Download PDF
Semin Reprod Med 2012; 30(05): 410-416
DOI: 10.1055/s-0032-1324725
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

MAMLD1 and 46,XY Disorders of Sex Development

Tsutomu Ogata
1   Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan
,
Shinichirou Sano
1   Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan
,
Eiko Nagata
1   Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan
,
Fumiko Kato
2   Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan
,
Maki Fukami
2   Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan
› Author Affiliations
Further Information

Publication History

Publication Date:
08 October 2012 (online)

    Permissions and Reprints

Abstract

MAMLD1 (mastermind-like domain containing 1) is a recently discovered causative gene for 46,XY disorders of sex development (DSD), with hypospadias as the salient clinical phenotype. To date, microdeletions involving MAMLD1 have been identified in six patients, and definitive mutations (nonsense and frameshift mutations that are predicted to undergo nonsense mediated mRNA decay [NMD]) have been found in six patients. In addition, specific MAMLD1 cSNP(s) and haplotype may constitute a susceptibility factor for hypospadias. Furthermore, in vitro studies have revealed that (1) the mouse homolog is expressed in fetal Sertoli and Leydig cells around the critical period for sex development; (2) transient Mamld1 knockdown results in significantly reduced testosterone production primarily because of compromised 17α-hydroxylation and Cyp17a1 expression in Murine Leydig tumor cells; (3) MAMLD1 localizes to the nuclear bodies and transactivates the promoter activity of a non-canonical Notch target gene hairy/enhancer of split 3, without demonstrable DNA-binding capacity; and (4) MAMLD1 is regulated by steroidogenic factor 1 (SF1). These findings suggest that the MAMLD1 mutations cause 46,XY DSD primarily because of compromised testosterone production around the critical period for sex development. Further studies will provide useful information for the molecular network involved in fetal testosterone production.

