臨床泌尿器科65巻12号

2011年11月発行

特集 専門医のための性分化疾患講座

ここまで明らかになっている性分化疾患の遺伝子異常

著者： 水野健太郎¹ 神沢英幸¹ 西尾英紀¹ 林祐太郎¹

所属機関： ¹名古屋市立大学大学院医学研究科腎・泌尿器科学分野

ページ範囲：P.911 - P.918

文献概要

要旨　性分化にかかわる遺伝子群について理解を深めることは，性分化疾患（性分化異常症）に適切に対応し，診断・治療を行ううえで必要不可欠と考えられる。SRY遺伝子をはじめ，性分化にかかわる遺伝子群が同定され，転写調節機構についての研究が行われているが，いまだその全容は明らかにされていない。本稿では，生殖細胞の選別過程をはじめ，これまで明らかにされてきた性分化メカニズムを概説するとともに，遺伝子異常と性分化疾患とのかかわりについても言及した。また，広義の性分化疾患ともいえるであろう，尿道下裂および停留精巣についても，その病態メカニズムと疾患関連遺伝子について最新の知見を紹介する。

参考文献

1）Tam PP and Zhou SX：The allocation of epiblast cells to ectodermal and germ-line lineages is influenced by the position of the cells in the gastrulating mouse embryo. Dev Biol 178：124-132, 1996

2）Lawson KA, Dunn NR, Roelen BA, et al：Bmp4 is required for the generation of primordial germ cells in the mouse embryo. Genes Dev 13：424-436, 1999

3）Ying Y, Liu XM, Marble A, et al：Requirement of Bmp8b for the generation of primordial germ cells in the mouse. Mol Endocrinol 14：1053-1063, 2000

4）Ying Y and Zhao GQ：Cooperation of endoderm-derived BMP2 and extraembryonic ectoderm-derived BMP4 in primordial germ cell generation in the mouse. Dev Biol 232：484-492, 2001

5）de Sousa Lopes SM, Roelen BA, Monteiro RM, et al：BMP signaling mediated by ALK2 in the visceral endoderm is necessary for the generation of primordial germ cells in the mouse embryo. Genes Dev 18：1838-1849, 2004

6）Kashimada K and Koopman P：Sry：the master switch in mammalian sex determination. Development 137：3921-3930, 2010

7）Ohinata Y, Payer B, O'Carroll D, et al：Blimp1 is a critical determinant of the germ cell lineage in mice. Nature 436：207-213, 2005

8）Yamaji M, Seki Y, Kurimoto K, et al：Critical function of Prdm14 for the establishment of the germ cell lineage in mice. Nat Genet 40：1016-1022, 2008

9）Hayashi K, de Sousa Lopes SM and Surani MA：Germ cell specification in mice. Science 316：394-396, 2007

. PNAS 100：11457-11462, 2003

11）Geijsen N, Horoschak M, Kim K, et al：Derivation of embryonic germ cells and male gametes from embryonic stem cells. Nature 427：148-154, 2004

12）Mizuno K, Tokumasu A, Nakamura A, et al：Genes associated with the formation of germ cells from embryonic stem cells in cultures containing different glucose concentrations. Mol Reprod Dev 73：437-445, 2006

13）Koopman P, Gubbay J, Vivian N, et al：Male development of chromosomally female mice transgenic for Sry. Nature 351：117-121, 1991

14）Colvin JS, Green RP, Schmahl J, et al：Male-to-female sex reversal in mice lacking fibroblast growth factor 9. Cell 104：875-889, 2001

15）Kim Y, Kobayashi A, Sekido R, et al：Fgf9 and Wnt4 act as antagonistic signals to regulate mammalian sex determination. PLoS Biol 4：e187, 2006

16）Chassot AA, Gregoire EP, Magliano M, et al：Genetics of ovarian differentiation：Rspo1, a major player. Sex Dev 2：219-227, 2008

17）Kojima Y, Hayashi Y, Mizuno K, et al：Up-regulation of SOX9 in human sex-determining region on the Y chromosome（SRY）-negative XX males. Clin Endocrinol（Oxf） 68：791-799, 2008

18）Morohashi K, Honda S, Inomata Y, et al：A common trans-acting factor, Ad4-binding protein, to the promoters of steroidogenic P-450s. J Biol Chem 267：17913-17919, 1992

19）Majdic G, Young M, Gomez-Sanchez E, et al：Knockout mice lacking steroidogenic factor 1 are a novel genetic model of hypothalamic obesity. Endocrinology 143：607-614, 2002

20）Zanaria E, Muscatelli F, Bardoni B, et al：An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita. Nature 372：635-641, 1994

