@article {781, title = {Organic Solute Transporter Alpha Deficiency: A Disorder With Cholestasis, Liver Fibrosis, and Congenital Diarrhea.}, journal = {Hepatology}, volume = {71}, year = {2020}, month = {2020 05}, pages = {1879-1882}, keywords = {Child, Preschool, Cholestasis, Diarrhea, Humans, Liver, Liver Cirrhosis, Male, Mutation, Pedigree, Receptors, G-Protein-Coupled}, issn = {1527-3350}, doi = {10.1002/hep.31087}, author = {Gao, Emily and Cheema, Huma and Waheed, Nadia and Mushtaq, Iqra and Erden, Nihan and Nelson-Williams, Carol and Jain, Dhanpat and Soroka, Carol J and Boyer, James L and Khalil, Youssef and Clayton, Peter T and Mistry, Pramod K and Lifton, Richard P and Vilarinho, S{\'\i}lvia} } @article {50, title = {Germline or somatic GPR101 duplication leads to X-linked acrogigantism: a clinico-pathological and genetic study.}, journal = {Acta Neuropathol Commun}, volume = {4}, year = {2016}, month = {2016 06 01}, pages = {56}, abstract = {

Non-syndromic pituitary gigantism can result from AIP mutations or the recently identified Xq26.3 microduplication causing X-linked acrogigantism (XLAG). Within Xq26.3, GPR101 is believed to be the causative gene, and the c.924G > C (p.E308D) variant in this orphan G protein-coupled receptor has been suggested to play a role in the pathogenesis of acromegaly.We studied 153 patients (58 females and 95 males) with pituitary gigantism. AIP mutation-negative cases were screened for GPR101 duplication through copy number variation droplet digital PCR and high-density aCGH. The genetic, clinical and histopathological features of XLAG patients were studied in detail. 395 peripheral blood and 193 pituitary tumor DNA samples from acromegaly patients were tested for GPR101 variants.We identified 12 patients (10 females and 2 males; 7.8~\%) with XLAG. In one subject, the duplicated region only contained GPR101, but not the other three genes in found to be duplicated in the previously reported patients, defining a new smallest region of overlap of duplications. While females presented with germline mutations, the two male patients harbored the mutation in a mosaic state. Nine patients had pituitary adenomas, while three had hyperplasia. The comparison of the features of XLAG, AIP-positive and GPR101\&AIP-negative patients revealed significant differences in sex distribution, age at onset, height, prolactin co-secretion and histological features. The pathological features of XLAG-related adenomas were remarkably similar. These tumors had a sinusoidal and lobular architecture. Sparsely and densely granulated somatotrophs were admixed with lactotrophs; follicle-like structures and calcifications were commonly observed. Patients with sporadic of familial~acromegaly did not have an increased prevalence of the c.924G > C (p.E308D) GPR101 variant compared to public databases.In conclusion, XLAG can result from germline or somatic duplication of GPR101. Duplication of GPR101 alone is sufficient for the development of XLAG, implicating it as the causative gene within the Xq26.3 region. The pathological features of XLAG-associated pituitary adenomas are typical and, together with the clinical phenotype, should prompt genetic testing.

}, keywords = {Acromegaly, Adenoma, Adolescent, Child, Child, Preschool, Female, Gene Duplication, Germ-Line Mutation, Gigantism, Humans, Infant, Intracellular Signaling Peptides and Proteins, Male, Pituitary Neoplasms, Receptors, G-Protein-Coupled, Treatment Outcome, Young Adult}, issn = {2051-5960}, doi = {10.1186/s40478-016-0328-1}, author = {Iacovazzo, Donato and Caswell, Richard and Bunce, Benjamin and Jose, Sian and Yuan, Bo and Hern{\'a}ndez-Ram{\'\i}rez, Laura C and Kapur, Sonal and Caimari, Francisca and Evanson, Jane and Ferra{\`u}, Francesco and Dang, Mary N and Gabrovska, Plamena and Larkin, Sarah J and Ansorge, Olaf and Rodd, Celia and Vance, Mary L and Ram{\'\i}rez-Renteria, Claudia and Mercado, Mois{\'e}s and Goldstone, Anthony P and Buchfelder, Michael and Burren, Christine P and Gurlek, Alper and Dutta, Pinaki and Choong, Catherine S and Cheetham, Timothy and Trivellin, Giampaolo and Stratakis, Constantine A and Lopes, Maria-Beatriz and Grossman, Ashley B and Trouillas, Jacqueline and Lupski, James R and Ellard, Sian and Sampson, Julian R and Roncaroli, Federico and Korbonits, M{\'a}rta} } @article {218, title = {Whole-exome sequencing identifies homozygous GPR161 mutation in a family with pituitary stalk interruption syndrome.}, journal = {J Clin Endocrinol Metab}, volume = {100}, year = {2015}, month = {2015 Jan}, pages = {E140-7}, abstract = {

CONTEXT: Pituitary stalk interruption syndrome (PSIS) is a rare, congenital anomaly of the pituitary gland characterized by pituitary gland insufficiency, thin or discontinuous pituitary stalk, anterior pituitary hypoplasia, and ectopic positioning of the posterior pituitary gland (neurohypophysis). The clinical presentation of patients with PSIS varies from isolated growth hormone (GH) deficiency to combined pituitary insufficiency and accompanying extrapituitary findings. Mutations in HESX1, LHX4, OTX2, SOX3, and PROKR2 have been associated with PSIS in less than 5\% of cases; thus, the underlying genetic etiology for the vast majority of cases remains to be determined.

