title: Mutations of the GREAT gene cause cryptorchidism.
abstract: In humans, failure of testicular descent (cryptorchidism) is one of the most frequent congenital malformations, affecting 1-3% of newborn boys. The clinical consequences of this abnormality are infertility in adulthood and a significantly increased risk of testicular malignancy. Recently, we described a mouse transgene insertional mutation, crsp, causing high intraabdominal cryptorchidism in homozygous males. A candidate gene Great (G-protein-coupled receptor affecting testis descent), was identified within the transgene integration site. Great encodes a seven-transmembrane receptor with a close similarity to the glycoprotein hormone receptors. The Great gene is highly expressed in the gubernaculum, the ligament that controls testicular movement during development, and therefore may be responsible for mediating hormonal signals that affect testicular descent. Here we show that genetic targeting of the Great gene in mice causes infertile bilateral intraabdominal cryptorchidism. The mutant gubernaculae fail to differentiate, indicating that the Great gene controls their development. Mutation screening of the human GREAT gene was performed using DHPLC analysis of the genomic DNA from 60 cryptorchid patients. Nucleotide variations in GREAT cDNA were found in both the patient and the control populations. A unique missense mutation (T222P) in the ectodomain of the GREAT receptor was identified in one of the patients. This mutant receptor fails to respond to ligand stimulation, implicating the GREAT gene in the etiology in some cases of cryptorchidism in humans.
authors.affiliation: Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ivan P
authors.initials: IP
authors.lastname: Gorlov
authors.forename: Aparna
authors.initials: A
authors.lastname: Kamat
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Bogatcheva
authors.forename: Eric
authors.initials: E
authors.lastname: Jones
authors.forename: Dolores J
authors.initials: DJ
authors.lastname: Lamb
authors.forename: Anne
authors.initials: A
authors.lastname: Truong
authors.forename: Colin E
authors.initials: CE
authors.lastname: Bishop
authors.forename: Ken
authors.initials: K
authors.lastname: McElreavey
authors.forename: Alexander I
authors.initials: AI
authors.lastname: Agoulnik
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D015152:Blotting, Northern; D003001:Cloning, Molecular; D003456:Cryptorchidism / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D012065:Relaxin / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013737:Testis / Q000473:pathology
chemical_list: C472867:RXFP2 protein, human; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C435187:relaxin receptor 2, mouse; D012065:Relaxin