Mutations of the GREAT gene cause cryptorchidism

Ivan P. Gorlov, Aparna Kamat, Natalia Bogatcheva, Eric Jones, Dolores J. Lamb, Anne Truong, Colin E. Bishop, Ken McElreavey, Alexander I. Agoulnik

Research output: Contribution to journalArticle

188 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2309-2318
Number of pages10
JournalHuman Molecular Genetics
Volume11
Issue number19
StatePublished - Sep 15 2002
Externally publishedYes

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Cryptorchidism
G-Protein-Coupled Receptors
Testis
Mutation
Genes
Transgenes
Missense Mutation
Ligaments
Infertility
Glycoproteins
Nucleotides
Complementary DNA
Newborn Infant
Hormones
Ligands
DNA
Population
Neoplasms
Proteins

ASJC Scopus subject areas

  • Genetics

Cite this

Gorlov, I. P., Kamat, A., Bogatcheva, N., Jones, E., Lamb, D. J., Truong, A., ... Agoulnik, A. I. (2002). Mutations of the GREAT gene cause cryptorchidism. Human Molecular Genetics, 11(19), 2309-2318.

Mutations of the GREAT gene cause cryptorchidism. / Gorlov, Ivan P.; Kamat, Aparna; Bogatcheva, Natalia; Jones, Eric; Lamb, Dolores J.; Truong, Anne; Bishop, Colin E.; McElreavey, Ken; Agoulnik, Alexander I.

In: Human Molecular Genetics, Vol. 11, No. 19, 15.09.2002, p. 2309-2318.

Research output: Contribution to journalArticle

Gorlov, IP, Kamat, A, Bogatcheva, N, Jones, E, Lamb, DJ, Truong, A, Bishop, CE, McElreavey, K & Agoulnik, AI 2002, 'Mutations of the GREAT gene cause cryptorchidism', Human Molecular Genetics, vol. 11, no. 19, pp. 2309-2318.
Gorlov IP, Kamat A, Bogatcheva N, Jones E, Lamb DJ, Truong A et al. Mutations of the GREAT gene cause cryptorchidism. Human Molecular Genetics. 2002 Sep 15;11(19):2309-2318.
Gorlov, Ivan P. ; Kamat, Aparna ; Bogatcheva, Natalia ; Jones, Eric ; Lamb, Dolores J. ; Truong, Anne ; Bishop, Colin E. ; McElreavey, Ken ; Agoulnik, Alexander I. / Mutations of the GREAT gene cause cryptorchidism. In: Human Molecular Genetics. 2002 ; Vol. 11, No. 19. pp. 2309-2318.
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