OBJECTIVE: We applied whole-exome sequencing (WES) to a consanguineous family with two affected siblings who have pituitary gland insufficiency and radiographic findings of hypoplastic (thin) pituitary gland, empty sella, ectopic neurohypophysis, and interrupted pitiutary stalk-characteristic clinical diagnostic findings of PSIS.

DESIGN AND PARTICIPANTS: WES was applied to two affected and one unaffected siblings.

RESULTS: WES of two affected and one unaffected sibling revealed a unique homozygous missense mutation in GPR161, which encodes the orphan G protein-coupled receptor 161, a protein responsible for transducing extracellular signals across the plasma membrane into the cell.

CONCLUSION: Mutations of GPR161 may be implicated as a potential novel cause of PSIS.

}, keywords = {Adolescent, Child, Preschool, Exome, Female, Genome-Wide Association Study, Humans, Hypopituitarism, Mutation, Pituitary Gland, Receptors, G-Protein-Coupled}, issn = {1945-7197}, doi = {10.1210/jc.2014-1984}, author = {Karaca, Ender and Buyukkaya, Ramazan and Pehlivan, Davut and Charng, Wu-Lin and Yaykasli, Kursat O and Bayram, Yavuz and Gambin, Tomasz and Withers, Marjorie and Atik, Mehmed M and Arslanoglu, Ilknur and Bolu, Semih and Erdin, Serkan and Buyukkaya, Ayla and Yaykasli, Emine and Jhangiani, Shalini N and Muzny, Donna M and Gibbs, Richard A and Lupski, James R} } @article {207, title = {Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation.}, journal = {N Engl J Med}, volume = {371}, year = {2014}, month = {2014 Dec 18}, pages = {2363-74}, abstract = {

BACKGROUND: Increased secretion of growth hormone leads to gigantism in children and acromegaly in adults; the genetic causes of gigantism and acromegaly are poorly understood.

METHODS: We performed clinical and genetic studies of samples obtained from 43 patients with gigantism and then sequenced an implicated gene in samples from 248 patients with acromegaly.

RESULTS: We observed microduplication on chromosome Xq26.3 in samples from 13 patients with gigantism; of these samples, 4 were obtained from members of two unrelated kindreds, and 9 were from patients with sporadic cases. All the patients had disease onset during early childhood. Of the patients with gigantism who did not carry an Xq26.3 microduplication, none presented before the age of 5 years. Genomic characterization of the Xq26.3 region suggests that the microduplications are generated during chromosome replication and that they contain four protein-coding genes. Only one of these genes, GPR101, which encodes a G-protein-coupled receptor, was overexpressed in patients{\textquoteright} pituitary lesions. We identified a recurrent GPR101 mutation (p.E308D) in 11 of 248 patients with acromegaly, with the mutation found mostly in tumors. When the mutation was transfected into rat GH3 cells, it led to increased release of growth hormone and proliferation of growth hormone-producing cells.

CONCLUSIONS: We describe a pediatric disorder (which we have termed X-linked acrogigantism [X-LAG]) that is caused by an Xq26.3 genomic duplication and is characterized by early-onset gigantism resulting from an excess of growth hormone. Duplication of GPR101 probably causes X-LAG. We also found a recurrent mutation in GPR101 in some adults with acromegaly. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.).

}, keywords = {Acromegaly, Adolescent, Adult, Age of Onset, Child, Child, Preschool, Chromosome Duplication, Chromosomes, Human, X, Female, Gigantism, Human Growth Hormone, Humans, Infant, Male, Mutation, Phenotype, Protein Conformation, Receptors, G-Protein-Coupled}, issn = {1533-4406}, doi = {10.1056/NEJMoa1408028}, author = {Trivellin, Giampaolo and Daly, Adrian F and Faucz, Fabio R and Yuan, Bo and Rostomyan, Liliya and Larco, Darwin O and Schernthaner-Reiter, Marie Helene and Szarek, Eva and Leal, Let{\'\i}cia F and Caberg, Jean-Hubert and Castermans, Emilie and Villa, Chiara and Dimopoulos, Aggeliki and Chittiboina, Prashant and Xekouki, Paraskevi and Shah, Nalini and Metzger, Daniel and Lysy, Philippe A and Ferrante, Emanuele and Strebkova, Natalia and Mazerkina, Nadia and Zatelli, Maria Chiara and Lodish, Maya and Horvath, Anelia and de Alexandre, Rodrigo Bertollo and Manning, Allison D and Levy, Isaac and Keil, Margaret F and Sierra, Maria de la Luz and Palmeira, Leonor and Coppieters, Wouter and Georges, Michel and Naves, Luciana A and Jamar, Mauricette and Bours, Vincent and Wu, T John and Choong, Catherine S and Bertherat, Jerome and Chanson, Philippe and Kamenick{\'y}, Peter and Farrell, William E and Barlier, Anne and Quezado, Martha and Bjelobaba, Ivana and Stojilkovic, Stanko S and Wess, Jurgen and Costanzi, Stefano and Liu, Pengfei and Lupski, James R and Beckers, Albert and Stratakis, Constantine A} }