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Gene Review

MCPH1  -  microcephalin 1

Homo sapiens

Synonyms: BRIT1, FLJ12847, MCT, Microcephalin
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Disease relevance of MCPH1


Psychiatry related information on MCPH1

  • SNP array-based homozygosity mapping reveals MCPH1 deletion in family with autosomal recessive mental retardation and mild microcephaly [5].
  • All procedures to measure auditory adaptation depend at least indirectly upon some subjective judgment of loudness, with the exception of the reaction-time (RT) study of Davis and Weiler (Brit. J. Audiol., 1976, 10, 102-106) [6].
  • Defense mechanisms in alcoholics attending outpatient treatment. Results from the MCT-test (Meta-Contrast Technique) [7].

High impact information on MCPH1

  • RNA interference (RNAi) of MCPH1 have implicated the protein it encodes as a DNA-damage response protein that regulates the transcription of Chk1 and BRCA1, two genes involved in the response to DNA damage [8].
  • We conclude that MCPH1 has a function downstream of Chk1 in the ATR-signalling pathway [8].
  • In contrast with ATR-Seckel syndrome cells, MCPH1-mutant cells have low levels of Tyr 15-phosphorylated Cdk1 (pY15-Cdk1) in S and G2 phases, which correlates with an elevated frequency of G2-like cells displaying premature chromosome condensation (PCC) [8].
  • However, like ATR-Seckel syndrome cells, MCPH1-mutant cell lines show defective G2-M checkpoint arrest and nuclear fragmentation after DNA damage, and contain supernumerary mitotic centrosomes [8].
  • During infusion of THL or SPE, the effects were smaller than during LCT or MCT [9].

Chemical compound and disease context of MCPH1

  • This study shows that infusion of MCT/LCT lipid emulsion can cause lithogenic changes in bile composition in humans and may thus contribute to sludge formation and cholelithiasis during long term parenteral nutrition [10].
  • Because metabolic acidosis occurred with the LCT formula, the chloride content was adjusted to that of the MCT were confirmed and, in addition, there was a higher (P smaller than .01) percent retention of nitrogen (67.3 leads to 82.1) [11].
  • MIBG (Meta Iodo Benzyl Guanidine) uptake by pheochromocytomas is now well known but very few cases of MIBG uptake in sporadic MCT have been described [12].
  • A majority of medullary carcinomas of the thyroid (MCT) have been portrayed by indium 111 octreotide and by 99mTc pentavalent dimercaptosuccinic acid; other agents have concentrated to lesser levels in the tumors or have not been investigated as extensively [13].
  • BACKGROUND: In long-term parenteral nutrition (LTPN) patients, the use of a 50:50 mixture of medium- and long-chain triglyceride emulsion (MCT/LCT) has been suggested to prevent or correct fatty liver infiltration [14].

Biological context of MCPH1


Anatomical context of MCPH1

  • This gene, microcephalin, is expressed in the developing cerebral cortex of the fetal brain [18].
  • Metachromatic cells in cytospins were identified as mast cells primarily on the basis of tryptase expression, and as MCT or MCTC by immunohistochemistry using monoclonal antibodies against tryptase and chymase, whereas basophils were metachromatic, polymorphonuclear, and lacked these proteases [19].
  • DEX also increased CTGF mRNA levels in cultured tubular epithelial cells derived from C57B6 (mProx24) but not SJL (MCT) mice via transcriptional up-regulation of CTGF mRNA [20].
  • Mast cells derived from cord blood progenitors after 7 wk of culture with rhSCF alone displayed an MCT phenotype and expressed Kit, FcepsilonRI, and IL-4R on their surface [21].
  • RESULTS: In normal synovium, the majority of mast cells belonged to the MCTC subset, outnumbering MCT cells by 5:1 [22].