Keywords

MAMLD1 - 46,XY DSD - hypospadias - testosterone
 

  • References

  • 1 Fukami M, Wada Y, Miyabayashi K , et al. CXorf6 is a causative gene for hypospadias. Nat Genet 2006; 38 (12) 1369-1371
    CrossrefPubMedSearch in Google Scholar
  • 2 Hu LJ, Laporte J, Kress W , et al. Deletions in Xq28 in two boys with myotubular myopathy and abnormal genital development define a new contiguous gene syndrome in a 430 kb region. Hum Mol Genet 1996; 5 (1) 139-143
    CrossrefPubMedSearch in Google Scholar
  • 3 Laporte J, Guiraud-Chaumeil C, Vincent MC , et al; ENMC International Consortium on Myotubular Myopathy. European Neuro-Muscular Center. Mutations in the MTM1 gene implicated in X-linked myotubular myopathy. Hum Mol Genet 1997; 6 (9) 1505-1511
    CrossrefPubMedSearch in Google Scholar
  • 4 Bartsch O, Kress W, Wagner A, Seemanova E. The novel contiguous gene syndrome of myotubular myopathy (MTM1), male hypogenitalism and deletion in Xq28:report of the first familial case. Cytogenet Cell Genet 1999; 85 (3–4) 310-314
    CrossrefPubMedSearch in Google Scholar
  • 5 Biancalana V, Caron O, Gallati S , et al. Characterisation of mutations in 77 patients with X-linked myotubular myopathy, including a family with a very mild phenotype. Hum Genet 2003; 112 (2) 135-142
    PubMedSearch in Google Scholar
  • 6 Laporte J, Kioschis P, Hu LJ , et al. Cloning and characterization of an alternatively spliced gene in proximal Xq28 deleted in two patients with intersexual genitalia and myotubular myopathy. Genomics 1997; 41 (3) 458-462
    CrossrefPubMedSearch in Google Scholar
  • 7 Ogata T, Laporte J, Fukami M. MAMLD1 (CXorf6): a new gene involved in hypospadias. Horm Res 2009; 71 (5) 245-252
    CrossrefPubMedSearch in Google Scholar
  • 8 Kuzmiak HA, Maquat LE. Applying nonsense-mediated mRNA decay research to the clinic: progress and challenges. Trends Mol Med 2006; 12 (7) 306-316
    CrossrefPubMedSearch in Google Scholar
  • 9 Fukami M, Wada Y, Okada M , et al. Mastermind-like domain-containing 1 (MAMLD1 or CXorf6) transactivates the Hes3 promoter, augments testosterone production, and contains the SF1 target sequence. J Biol Chem 2008; 283 (9) 5525-5532
    PubMedSearch in Google Scholar
  • 10 Tsai TC, Horinouchi H, Noguchi S , et al. Characterization of MTM1 mutations in 31 Japanese families with myotubular myopathy, including a patient carrying 240 kb deletion in Xq28 without male hypogenitalism. Neuromuscul Disord 2005; 15 (3) 245-252
    CrossrefPubMedSearch in Google Scholar
  • 11 Kalfa N, Liu B, Klein O , et al. Mutations of CXorf6 are associated with a range of severities of hypospadias. Eur J Endocrinol 2008; 159 (4) 453-458
    CrossrefPubMedSearch in Google Scholar
  • 12 Chen Y, Thai HT, Lundin J , et al. Mutational study of the MAMLD1-gene in hypospadias. Eur J Med Genet 2010; 53 (3) 122-126
    CrossrefPubMedSearch in Google Scholar
  • 13 Brandão MP, Costa EM, Fukami M , et al. MAMLD1 (mastermind-like domain containing 1) homozygous gain-of-function missense mutation causing 46,XX disorder of sex development in a virilized female. Adv Exp Med Biol 2011; 707: 129-131
    PubMedSearch in Google Scholar
  • 14 Zitzmann M. The role of the CAG repeat androgen receptor polymorphism in andrology. Front Horm Res 2009; 37: 52-61
    PubMedSearch in Google Scholar
  • 15 O'Shaughnessy PJ, Baker PJ, Monteiro A, Cassie S, Bhattacharya S, Fowler PA. Developmental changes in human fetal testicular cell numbers and messenger ribonucleic acid levels during the second trimester. J Clin Endocrinol Metab 2007; 92 (12) 4792-4801
    CrossrefPubMedSearch in Google Scholar
  • 16 Morohashi KI, Omura T. Ad4BP/SF-1, a transcription factor essential for the transcription of steroidogenic cytochrome P450 genes and for the establishment of the reproductive function. FASEB J 1996; 10 (14) 1569-1577
    PubMedSearch in Google Scholar
  • 17 Parker KL, Schimmer BP. Steroidogenic factor 1: a key determinant of endocrine development and function. Endocr Rev 1997; 18 (3) 361-377
    CrossrefPubMedSearch in Google Scholar
  • 18 Nakamura M, Fukami M, Sugawa F, Miyado M, Nonomura K, Ogata T. Mamld1 knockdown reduces testosterone production and Cyp17a1 expression in mouse Leydig tumor cells. PLoS ONE 2011; 6 (4) e19123
    CrossrefPubMedSearch in Google Scholar
  • 19 Panesar NS, Chan KW, Ho CS. Mouse Leydig tumor cells produce C-19 steroids, including testosterone. Steroids 2003; 68 (3) 245-251
    CrossrefPubMedSearch in Google Scholar
  • 20 Ascoli M, Puett D. Gonadotropin binding and stimulation of steroidogenesis in Leydig tumor cells. Proc Natl Acad Sci U S A 1978; 75 (1) 99-102
    CrossrefPubMedSearch in Google Scholar
  • 21 Rebois RV. Establishment of gonadotropin-responsive murine leydig tumor cell line. J Cell Biol 1982; 94 (1) 70-76
    CrossrefPubMedSearch in Google Scholar
  • 22 Achermann JC, Hughes IA. Disorders of sex development. In: Kronenberg HM, Melmed M, Polonsky KS, Larsen PR, , eds. Williams textbook of endocrinology. 11th editions. Philadelphia: Saunders; 2008: 783-848
    Search in Google Scholar
  • 23 Lin SE, Oyama T, Nagase T, Harigaya K, Kitagawa M. Identification of new human mastermind proteins defines a family that consists of positive regulators for notch signaling. J Biol Chem 2002; 277 (52) 50612-50620
    CrossrefPubMedSearch in Google Scholar
  • 24 Wu L, Sun T, Kobayashi K, Gao P, Griffin JD. Identification of a family of mastermind-like transcriptional coactivators for mammalian notch receptors. Mol Cell Biol 2002; 22 (21) 7688-7700
    CrossrefPubMedSearch in Google Scholar
  • 25 Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science 1999; 284 (5415) 770-776
    CrossrefPubMedSearch in Google Scholar
  • 26 Iso T, Kedes L, Hamamori Y. HES and HERP families: multiple effectors of the Notch signaling pathway. J Cell Physiol 2003; 194 (3) 237-255
    CrossrefPubMedSearch in Google Scholar
  • 27 Nam Y, Sliz P, Song L, Aster JC, Blacklow SC. Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes. Cell 2006; 124 (5) 973-983
    CrossrefPubMedSearch in Google Scholar
  • 28 Wilson JJ, Kovall RA. Crystal structure of the CSL-Notch-Mastermind ternary complex bound to DNA. Cell 2006; 124 (5) 985-996
    CrossrefPubMedSearch in Google Scholar
  • 29 Tonon G, Modi S, Wu L , et al. t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway. Nat Genet 2003; 33 (2) 208-213
    CrossrefPubMedSearch in Google Scholar
  • 30 Androutsellis-Theotokis A, Leker RR, Soldner F , et al. Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 2006; 442 (7104) 823-826
    CrossrefPubMedSearch in Google Scholar
  • 31 Ito M, Achermann JC, Jameson JL. A naturally occurring steroidogenic factor-1 mutation exhibits differential binding and activation of target genes. J Biol Chem 2000; 275 (41) 31708-31714
    CrossrefPubMedSearch in Google Scholar