title: Functional phosphodiesterase 11A mutations may modify the risk of familial and bilateral testicular germ cell tumors.
abstract: Inactivating germline mutations in phosphodiesterase 11A (PDE11A) have been implicated in adrenal tumor susceptibility. PDE11A is highly expressed in endocrine steroidogenic tissues, especially the testis, and mice with inactivated Pde11a exhibit male infertility, a known testicular germ cell tumor (TGCT) risk factor. We sequenced the PDE11A gene-coding region in 95 patients with TGCT from 64 unrelated kindreds. We identified 8 nonsynonymous substitutions in 20 patients from 15 families: four (R52T, F258Y, G291R, and V820M) were newly recognized, three (R804H, R867G, and M878V) were functional variants previously implicated in adrenal tumor predisposition, and one (Y727C) was a known polymorphism. We compared the frequency of these variants in our patients to unrelated controls that had been screened and found negative for any endocrine diseases: only the two previously reported variants, R804H and R867G, known to be frequent in general population, were detected in these controls. The frequency of all PDE11A-gene variants (combined) was significantly higher among patients with TGCT (P = 0.0002), present in 19% of the families of our cohort. Most variants were detected in the general population, but functional studies showed that all these mutations reduced PDE activity, and that PDE11A protein expression was decreased (or absent) in TGCT samples from carriers. This is the first demonstration of the involvement of a PDE gene in TGCT, although the cyclic AMP signaling pathway has been investigated extensively in reproductive organ function and their diseases. In conclusion, we report that PDE11A-inactivating sequence variants may modify the risk of familial and bilateral TGCT.
authors: Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, 10 Center Drive, CRC, Room 1-3330, Bethesda, MD 20892, USA. horvatha@mail.nih.gov
authors: Anelia
authors: A
authors: Horvath
authors: Larissa
authors: L
authors: Korde
authors: Mark H
authors: MH
authors: Greene
authors: Rossella
authors: R
authors: Libe
authors: Paulo
authors: P
authors: Osorio
authors: Fabio Rueda
authors: FR
authors: Faucz
authors: Marie Laure
authors: ML
authors: Raffin-Sanson
authors: Kit Man
authors: KM
authors: Tsang
authors: Limor
authors: L
authors: Drori-Herishanu
authors: Yianna
authors: Y
authors: Patronas
authors: Elaine F
authors: EF
authors: Remmers
authors: Maria Eleni
authors: ME
authors: Nikita
authors: Jason
authors: J
authors: Moran
authors: Joseph
authors: J
authors: Greene
authors: Maria
authors: M
authors: Nesterova
authors: Maria
authors: M
authors: Merino
authors: Jerome
authors: J
authors: Bertherat
authors: Constantine A
authors: CA
authors: Stratakis
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002460:Cell Line; D005787:Gene Frequency; D014644:Genetic Variation; D006801:Humans; D007668:Kidney; D008297:Male; D008875:Middle Aged; D009154:Mutation; D054547:National Cancer Institute (U.S.); D009373:Neoplasms, Germ Cell and Embryonal / Q000453:epidemiology / Q000235:genetics*; D010727:Phosphoric Diester Hydrolases / Q000235:genetics*; D012307:Risk Factors; D013736:Testicular Neoplasms / Q000453:epidemiology / Q000235:genetics*; D014162:Transfection; D014481:United States; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; C406737:PDE11A protein, human