Associations of MCPH1 with chemical compounds

  • We report here the first patient with a homozygous substitution of a highly conserved threonine residue by an arginine (c.80C>G, Thr27Arg) localized in the N-terminal BRCT domain of MCPH1 [23].
  • The cholesterol saturation index increased significantly (p < 0.005) with the MCT/LCT emulsion and there was shortening in the nucleation time but this was not significant [10].
  • The palmitic acid and total saturated fatty acid content of plasma triacylglycerols in the MCT-oil diet was not significantly different from that in the palm oil diet [24].
  • Plasma concentrations of glucose and lactate were not affected in control subjects but increased during both LCT and MCT in ARF [25].
  • MCT oil tended to result in higher triacylglycerol concentrations than either palm oil or high oleic acid sunflower oil, but this difference was not significant [24].

Physical interactions of MCPH1

  • We also show that MCPH1 binds to a phospho-H2AX peptide in vitro with an affinity similar to that of MDC1, and overexpression of wild type, but not C-BRCT mutants of MCPH1, can interfere with the foci formation of MDC1 and 53BP1 [26].

Other interactions of MCPH1


Analytical, diagnostic and therapeutic context of MCPH1

  • METHODS: In a double-blind study, 15 healthy subjects were studied on 5 occasions during which LCT or MCT emulsions (2 kcal/min), with or without 120 mg tetrahydrolipstatin (THL, lipase inhibitor), or sucrose polyester (SPE, nondigestible fat) were infused intraduodenally in randomized order [9].
  • All four children were found to have very small foci of MCT, in both thyroid lobes at the time of total thyroidectomy [4].
  • DESIGN: A crossover design was used to compare the postprandial effects on coagulant and fibrinolytic activities in 12 men of 3 high-fat (95 g) meals--high oleate, butter, and oleate + medium-chain triacylglycerols (oleate+MCT)--with an isoenergetic low-fat meal (18 g MCT) [30].
  • The evaluation of engraftment after transplantation was accomplished by PCR analysis of four hypervariable genomic regions (VNTR) (ApoB, ApoC2, YNZ-22, and MCT 118) which allowed to demonstrate the condition of donor chimaera in all patients after transplantation [31].
  • We have overcome the technical obstacles that have blocked FTIR access to low-frequency substrate, cofactor, and protein vibrational modes by using partially dehydrated samples, appropriate window materials, a wide-range MCT detector, a novel band-pass filter, and a closely regulated temperature control system [32].


  1. Reconstructing the evolutionary history of microcephalin, a gene controlling human brain size. Evans, P.D., Anderson, J.R., Vallender, E.J., Choi, S.S., Lahn, B.T. Hum. Mol. Genet. (2004) [Pubmed]
  2. BRIT1 regulates early DNA damage response, chromosomal integrity, and cancer. Rai, R., Dai, H., Multani, A.S., Li, K., Chin, K., Gray, J., Lahad, J.P., Liang, J., Mills, G.B., Meric-Bernstam, F., Lin, S.Y. Cancer Cell (2006) [Pubmed]
  3. Human microcephaly. Woods, C.G. Curr. Opin. Neurobiol. (2004) [Pubmed]
  4. The early diagnosis of medullary carcinoma of the thyroid gland in patients with multiple endocrine neoplasia type II. Wells, S.A., Ontjes, D.A., Cooper, C.W., Hennessy, J.F., Ellis, G.J., McPherson, H.T., Sabiston, D.C. Ann. Surg. (1975) [Pubmed]
  5. SNP array-based homozygosity mapping reveals MCPH1 deletion in family with autosomal recessive mental retardation and mild microcephaly. Garshasbi, M., Motazacker, M.M., Kahrizi, K., Behjati, F., Abedini, S.S., Nieh, S.E., Firouzabadi, S.G., Becker, C., Rüschendorf, F., Nürnberg, P., Tzschach, A., Vazifehmand, R., Erdogan, F., Ullmann, R., Lenzner, S., Kuss, A.W., Ropers, H.H., Najmabadi, H. Hum. Genet. (2006) [Pubmed]
  6. Monaural auditory adaptation of reaction times at .5, 1, and 3 kc/s. Davis, J.M., Weiler, E.M., Sandman, D.E. The Journal of auditory research. (1986) [Pubmed]
  7. Defense mechanisms in alcoholics attending outpatient treatment. Results from the MCT-test (Meta-Contrast Technique). Ojehagen, A., Smith, G.J. Scandinavian journal of psychology. (1993) [Pubmed]
  8. Regulation of mitotic entry by microcephalin and its overlap with ATR signalling. Alderton, G.K., Galbiati, L., Griffith, E., Surinya, K.H., Neitzel, H., Jackson, A.P., Jeggo, P.A., O'Driscoll, M. Nat. Cell Biol. (2006) [Pubmed]
  9. Fat digestion modulates gastrointestinal sensations induced by gastric distention and duodenal lipid in humans. Feinle, C., Rades, T., Otto, B., Fried, M. Gastroenterology (2001) [Pubmed]
  10. Effect of lipid infusion on bile composition and lithogenicity in patients without cholesterol gall stones. Rubin, M., Halpern, Z., Charach, G., Dvir, A., Antebi, E., Gilat, T., Lichtenberg, D. Gut (1992) [Pubmed]
  11. Correction of the malabsorption of the preterm infant with a medium-chain triglyceride formula. Roy, C.C., Ste-Marie, M., Chartrand, L., Weber, A., Bard, H., Doray, B. J. Pediatr. (1975) [Pubmed]
  12. Uptake of 131I-MIBG by medullary carcinoma of thyroid in familial cases. Coutris, G., Talbot, J.N., Kabla, G., Calmettes, C., Milhaud, G. European journal of nuclear medicine. (1986) [Pubmed]
  13. Selection of the optimal scanning agent for thyroid cancer. Sisson, J.C. Thyroid (1997) [Pubmed]
  14. Replacement of long-chain triglyceride with medium-chain triglyceride/long-chain triglyceride lipid emulsion in patients receiving long-term parenteral nutrition: effects on essential fatty acid status and plasma vitamin K1 levels. Chambrier, C., Bannier, E., Lauverjat, M., Drai, J., Bryssine, S., Boulétreau, P. JPEN. Journal of parenteral and enteral nutrition. (2004) [Pubmed]
  15. Molecular genetic determinants of human brain size. Tang, B.L. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  16. Microcephalin is a DNA damage response protein involved in regulation of CHK1 and BRCA1. Xu, X., Lee, J., Stern, D.F. J. Biol. Chem. (2004) [Pubmed]
  17. Mutations in microcephalin cause aberrant regulation of chromosome condensation. Trimborn, M., Bell, S.M., Felix, C., Rashid, Y., Jafri, H., Griffiths, P.D., Neumann, L.M., Krebs, A., Reis, A., Sperling, K., Neitzel, H., Jackson, A.P. Am. J. Hum. Genet. (2004) [Pubmed]
  18. Identification of microcephalin, a protein implicated in determining the size of the human brain. Jackson, A.P., Eastwood, H., Bell, S.M., Adu, J., Toomes, C., Carr, I.M., Roberts, E., Hampshire, D.J., Crow, Y.J., Mighell, A.J., Karbani, G., Jafri, H., Rashid, Y., Mueller, R.F., Markham, A.F., Woods, C.G. Am. J. Hum. Genet. (2002) [Pubmed]
  19. Recombinant human stem cell factor stimulates differentiation of mast cells from dispersed human fetal liver cells. Irani, A.M., Nilsson, G., Miettinen, U., Craig, S.S., Ashman, L.K., Ishizaka, T., Zsebo, K.M., Schwartz, L.B. Blood (1992) [Pubmed]
  20. Dexamethasone induces connective tissue growth factor expression in renal tubular epithelial cells in a mouse strain-specific manner. Okada, H., Kikuta, T., Inoue, T., Kanno, Y., Ban, S., Sugaya, T., Takigawa, M., Suzuki, H. Am. J. Pathol. (2006) [Pubmed]
  21. Recombinant human (rh)IL-4-mediated apoptosis and recombinant human IL-6-mediated protection of recombinant human stem cell factor-dependent human mast cells derived from cord blood mononuclear cell progenitors. Oskeritzian, C.A., Wang, Z., Kochan, J.P., Grimes, M., Du, Z., Chang, H.W., Grant, S., Schwartz, L.B. J. Immunol. (1999) [Pubmed]
  22. Mast cell responses in rheumatoid synovium. Association of the MCTC subset with matrix turnover and clinical progression. Gotis-Graham, I., McNeil, H.P. Arthritis Rheum. (1997) [Pubmed]
  23. The first missense alteration in the MCPH1 gene causes autosomal recessive microcephaly with an extremely mild cellular and clinical phenotype. Trimborn, M., Richter, R., Sternberg, N., Gavvovidis, I., Schindler, D., Jackson, A.P., Prott, E.C., Sperling, K., Gillessen-Kaesbach, G., Neitzel, H. Hum. Mutat. (2005) [Pubmed]
  24. Comparison of the effects of medium-chain triacylglycerols, palm oil, and high oleic acid sunflower oil on plasma triacylglycerol fatty acids and lipid and lipoprotein concentrations in humans. Cater, N.B., Heller, H.J., Denke, M.A. Am. J. Clin. Nutr. (1997) [Pubmed]
  25. Fat elimination in acute renal failure: long-chain vs medium-chain triglycerides. Druml, W., Fischer, M., Sertl, S., Schneeweiss, B., Lenz, K., Widhalm, K. Am. J. Clin. Nutr. (1992) [Pubmed]
  26. MCPH1 functions in an H2AX-dependent but MDC1-independent pathway in response to DNA damage. Wood, J.L., Singh, N., Mer, G., Chen, J. J. Biol. Chem. (2007) [Pubmed]
  27. BRIT1/MCPH1 is a DNA damage responsive protein that regulates the Brca1-Chk1 pathway, implicating checkpoint dysfunction in microcephaly. Lin, S.Y., Rai, R., Li, K., Xu, Z.X., Elledge, S.J. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  28. Genetic analysis of primary microcephaly in Indian families: novel ASPM mutations. Kumar, A., Blanton, S.H., Babu, M., Markandaya, M., Girimaji, S.C. Clin. Genet. (2004) [Pubmed]
  29. A third novel locus for primary autosomal recessive microcephaly maps to chromosome 9q34. Moynihan, L., Jackson, A.P., Roberts, E., Karbani, G., Lewis, I., Corry, P., Turner, G., Mueller, R.F., Lench, N.J., Woods, C.G. Am. J. Hum. Genet. (2000) [Pubmed]
  30. Postprandial effects of an oleic acid-rich oil compared with butter on clotting factor VII and fibrinolysis in healthy men. Oakley, F.R., Sanders, T.A., Miller, G.J. Am. J. Clin. Nutr. (1998) [Pubmed]
  31. G-CSF-mobilized peripheral blood progenitor cells for allogeneic transplantation of resistant or relapsing acute leukemias. Rambaldi, A., Viero, P., Bassan, R., Buelli, M., Rossi, A., Bellavita, P., Spinelli, O., Amaru, R., Micheletti, M., Borleri, G., Cortelazzo, S., Comotti, B., Barbui, T. Leukemia (1996) [Pubmed]
  32. Low-frequency fourier transform infrared spectroscopy of the oxygen-evolving and quinone acceptor complexes in photosystem II. Chu, H.A., Gardner, M.T., O'Brien, J.P., Babcock, G.T. Biochemistry (1999) [Pubmed]
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