21）Bouma GJ, Albrecht KH, Washburn LL, et al：Gonadal sex reversal in mutant Dax1 XY mice：a failure to upregulate Sox9 in pre-Sertoli cells. Development 132：3045-3054, 2005

22）Gao F, Maiti S, Alam N, et al：The Wilms tumor gene, Wt1, is required for Sox9 expression and maintenance of tubular architecture in the developing testis. PNAS 103：11987-11992, 2006

23）Chang H, Gao F, Guillou F, et al：Wt1 negatively regulates beta-catenin signaling during testis development. Development 135：1875-1885, 2008

24）Domenice S, Corrêa RV, Costa EM, et al：Mutations in the SRY, DAX1, SF1 and WNT4 genes in Brazilian sex-reversed patients. Braz J Med Biol Res 37：145-150, 2004

25）Köhler B, Biebermann H, Friedsam V, et al：Analysis of the wilms' tumor suppressor gene（WT1）in patients 46, XY disorders of sex development. J Clin Endocrinol Metab 96：E1131-1136, 2011［Epub］

26）White S, Ohnesorg T, Notini A, et al：Copy number variation in patients with disorders of sex development due to 46, XY gonadal dysgenesis. PLoS One 6：e17793, 2011

27）Kojima Y, Kohri K and Hayashi Y：Genetic pathway of external genitalia formation and molecular etiology of hypospadias. J Pediatr Urol 6：346-354, 2010

28）Hayashi Y, Mizuno K, Kojima Y, et al：Characterization of the urethral plate and the underlying tissue defined by expression of collagen subtypes and microarchitecture in hypospadias. Int J Urol, 2011［Epub ahead of print］

29）Fukami M, Wada Y, Miyabayashi K, et al：CXorf6 is a causative gene for hypospadias. Nat Genet 38：1369-1371, 2006

30）Willingham E and Baskin LS：Candidate genes and their response to environmental agents in the etiology of hypospadias. Nat Clin Pract Urol 4：270-279, 2007

31）Kojima Y, Hayashi Y, Mizuno K, et al：Spermatogenesis, fertility and sexual behavior in a hypospadiac mouse model. J Urol 167：1532-1537, 2002

32）Uda A, Kojima Y, Hayashi Y, et al：Morphological features of external genitalia in hypospadiac rat model：3-dimensional analysis. J Urol 171：1362-1366, 2004

33）Watanabe M, Yoshida R, Ueoka K, et al：Haplotype analysis of the estrogen receptor 1 gene in male genital and reproductive abnormalities. Hum Reprod 22：1279-1284, 2007

34）Kojima Y, Mizuno K, Kohri K, et al：Advances in molecular genetics of cryptorchidism. Urology 74：571-578, 2009

35）Mizuno K, Hayashi Y, Kojima Y, et al：Influence for testicular development and histological peculiarity in the testes of flutamide-induced cryptorchid rat model. Int J Urol 14：67-72, 2007

36）Mizuno K, Hayashi Y, Kojima Y, et al：Activation of NF-kappaB associated with germ cell apoptosis in testes of experimentally induced cryptorchid rat model. Urology 73：389-393, 2009

37）Mizuno K, Kojima Y, Kurokawa S, et al：Altered expression and localization of estrogen receptors alpha and beta in the testes of a cryptorchid rat model. Urology 77：251. e1-6, 2011

38）Mizuno K, Hayashi Y, Kojima Y, et al：Early orchiopexy improves subsequent testicular development and spermatogenesis in the experimental cryptorchid rat model. J Urol 179：1195-1199, 2008

39）Kamisawa H, Kojima Y, Mizuno K, et al：Spermatogenesis after 1-stage fowler-stephens orchiopexy in experimental cryptorchid rat model. J Urol 183：2380-2384, 2010

40）Kurokawa S, Kojima Y, Mizuno K, et al：Effect of epidermal growth factor on spermatogenesis in the cryptorchid rat. J Urol 174：2415-2419, 2005

41）Kojima Y, Hayashi Y, Mizuno K, et al：Assessment of serum follicle-stimulating hormone level and testicular volume for prediction of paternity potential in pubertal boys who underwent bilateral orchiopexy in childhood. J Urol 175：2290-2294, 2006

42）Mizuno K, Kojima Y, Kurokawa S, et al：Identification of differentially expressed genes in human cryptorchid testes using suppression subtractive hybridization. J Urol 181：1330-1337；discussion 1337, 2009

43）Kojima Y, Kurokawa S, Mizuno K, et al：Gene transfer to sperm and testis：future prospects of gene therapy for male infertility. Curr Gene Ther 8：121-134, 2008