Opitz syndrome (OS) is an inherited disorder characterized by midline defects including hypertelorism, hypospadias, lip-palate-laryngotracheal clefts and imperforate anus. We have identified a new gene on Xp22f MIDI (Midline 1), which is disrupted in an OS patient carrying an X-chromosome inversion and is also mutated in several OS families. MID1 encodes a member of the B-box family of proteins, which contain protein–protein interaction domains, including a RING finger, and are implicated in fundamental processes such as body axis patterning and control of cell proliferation. The association of MID1 with OS suggests an important role for this gene in midline development.

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  1. 1

    Opitz, J.M., Summitt, R.L. & Smith, D.W. The BBB syndrome familial telecanthus with associated congenital anomalies. Birth Defects Orig. Art. Ser. (V)2, 86–94 (1969).

  2. 2

    Opitz, J.M., Frias, J.L., Guttenberger, J.E. & Pellet, J.R. The G syndrome of multiple congenital anomalies. Birth Defects Orig. Art. Ser. (V)2, 95–102 (1969).

  3. 3

    Opitz, J.M. G syndrome (hypertelorism with esophageal abnormality and hypospadias, or hypospadias-dysphagia, or ‘Opitz-Frias’ or ‘Opitz-G’ syndrome): perspective in 1987 and bibliography. Am. J. Med. Genet. 28, 275–285 (1987).

  4. 4

    Robin, N.H., Opitz, J.M. & Muenke, M. Opitz G/BBB syndrome: clinical comparisons of families linked to Xp22 and 22q, and a review of the literature. Am. J. Med. Genet. 62, 305–317 (1996).

  5. 5

    Bershof, J.F., Guyuron, B. & Olsen, M.M. G syndrome: a review of the literature and a case report. J. Craniomaxillofac. Surg. 20, 24–27 (1992).

  6. 6

    Cappa, M., Borrelli, P., Marini, R. & Neri, G., Opitz syndrome: a new designation for the clinically indistinguishable BBB and G syndromes. Am. J. Med. Genet. 28, 303–309 (1987).

  7. 7

    Cordero, J.F. & Holmes, L.B. Phenotypic overlap of the BBB and G syndromes. Am. J. Med. Genet. 2, 145–152 (1978).

  8. 8

    Farndon, P.A. & Donnai, D. Male-to-male transmission of the G syndrome. Clin. Genet. 23, 446–448 (1983).

  9. 9

    Fryns, J.P., Delooz, J. & van den Berghe, H. Posterior scalp defects in Opitz syndrome: another symptom related to a defect in midline development. Clin. Genet. 42, 314–316 (1992).

  10. 10

    Guion-Almeida, M.L. & Richieri-Costa, A. CMS midline anomalies in the Opitz G/BBB syndrome: report on 12 Brazilian patients. Am. J. Med. Genet. 43, 918–928 (1992).

  11. 11

    Howell, L & Smith, J.D. G syndrome and its otolaryngological manifestations. Ann. Otol. Rhinol. Laryngol. 98, 185–190 (1989).

  12. 12

    MacDonald, M.R., Schaefer, G.B., Olney, A.M., Tamayo, M. & Frias, J.L. Brain magnetic resonance imaging findings in the Opitz G/BBB syndrome: extension of the spectrum of midline brain anomalies. Am. J. Med. Genet. 46, 706–711 (1993).

  13. 13

    Sedano, H.O. & Gorlin, R.J. Opitz oculo-genital-laryngeal syndrome (Opitz BBB/G compound syndrome). Am. J. Med. Genet. 30, 847–849 (1988).

  14. 14

    Stevens, C.A. & Wilroy, R.S. Jr., The telecanthus-hypospadias syndrome. J. Med. Genet. 25, 536–542 (1988).

  15. 15

    Tolmie, J.L., Coutts, N. & Drainer, I.K. Congenital anal anomalies in two families with the Opitz G syndrome. J. Med. Genet. 24, 688–691 (1987).

  16. 16

    Verloes, A., Le Merrer, M. & Briard, M.-L. BBBG syndrome or Opitz syndrome: new family. Am. J. Med. Genet. 34, 313–316 (1989).

  17. 17

    Robin, N.H. et al. Opitz syndrome is genetically heterogeneous, with one locus on Xp22, and a second locus on 22q11.2. Nature Genet. 11, 459–461 (1995).

  18. 18

    May, M., Huston, S., Wilroy, R.S. & Schwartz, C., Linkage analysis in a family with the Opitz GBBB syndrome refines the location of the gene in Xp22 to a 4 cM region. Am. J. Med. Genet. 68, 244–248 (1997).

  19. 19

    Verloes, A. et al. Opitz GBBB syndrome: chromosomal evidence of an X-linked form. Am. J. Med. Genet. 59, 123–128 (1995).

  20. 20

    Ferrero, G.B. et al. An integrated physical and genetic map of a 35 Mb region on chromosome Xp22.3–Xp21.3. Hum. Mol. Genet. 4, 1821–1827 (1995).

  21. 21

    Wapenaar, M.C. et al. The genes for X-linked ocular albinism (OA1) and microphthalmia with linear skin defects (MLS): cloning and characterization of the critical regions. Hum. Mol. Genet. 2, 947–952 (1993).

  22. 22

    Miller, M. et al. The nuclear-cytoplasmic distribution of the Xenopus nuclearfactor, xnf7, coincides with its state of phosphorylation during early development. Development 113, 569–575 (1991).

  23. 23

    Li, X. & Etkin, L.D. Xenopus nuclear factor 7 (xnf7) possesses an NLS that functions efficiently in both oocytes and embryos. J. Cell Sci. 105, 389–395 (1993).

  24. 24

    Li, X., Shou, W., Kloc, M., Reddy, B.A. & Etkin, L.D. Cytoplasmic retention of Xenopus nuclear factor 7 before the mid blastula transition uses a unique anchoring mechanism involving a retention domain and several phosphorylation sites. J. Cell Biol. 124, 7–17 (1994).

  25. 25

    Shou, W. et al. Finely tuned regulation of cytoplasmic retention of Xenopus nuclear factor 7 by phosphorylation of individual threonine residues. Mol. Cell. Biol. 16, 990–997 (1996).

  26. 26

    de The, H. et al. The PML-RARα fusion mRNA generated by t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. Cell 66, 675–684 (1991).

  27. 27

    Grignani, F. et al. Acute promyelocytic leukemia: from genetics to treatment. Blood 83, 10–25 (1994).

  28. 28

    Wapenaar, M.C. et al. A YAC-based binning strategy facilitating the rapid assembly of cosmid contigs: 1.6 Mb of overlapping cosmids in Xp22. Hum. Mol. Genet. 3, 1155–1161 (1994).

  29. 29

    Schuler, G.D. et al. A gene map of the human genome. Science 274, 540–546 (1996).

  30. 30

    Kozak, M. Compilation and analysis of sequences upstream from the translational start site in eukaryotic mRNAs. Nucleic Adds Res. 12, 857–873 (1984).

  31. 31

    Johnston, K. et al. De novo X;Y translocation associated with imperforate anus and retinal pigmentary abnormalities. Am. J. Med. Genet. 27, 603–611 (1987).

  32. 32

    Borden, K.L.B. et al. Characterisation of a novel cysteine/histidine-rich metal binding domain from Xenopus nuclear factor XNF7. FEBS Lett. 335, 255–260 (1993).

  33. 33

    Mather, I.H. & Jack, L.J. A review of the molecular and cellular biology of butyrophilin, the major protein of bovine milk fat globule membrane. J. Dairy Sci. 76, 3832–3850 (1993).

  34. 34

    Borden, K.L.B. & Freemont, P.S. The RING finger domain: a recent example of a sequence-structure family. Curr. Opin. Struct. Biol. 6, 395–401 (1996).

  35. 35

    Borden, K.L.B. et al. In viv and in vitro characterization of the B1 and B2 zinc-binding domains from the acute promyelocytic leukemia protooncoprotein PML Proc. Natl. Acad. Sci. USA 93, 1601–1606 (1996).

  36. 36

    Takahashi, M., Inaguma, Y., Hiai, H. & Hirose, F. Developmentally regulated expression of a human “finger”-containing gene encoded by the 5′ half of the ret transforming gene. Mol. Cell. Biol. 8, 1853–1856 (1988).

  37. 37

    LeDouarin, B. et al. The N-terminal part of TIF1, a putative mediator of the ligand-dependent activation function (AF-2) of nuclear receptors, is fused to B-raf in the oncogenic protein T18. EMBO J. 14, 2020–2033 (1995).

  38. 38

    Reddy, B.A., Kloc, M. & Etkin, L. The cloning and characterization of a maternally expressed novel zinc finger nuclear phosphoprotein (xnf7) in Xenopus laevis. Dev. Biol. 148, 107–116 (1991).

  39. 39

    Patarca, R. et al., rpt-1, an intracellular protein from helper/inducer T cells that regulates gene expression of interleukin 2 receptor and human immunodeficiency virus type 1. Proc. Natl. Acad. Sci. USA 85, 2733–2737 (1988).

  40. 40

    Inoue, S. et al. Genomic binding-site cloning reveals an estrogen-responsive gene that encodes a RING finger protein. Proc. Natl. Acad. Sci. USA 90, 11117–11121 (1993).

  41. 41

    Bellini, M., Lacroix, J.-C. & Gall, J.G. A putative zinc-binding protein on lampbrush chromosome loops. EMBO J. 12, 107–114 (1993).

  42. 42

    Chan, E.K.L, Hamel, J.C., Buyon, J.P .& Tan, E.M. Molecular definition and sequence motifs of the 52-kD component of human SS-A/Ro autoantigen. J. Clin. Invest. 87, 68–76 (1991).

  43. 43

    Ishii, T. et al. Carboxy-terminal cytoplasmic domain of mouse butyrophilin specifically associates with a 150-kDa protein of mammary epithelial cells and milk fat globule membrane. Biochim. Biophys. Acta. 1245, 285–292 (1995).

  44. 44

    al-Gazali, L.I. et al.Two 46,XX,t(X;Y) females with linear skin defects and congenital microphthalmia: a new syndrome at Xp22.3. J. Med. Genet. 27, 59–63 (1990).

  45. 45

    Temple, I.K., Hurst, J.A., Hing, S., Butler, L. & Baraitser, M. De novo deletion of Xp22. 2-pter in a female with linear skin lesions of the face and neck, microphthalmia, and anterior chamber eye anomalies. J. Med. Genet. 27, 56–58 (1990).

  46. 46

    Bird, L.M., Krous, H.F., Eichenfield, L.F., Swalwell, C.I. & Jones, M.C. Female infant with oncocytic cardiomyopathy and microphthalmia with linear skin defects (MLS): a clue to the pathogenesis of oncocytic cardiomyopathy? Am. J. Med. Genet. 53, 141–148 (1994).

  47. 47

    Lindsay, E.A. et al. Microphthalmia with linear skin defects (MLS) syndrome: clinical, cytogenetic and molecular characterization. Am. J. Med. Genet. 49, 229–234 (1994).

  48. 48

    Vortkamp, A., Gessler, M. & Grzeschik, K.-H. GLI3 zinc-finger gene interrupted by translocations in Greig syndrome families. Nature 352, 539–540 (1991).

  49. 49

    Marigo, V., Johnson, R.L., Vortkamp, A. & Tabin, C.J. Sonic hedgehog differentially regulates expression of GLI and GLI3 during limb development. Dev. Biol. 180, 273–283 (1996).

  50. 50

    Hammerschmidt, M., Brook, A. & McMahon, A.P. The world according to hedgehog. Trends Genet. 13, 14–21 (1997).

  51. 51

    Belloni, E. et al. Identification of Sonic hedgehog as a candidate gene responsible for holoprosencephaly. Nature Genet. 14, 353–356 (1996).

  52. 52

    Roessler, E. et al. Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nature Genet. 14, 357–360 (1996).

  53. 53

    Banfi, S. et al. Identification and mapping of human cDNAs homologous to Drosophila mutant genes through EST database searching. Nature Genet. 13, 167–174 (1996).

  54. 54

    Bailey, T.L. & Elkan, C. Fitting a mixture model by expectation maximization to discover motifs in biopolymers. Second International Conference on Intelligent Systems for Molecular Biology 28–36 (AAAI Press, Menlo Park, California, 1994).

  55. 55

    Lupas, A., Van Dyke, M. & Stock, J. Predicting coiled coils from protein sequences. Science 252, 1162–1164 (1991).

  56. 56

    Maniatis, T., Fritsch, E.S. & Sambrook, J. Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, 1982).

  57. 57

    Franco, B. et al. A cluster of sulfatase genes on Xp22.3: mutations in chondrodysplasia punctata (CDPX) and implications for warfarin embryopathy. Cell 81, 15–25 (1995).

  58. 58

    Riddle, R.D., Johnson, R.L., Laufer, E. & Tabin, C. Sonic hedgehog mediates the polarizing activity of the ZPA. Cell 75, 1401–1416 (1993).

  59. 59

    Orita, M., Iwahana, H., Kanazawa, H., Hayashi, K. & Sekiya, T. Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc. Natl. Acad. Sci. USA 86, 2766–2770 (1989).

  60. 60

    Schaefer, L. et al. A high resolution deletion map of human chromosome Xp22. Nature Genet. 4, 272–279 (1993).

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  1. Telethon Institute of Genetics and Medicine (TIGEM), San Raffaele Biomedical Science Park, 20132, Milan, Italy

    • Nandita A. Quaderi
    • , Brunella Franco
    • , Elena I. Rugarli
    • , Manuela Volta
    • , Grazia Andolfi
    •  & Andrea Ballabio
  2. Max Planck Institute for Molecular Genetics, 14195, Berlin, Germany

    • Susann Schweiger
    • , Wolfgang Berger
    •  & Hilger H. Ropers
  3. The Children's Hospital of Philadelphia, Division of Human Genetics and Molecular Biology, Departments of Pediatrics and Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104–4399, USA

    • Karin Gaudenz
    • , George J. Feldman
    •  & Maximilian Muenke
  4. Nancy, France

    • S. Gilgenkrantz
  5. Department of Pediatrics, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York, 10467–2401, USA

    • Robert W. Marion
  6. Institute of Human Genetics, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands

    • Raoul C.M. Hennekam
  7. Department of Pediatrics, Human Genetics and Obstetrics & Gynecology, University of Utah, Salt Lake City, Utah, 84132, USA

    • John M. Opitz
  8. Department of Human Genetics, University of Nijmegen, 6500 HB, Nijmegen, The Netherlands

    • Hilger H. Ropers


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