Gigantism and Acromegaly Due to Xq26 Microduplications and GPR101 Mutation

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' 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.).

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References

Beckers A, Aaltonen L, Daly A, Karhu A . Familial isolated pituitary adenomas (FIPA) and the pituitary adenoma predisposition due to mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. Endocr Rev. 2013; 34(2):239-77. PMC: 3610678. DOI: 10.1210/er.2012-1013. View

Zhang F, Khajavi M, Connolly A, Towne C, Batish S, Lupski J . The DNA replication FoSTeS/MMBIR mechanism can generate genomic, genic and exonic complex rearrangements in humans. Nat Genet. 2009; 41(7):849-53. PMC: 4461229. DOI: 10.1038/ng.399. View

Sali A, Overington J . Derivation of rules for comparative protein modeling from a database of protein structure alignments. Protein Sci. 1994; 3(9):1582-96. PMC: 2142932. DOI: 10.1002/pro.5560030923. View

Bergamaschi S, Ronchi C, Giavoli C, Ferrante E, Verrua E, Ferrari D . Eight-year follow-up of a child with a GH/prolactin-secreting adenoma: efficacy of pegvisomant therapy. Horm Res Paediatr. 2010; 73(1):74-9. DOI: 10.1159/000271919. View

Glasker S, Vortmeyer A, Lafferty A, Hofman P, Li J, Weil R . Hereditary pituitary hyperplasia with infantile gigantism. J Clin Endocrinol Metab. 2011; 96(12):E2078-87. PMC: 3232621. DOI: 10.1210/jc.2011-1401. View

Daly A, Jaffrain-Rea M, Ciccarelli A, Valdes-Socin H, Rohmer V, Tamburrano G . Clinical characterization of familial isolated pituitary adenomas. J Clin Endocrinol Metab. 2006; 91(9):3316-23. DOI: 10.1210/jc.2005-2671. View

Stankiewicz P, Thiele H, Schlicker M, Cseke-Friedrich A, Bartel-Friedrich S, Yatsenko S . Duplication of Xq26.2-q27.1, including SOX3, in a mother and daughter with short stature and dyslalia. Am J Med Genet A. 2005; 138(1):11-7. DOI: 10.1002/ajmg.a.30910. View

Moller R, Jensen L, Maas S, Filmus J, Capurro M, Hansen C . X-linked congenital ptosis and associated intellectual disability, short stature, microcephaly, cleft palate, digital and genital abnormalities define novel Xq25q26 duplication syndrome. Hum Genet. 2013; 133(5):625-38. DOI: 10.1007/s00439-013-1403-3. View

Tatton-Brown K, Rahman N . Sotos syndrome. Eur J Hum Genet. 2006; 15(3):264-71. DOI: 10.1038/sj.ejhg.5201686. View

10.

Gurrieri F, Pomponi M, Pietrobono R, Lucci-Cordisco E, Silvestri E, Storniello G . The Simpson-Golabi-Behmel syndrome: A clinical case and a detective story. Am J Med Genet A. 2011; 155A(1):145-8. DOI: 10.1002/ajmg.a.33586. View

11.

Nilaweera K, Ozanne D, Wilson D, Mercer J, Morgan P, Barrett P . G protein-coupled receptor 101 mRNA expression in the mouse brain: altered expression in the posterior hypothalamus and amygdala by energetic challenges. J Neuroendocrinol. 2006; 19(1):34-45. DOI: 10.1111/j.1365-2826.2006.01502.x. View

12.

Regard J, Sato I, Coughlin S . Anatomical profiling of G protein-coupled receptor expression. Cell. 2008; 135(3):561-71. PMC: 2590943. DOI: 10.1016/j.cell.2008.08.040. View

13.

Stratakis C, Tichomirowa M, Boikos S, Azevedo M, Lodish M, Martari M . The role of germline AIP, MEN1, PRKAR1A, CDKN1B and CDKN2C mutations in causing pituitary adenomas in a large cohort of children, adolescents, and patients with genetic syndromes. Clin Genet. 2010; 78(5):457-63. PMC: 3050035. DOI: 10.1111/j.1399-0004.2010.01406.x. View

14.

Leontiou C, Gueorguiev M, van der Spuy J, Quinton R, Lolli F, Hassan S . The role of the aryl hydrocarbon receptor-interacting protein gene in familial and sporadic pituitary adenomas. J Clin Endocrinol Metab. 2008; 93(6):2390-401. DOI: 10.1210/jc.2007-2611. View

15.

Madrigal I, Fernandez-Burriel M, Rodriguez-Revenga L, Cabrera J, Marti M, Mur A . Xq26.2-q26.3 microduplication in two brothers with intellectual disabilities: clinical and molecular characterization. J Hum Genet. 2010; 55(12):822-6. DOI: 10.1038/jhg.2010.119. View

16.

Cho-Clark M, Larco D, Semsarzadeh N, Vasta F, Mani S, Wu T . GnRH-(1-5) transactivates EGFR in Ishikawa human endometrial cells via an orphan G protein-coupled receptor. Mol Endocrinol. 2013; 28(1):80-98. PMC: 5426651. DOI: 10.1210/me.2013-1203. View

17.

Kurth I, Klopocki E, Stricker S, Oosterwijk J, Vanek S, Altmann J . Duplications of noncoding elements 5' of SOX9 are associated with brachydactyly-anonychia. Nat Genet. 2009; 41(8):862-3. DOI: 10.1038/ng0809-862. View

18.

Bates B, Zhang L, Nawoschik S, Kodangattil S, Tseng E, Kopsco D . Characterization of Gpr101 expression and G-protein coupling selectivity. Brain Res. 2006; 1087(1):1-14. DOI: 10.1016/j.brainres.2006.02.123. View

19.

de Herder W . Acromegaly and gigantism in the medical literature. Case descriptions in the era before and the early years after the initial publication of Pierre Marie (1886). Pituitary. 2008; 12(3):236-44. PMC: 2712620. DOI: 10.1007/s11102-008-0138-y. View

20.

Lee D, Nguyen T, Lynch K, Cheng R, Vanti W, Arkhitko O . Discovery and mapping of ten novel G protein-coupled receptor genes. Gene. 2001; 275(1):83-91. DOI: 10.1016/s0378-1119(01)00651-5. View