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Gene Review

MID1  -  midline 1

Homo sapiens

Synonyms: BBBG1, E3 ubiquitin-protein ligase Midline-1, FXY, GBBB1, MIDIN, ...
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Disease relevance of MID1


Psychiatry related information on MID1


High impact information on MID1


Chemical compound and disease context of MID1

  • Neuropathological examination of animals killed by perfusion-fixation after 24 hours revealed fewer pentobarbital-treated animals with shift of midline structures and with ipsilateral ischemic damage (including infarction) [15].
  • Afferents excited by a movement of the receptor apodeme that is equivalent to an imposed extension of the femorotibial joint excite flexor tibiae motor neurons and some spiking local interneurons with cell bodies at the ventral midline of the metathoracic ganglion [16].
  • Antineutrophil cytoplasmic antibodies reacting with human neutrophil elastase as a diagnostic marker for cocaine-induced midline destructive lesions but not autoimmune vasculitis [17].
  • A 51-year-old man with midline granuloma was treated successfully with a combination of local radiation and oral cyclophosphamide [18].
  • Midline shift, ventricular compression, edema, enhancement intensity, and the size of the enhancing mass often improved with steroid treatment [19].

Biological context of MID1

  • We show that mutation of MID1 leads to a marked accumulation of the catalytic subunit of protein phosphatase 2A (PP2Ac), a central cellular regulator [20].
  • Here we have determined the complete gene structure of the MID1 gene and have analyzed all nine exons for mutations in a set of 40 unrelated Opitz G/BBB patients [21].
  • Opitz G/BBB syndrome in Xp22: mutations in the MID1 gene cluster in the carboxy-terminal domain [21].
  • These new data and the finding of linkage to MID1 in the absence of a demonstrable open reading frame mutation in a further family support the conclusion that X-linked OS results from loss of function of MID1 [22].
  • The Opitz syndrome gene MID1 is essential for establishing asymmetric gene expression in Hensen's node [23].

Anatomical context of MID1

  • A protein highly related to MID1, called MID2, has also been described that similarly associates with microtubules [24].
  • Ventral midline cells at different rostrocaudal levels of the central nervous system exhibit distinct properties but share the ability to pattern the dorsoventral axis of the neural tube [25].
  • Signals from prechordal mesoderm control the differentiation of rostral diencephalic ventral midline cells, whereas notochord induces floor plate cells caudally [25].
  • We show here that ventral midline cells acquire distinct identities in response to the different signaling activities of underlying mesoderm [25].
  • Retinal ganglion cell (RGC) axons grow towards the diencephalic ventral midline during embryogenesis guided by cues whose nature is largely unknown [26].

Associations of MID1 with chemical compounds

  • We randomly assigned 50 adults with symptomatic chronic posterior anal fissures to receive treatment with either a total of 20 U of botulinum toxin injected into the internal anal sphincter on each side of the anterior midline or 0.2 percent nitroglycerin ointment applied twice daily for six weeks [27].
  • The importance of this interactive signaling is illustrated by the action of glial transcription factors and of glial axon guidance cues such as netrin and slit, which together regulate the commissural crossing of pioneer axons at the neural midline [28].
  • In the grasshopper CNS, serotonergic growth cones cross the midline early in development and initiate expression of serotonin uptake activity, or SERT [29].
  • We conclude that buildup of pre-cholesterol sterol intermediates interferes with midline fusion of facial structures in mice [30].
  • RESULTS: From the neutral to the cigarette cue scan, heavy smokers had greater increases than nonsmoking controls in relative glucose metabolism in the perigenual anterior cingulate gyrus spanning the midline [31].

Enzymatic interactions of MID1


Regulatory relationships of MID1

  • FGF8 beads can induce midline properties (e.g. a sulcus) and can modulate the specification and differentiation of adjacent tissues [33].
  • Sonic hedgehog (SHH) is expressed throughout axial mesoderm and is required for the induction of both rostral diencephalic ventral midline cells and floor plate [25].
  • The rhombic lip and ventral midline express Slit2 and both early and late migrants are repelled by sources of Slit2 in co-culture [34].
  • Drosophila center divider gene is expressed in CNS midline cells and encodes a developmentally regulated protein kinase orthologous to human TESK1 [35].
  • Blissful state was accompanied by increased anterior frontal and midline theta synchronization as well as enhanced theta long-distant connectivity between prefrontal and posterior association cortex with distinct "center of gravity" in the left prefrontal region (AF3 site) [36].

