, 20892, United States.
authors.forename: Martha
authors.initials: M
authors.lastname: Quezado
authors.affiliation: A Daly, Department of Endocrinology, University of Liège, Liège, Belgium.
authors.forename: Adrian F
authors.initials: AF
authors.lastname: Daly
authors.affiliation: S Stojilkovic, Section on Cellular Signaling, Eunice Kennedy Shriver National Institute of Child Health and Human Development , National Institutes of Health, Bethesda, United States.
authors.forename: Stanko S
authors.initials: SS
authors.lastname: Stojilkovic
authors.affiliation: T Wu, Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, United States.
authors.forename: T John
authors.initials: TJ
authors.lastname: Wu
authors.affiliation: A Beckers, Department of Endocrinology, CHU de Liege, Liege, Belgium.
authors.forename: Albert
authors.initials: A
authors.lastname: Beckers
authors.affiliation: M Lodish, Pediatric Endocrinology, NIH, Bethesda, 20892, United States.
authors.forename: Maya
authors.initials: M
authors.lastname: Lodish
authors.affiliation: C Stratakis, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States stratakc@cc1.nichd.nih.gov.
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis