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Structural highlights

Disease

[MCPH1_HUMAN] Premature chromosome condensation with microcephaly and intellectual deficit;Autosomal recessive primary microcephaly. Defects in MCPH1 are the cause of microcephaly primary type 1 (MCPH1) [MIM:251200]; also known as true microcephaly or microcephaly vera. Microcephaly is defined as a head circumference more than 3 standard deviations below the age-related mean. Brain weight is markedly reduced and the cerebral cortex is disproportionately small. Despite this marked reduction in size, the gyral pattern is relatively well preserved, with no major abnormality in cortical architecture. Primary microcephaly is further defined by the absence of other syndromic features or significant neurological deficits. This entity is inherited as autosomal recessive trait.^{[1] [2] [3]}

Function

[MCPH1_HUMAN] Implicated in chromosome condensation and DNA damage induced cellular responses. May play a role in neurogenesis and regulation of the size of the cerebral cortex.^{[4] [5] [6]} [H2AX_HUMAN] Variant histone H2A which replaces conventional H2A in a subset of nucleosomes. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling. Required for checkpoint-mediated arrest of cell cycle progression in response to low doses of ionizing radiation and for efficient repair of DNA double strand breaks (DSBs) specifically when modified by C-terminal phosphorylation.^{[7] [8] [9] [10]}

References

1. ↑ Jackson AP, Eastwood H, Bell SM, Adu J, Toomes C, Carr IM, Roberts E, Hampshire DJ, Crow YJ, Mighell AJ, Karbani G, Jafri H, Rashid Y, Mueller RF, Markham AF, Woods CG. Identification of microcephalin, a protein implicated in determining the size of the human brain. Am J Hum Genet. 2002 Jul;71(1):136-42. Epub 2002 Jun 3. PMID:12046007 doi:10.1086/341283
2. ↑ Trimborn M, Bell SM, Felix C, Rashid Y, Jafri H, Griffiths PD, Neumann LM, Krebs A, Reis A, Sperling K, Neitzel H, Jackson AP. Mutations in microcephalin cause aberrant regulation of chromosome condensation. Am J Hum Genet. 2004 Aug;75(2):261-6. Epub 2004 Jun 15. PMID:15199523 doi:10.1086/422855
3. ↑ Trimborn M, Richter R, Sternberg N, Gavvovidis I, Schindler D, Jackson AP, Prott EC, Sperling K, Gillessen-Kaesbach G, Neitzel H. The first missense alteration in the MCPH1 gene causes autosomal recessive microcephaly with an extremely mild cellular and clinical phenotype. Hum Mutat. 2005 Nov;26(5):496. PMID:16211557 doi:10.1002/humu.9382
4. ↑ Jackson AP, Eastwood H, Bell SM, Adu J, Toomes C, Carr IM, Roberts E, Hampshire DJ, Crow YJ, Mighell AJ, Karbani G, Jafri H, Rashid Y, Mueller RF, Markham AF, Woods CG. Identification of microcephalin, a protein implicated in determining the size of the human brain. Am J Hum Genet. 2002 Jul;71(1):136-42. Epub 2002 Jun 3. PMID:12046007 doi:10.1086/341283
5. ↑ Trimborn M, Bell SM, Felix C, Rashid Y, Jafri H, Griffiths PD, Neumann LM, Krebs A, Reis A, Sperling K, Neitzel H, Jackson AP. Mutations in microcephalin cause aberrant regulation of chromosome condensation. Am J Hum Genet. 2004 Aug;75(2):261-6. Epub 2004 Jun 15. PMID:15199523 doi:10.1086/422855
6. ↑ Xu X, Lee J, Stern DF. Microcephalin is a DNA damage response protein involved in regulation of CHK1 and BRCA1. J Biol Chem. 2004 Aug 13;279(33):34091-4. Epub 2004 Jun 25. PMID:15220350 doi:10.1074/jbc.C400139200
7. ↑ Paull TT, Rogakou EP, Yamazaki V, Kirchgessner CU, Gellert M, Bonner WM. A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage. Curr Biol. 2000 Jul 27-Aug 10;10(15):886-95. PMID:10959836
8. ↑ Kobayashi J, Tauchi H, Sakamoto S, Nakamura A, Morishima K, Matsuura S, Kobayashi T, Tamai K, Tanimoto K, Komatsu K. NBS1 localizes to gamma-H2AX foci through interaction with the FHA/BRCT domain. Curr Biol. 2002 Oct 29;12(21):1846-51. PMID:12419185
9. ↑ Stewart GS, Wang B, Bignell CR, Taylor AM, Elledge SJ. MDC1 is a mediator of the mammalian DNA damage checkpoint. Nature. 2003 Feb 27;421(6926):961-6. PMID:12607005 doi:10.1038/nature01446
10. ↑ Lukas C, Melander F, Stucki M, Falck J, Bekker-Jensen S, Goldberg M, Lerenthal Y, Jackson SP, Bartek J, Lukas J. Mdc1 couples DNA double-strand break recognition by Nbs1 with its H2AX-dependent chromatin retention. EMBO J. 2004 Jul 7;23(13):2674-83. Epub 2004 Jun 17. PMID:15201865 doi:10.1038/sj.emboj.7600269
11. ↑ Singh N, Basnet H, Wiltshire TD, Mohammad DH, Thompson JR, Heroux A, Botuyan MV, Yaffe MB, Couch FJ, Rosenfeld MG, Mer G. Dual recognition of phosphoserine and phosphotyrosine in histone variant H2A.X by DNA damage response protein MCPH1. Proc Natl Acad Sci U S A. 2012 Aug 20. PMID:22908299 doi:10.1073/pnas.1212366109