Other interactions of MID1

  • Together, these data suggest that midin and MID2 have a similar biochemical function but a different physiological role during development [37].
  • Altered expression of Alpha 4, through either a change in translational efficiency, mRNA stability or splicing, could explain the clinical phenotype in these boys and the phenotypic overlap with Opitz GBBB syndrome [38].
  • These searches revealed a fusion transcript containing the LTR of an HERV-E element linked to the Opitz syndrome gene Mid1 [39].
  • Cooperation of BMP7 and SHH in the induction of forebrain ventral midline cells by prechordal mesoderm [25].
  • This study confirms the genetic heterogeneity of HPE, and further demonstrates that SHH mutations are associated with a broad spectrum of cerebral midline defects [40].

Analytical, diagnostic and therapeutic context of MID1

  • Immunoprecipitation experiments demonstrated the ability of the tripartite motif to mediate midin homodimerization, consistent with the evidence, obtained by gel filtration analysis, that midin exists in the form of large protein complexes [41].
  • These data suggest that this conserved domain of the B-box proteins may play a fundamental role in the pathogenesis of Opitz syndrome and in morphogenetic events at the midline during blastogenesis [21].
  • In situ hybridization in mouse embryos demonstrates dorsal midline staining and staining of the aorto-gonadal-mesonephric region, which is known to host vascular precursor cells [42].
  • The tumors of nine patients with carcinomas of uncertain histogenesis (eight with poorly differentiated carcinomas involving primarily midline structures and one with a diagnosis of seminoma and atypical clinical features) were studied by cytogenetic and Southern blot analyses [43].
  • BACKGROUND: Wound complications that occur after closure of midline laparotomy remain challenging [44].


  1. Opitz G/BBB syndrome, a defect of midline development, is due to mutations in a new RING finger gene on Xp22. Quaderi, N.A., Schweiger, S., Gaudenz, K., Franco, B., Rugarli, E.I., Berger, W., Feldman, G.J., Volta, M., Andolfi, G., Gilgenkrantz, S., Marion, R.W., Hennekam, R.C., Opitz, J.M., Muenke, M., Ropers, H.H., Ballabio, A. Nat. Genet. (1997) [Pubmed]
  2. FXY2/MID2, a gene related to the X-linked Opitz syndrome gene FXY/MID1, maps to Xq22 and encodes a FNIII domain-containing protein that associates with microtubules. Perry, J., Short, K.M., Romer, J.T., Swift, S., Cox, T.C., Ashworth, A. Genomics (1999) [Pubmed]
  3. X-linked Opitz syndrome: novel mutations in the MID1 gene and redefinition of the clinical spectrum. De Falco, F., Cainarca, S., Andolfi, G., Ferrentino, R., Berti, C., Rodríguez Criado, G., Rittinger, O., Dennis, N., Odent, S., Rastogi, A., Liebelt, J., Chitayat, D., Winter, R., Jawanda, H., Ballabio, A., Franco, B., Meroni, G. Am. J. Med. Genet. A (2003) [Pubmed]
  4. The Opitz syndrome gene product, MID1, associates with microtubules. Schweiger, S., Foerster, J., Lehmann, T., Suckow, V., Muller, Y.A., Walter, G., Davies, T., Porter, H., van Bokhoven, H., Lunt, P.W., Traub, P., Ropers, H.H. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  5. Phosphorylation and microtubule association of the Opitz syndrome protein mid-1 is regulated by protein phosphatase 2A via binding to the regulatory subunit alpha 4. Liu, J., Prickett, T.D., Elliott, E., Meroni, G., Brautigan, D.L. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  6. The role of the floor plate in axon guidance. Colamarino, S.A., Tessier-Lavigne, M. Annu. Rev. Neurosci. (1995) [Pubmed]
  7. Species-typical behavior of hamsters deprived from birth of the neocortex. Murphy, M.R., MacLean, P.D., Hamilton, S.C. Science (1981) [Pubmed]
  8. Microdeletion of LIT1 in familial Beckwith-Wiedemann syndrome. Niemitz, E.L., DeBaun, M.R., Fallon, J., Murakami, K., Kugoh, H., Oshimura, M., Feinberg, A.P. Am. J. Hum. Genet. (2004) [Pubmed]
  9. Equivalent forgetting rates in long-term memory for diencephalic and medial temporal lobe amnesia. McKee, R.D., Squire, L.R. J. Neurosci. (1992) [Pubmed]
  10. Volition to action--an event-related fMRI study. Winterer, G., Adams, C.M., Jones, D.W., Knutson, B. Neuroimage (2002) [Pubmed]
  11. Architecture of the optic chiasm and the mechanisms that sculpt its development. Jeffery, G. Physiol. Rev. (2001) [Pubmed]
  12. SOX3 is required during the formation of the hypothalamo-pituitary axis. Rizzoti, K., Brunelli, S., Carmignac, D., Thomas, P.Q., Robinson, I.C., Lovell-Badge, R. Nat. Genet. (2004) [Pubmed]
  13. Mutations in the polyglutamine binding protein 1 gene cause X-linked mental retardation. Kalscheuer, V.M., Freude, K., Musante, L., Jensen, L.R., Yntema, H.G., Gécz, J., Sefiani, A., Hoffmann, K., Moser, B., Haas, S., Gurok, U., Haesler, S., Aranda, B., Nshedjan, A., Tzschach, A., Hartmann, N., Roloff, T.C., Shoichet, S., Hagens, O., Tao, J., Van Bokhoven, H., Turner, G., Chelly, J., Moraine, C., Fryns, J.P., Nuber, U., Hoeltzenbein, M., Scharff, C., Scherthan, H., Lenzner, S., Hamel, B.C., Schweiger, S., Ropers, H.H. Nat. Genet. (2003) [Pubmed]
  14. Loss of the SKI proto-oncogene in individuals affected with 1p36 deletion syndrome is predicted by strain-dependent defects in Ski-/- mice. Colmenares, C., Heilstedt, H.A., Shaffer, L.G., Schwartz, S., Berk, M., Murray, J.C., Stavnezer, E. Nat. Genet. (2002) [Pubmed]
  15. Delayed pentobarbital administration limits ischemic brain damage in gerbils. Levy, D.E., Brierley, J.B. Ann. Neurol. (1979) [Pubmed]
  16. Parallel processing of proprioceptive signals by spiking local interneurons and motor neurons in the locust. Burrows, M. J. Neurosci. (1987) [Pubmed]
  17. Antineutrophil cytoplasmic antibodies reacting with human neutrophil elastase as a diagnostic marker for cocaine-induced midline destructive lesions but not autoimmune vasculitis. Wiesner, O., Russell, K.A., Lee, A.S., Jenne, D.E., Trimarchi, M., Gregorini, G., Specks, U. Arthritis Rheum. (2004) [Pubmed]
  18. Adenocarcinoma developing in a patient with midline granuloma. Meyer, T.J., Stanford, R.E., Pearlman, N. Arch. Intern. Med. (1983) [Pubmed]
  19. Steroid-induced CT changes in patients with recurrent malignant glioma. Cairncross, J.G., Macdonald, D.R., Pexman, J.H., Ives, F.J. Neurology (1988) [Pubmed]
  20. MID1, mutated in Opitz syndrome, encodes an ubiquitin ligase that targets phosphatase 2A for degradation. Trockenbacher, A., Suckow, V., Foerster, J., Winter, J., Krauss, S., Ropers, H.H., Schneider, R., Schweiger, S. Nat. Genet. (2001) [Pubmed]
  21. Opitz G/BBB syndrome in Xp22: mutations in the MID1 gene cluster in the carboxy-terminal domain. Gaudenz, K., Roessler, E., Quaderi, N., Franco, B., Feldman, G., Gasser, D.L., Wittwer, B., Horst, J., Montini, E., Opitz, J.M., Ballabio, A., Muenke, M. Am. J. Hum. Genet. (1998) [Pubmed]
  22. New mutations in MID1 provide support for loss of function as the cause of X-linked Opitz syndrome. Cox, T.C., Allen, L.R., Cox, L.L., Hopwood, B., Goodwin, B., Haan, E., Suthers, G.K. Hum. Mol. Genet. (2000) [Pubmed]
  23. The Opitz syndrome gene MID1 is essential for establishing asymmetric gene expression in Hensen's node. Granata, A., Quaderi, N.A. Dev. Biol. (2003) [Pubmed]
  24. MID1 and MID2 homo- and heterodimerise to tether the rapamycin-sensitive PP2A regulatory subunit, alpha 4, to microtubules: implications for the clinical variability of X-linked Opitz GBBB syndrome and other developmental disorders. Short, K.M., Hopwood, B., Yi, Z., Cox, T.C. BMC Cell Biol. (2002) [Pubmed]
  25. Cooperation of BMP7 and SHH in the induction of forebrain ventral midline cells by prechordal mesoderm. Dale, J.K., Vesque, C., Lints, T.J., Sampath, T.K., Furley, A., Dodd, J., Placzek, M. Cell (1997) [Pubmed]
  26. Control of retinal ganglion cell axon growth: a new role for Sonic hedgehog. Trousse, F., Martí, E., Gruss, P., Torres, M., Bovolenta, P. Development (2001) [Pubmed]
  27. A comparison of injections of botulinum toxin and topical nitroglycerin ointment for the treatment of chronic anal fissure. Brisinda, G., Maria, G., Bentivoglio, A.R., Cassetta, E., Gui, D., Albanese, A. N. Engl. J. Med. (1999) [Pubmed]
  28. Glial control of neuronal development. Lemke, G. Annu. Rev. Neurosci. (2001) [Pubmed]
  29. Serotonergic neurons transiently require a midline-derived FGF signal. Condron, B.G. Neuron (1999) [Pubmed]
  30. Severe facial clefting in Insig-deficient mouse embryos caused by sterol accumulation and reversed by lovastatin. Engelking, L.J., Evers, B.M., Richardson, J.A., Goldstein, J.L., Brown, M.S., Liang, G. J. Clin. Invest. (2006) [Pubmed]
  31. Brain metabolic changes during cigarette craving. Brody, A.L., Mandelkern, M.A., London, E.D., Childress, A.R., Lee, G.S., Bota, R.G., Ho, M.L., Saxena, S., Baxter, L.R., Madsen, D., Jarvik, M.E. Arch. Gen. Psychiatry (2002) [Pubmed]
  32. Netrin/DCC signaling controls contralateral dendrites of octavolateralis efferent neurons. Suli, A., Mortimer, N., Shepherd, I., Chien, C.B. J. Neurosci. (2006) [Pubmed]
  33. Coordinate expression of Fgf8, Otx2, Bmp4, and Shh in the rostral prosencephalon during development of the telencephalic and optic vesicles. Crossley, P.H., Martinez, S., Ohkubo, Y., Rubenstein, J.L. Neuroscience (2001) [Pubmed]
  34. The migration of cerebellar rhombic lip derivatives. Gilthorpe, J.D., Papantoniou, E.K., Chédotal, A., Lumsden, A., Wingate, R.J. Development (2002) [Pubmed]
  35. Drosophila center divider gene is expressed in CNS midline cells and encodes a developmentally regulated protein kinase orthologous to human TESK1. Matthews, B.B., Crews, S.T. DNA Cell Biol. (1999) [Pubmed]
  36. Human anterior and frontal midline theta and lower alpha reflect emotionally positive state and internalized attention: high-resolution EEG investigation of meditation. Aftanas, L.I., Golocheikine, S.A. Neurosci. Lett. (2001) [Pubmed]
  37. MID2, a homologue of the Opitz syndrome gene MID1: similarities in subcellular localization and differences in expression during development. Buchner, G., Montini, E., Andolfi, G., Quaderi, N., Cainarca, S., Messali, S., Bassi, M.T., Ballabio, A., Meroni, G., Franco, B. Hum. Mol. Genet. (1999) [Pubmed]
  38. A new X-linked syndrome with agenesis of the corpus callosum, mental retardation, coloboma, micrognathia, and a mutation in the Alpha 4 gene at Xq13. Graham, J.M., Wheeler, P., Tackels-Horne, D., Lin, A.E., Hall, B.D., May, M., Short, K.M., Schwartz, C.E., Cox, T.C. Am. J. Med. Genet. A (2003) [Pubmed]
  39. The Opitz syndrome gene Mid1 is transcribed from a human endogenous retroviral promoter. Landry, J.R., Rouhi, A., Medstrand, P., Mager, D.L. Mol. Biol. Evol. (2002) [Pubmed]
  40. Expression of the Sonic hedgehog (SHH ) gene during early human development and phenotypic expression of new mutations causing holoprosencephaly. Odent, S., Atti-Bitach, T., Blayau, M., Mathieu, M., Aug, J., Delezo de, A.L., Gall, J.Y., Le Marec, B., Munnich, A., David, V., Vekemans, M. Hum. Mol. Genet. (1999) [Pubmed]
  41. Functional characterization of the Opitz syndrome gene product (midin): evidence for homodimerization and association with microtubules throughout the cell cycle. Cainarca, S., Messali, S., Ballabio, A., Meroni, G. Hum. Mol. Genet. (1999) [Pubmed]
  42. BMPER, a novel endothelial cell precursor-derived protein, antagonizes bone morphogenetic protein signaling and endothelial cell differentiation. Moser, M., Binder, O., Wu, Y., Aitsebaomo, J., Ren, R., Bode, C., Bautch, V.L., Conlon, F.L., Patterson, C. Mol. Cell. Biol. (2003) [Pubmed]
  43. Genetic analysis as an aid in diagnosis for patients with midline carcinomas of uncertain histologies. Motzer, R.J., Rodriguez, E., Reuter, V.E., Samaniego, F., Dmitrovsky, E., Bajorin, D.F., Pfister, D.G., Parsa, N.Z., Chaganti, R.S., Bosl, G.J. J. Natl. Cancer Inst. (1991) [Pubmed]
  44. Influence of abdominal-wound closure technique on complications after surgery: a randomised study. Niggebrugge, A.H., Trimbos, J.B., Hermans, J., Steup, W.H., Van De Velde, C.J. Lancet (1999) [Pubmed]
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