Alternative titles; symbols
HGNC Approved Gene Symbol: MCPH1
Cytogenetic location: 8p23.1 Genomic coordinates (GRCh38) : 8:6,406,627-6,648,508 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8p23.1 | Microcephaly 1, primary, autosomal recessive | 251200 | Autosomal recessive | 3 |
The MCPH1 gene encodes a regulator of chromosome condensation (Trimborn et al., 2004).
To identify the causative gene in a form of primary microcephaly linked to chromosome 8p23 (MCPH1; 251200), Jackson et al. (2002) sought a founder effect in 2 linked families and then sequenced positional candidates. Of 2 genes identified in the MCPH1 interval, angiopoietin-2 (ANGPT2; 601922) showed no changes. However, the other gene, which was previously uncharacterized, showed a nonsense mutation (607117.0001) in both families sharing the ancestral 8p23 haplotype. Jackson et al. (2002) termed the predicted 835-amino acid protein encoded by this gene microcephalin. Microcephalin contains 3 BRCA1 (113705) C-terminal (BRCT) domains. It shares only 57% identity with its mouse ortholog, with the most conserved regions being the BRCT domains, where there is 80% identity.
Using RT-PCR of fetal tissues, Jackson et al. (2002) confirmed that microcephalin is expressed in fetal brain. A similar level of expression was present in fetal liver and kidney, and transcripts were detectable at low levels in a range of other fetal tissues, as well as in a number of adult tissues. In situ hybridization experiments on fetal mouse sections showed that microcephalin is expressed during neurogenesis. In fetal brain, high levels of gene expression localized to the developing forebrain and, in particular, to the walls of the lateral ventricles. Progenitor cells in this region divide to produce neurons that migrate to form the cerebral cortex.
Using Western blot analysis, Xu et al. (2004) detected a 100-kD MCPH1 protein in human cell lines.
Lin et al. (2005) examined the role of BRIT1 in DNA damage response and found that it was required for intra-S and G2/M checkpoints after irradiation damage in a human osteosarcoma cell line. These BRIT1 activities appeared to result from regulation or activation of at least 3 other checkpoint regulators, CHK1 (CHEK1; 603078), BRCA1, and NBS1 (602667).
Using immunofluorescence, Xu et al. (2004) showed MCPH1 colocalized in ionizing irradiation (IR)-induced foci with NFBD1 (MDC1; 607593) and other DNA damage checkpoint proteins in human embryonic kidney cells following IR exposure. Inhibition of MCPH1 expression by small interfering RNA led to defective IR-induced intra-S-phase and G2/M checkpoints and was associated with decreased BRCA1 and CHK1 mRNA and protein.
Alderton et al. (2006) found defective G2/M checkpoint arrest, nuclear fragmentation after DNA damage, and supernumerary mitotic centrosomes in human lymphoblastoid cell lines with different truncating mutations in MCPH1. Mutant cells failed to inhibit CDC45 (603465) loading onto chromatin after replication arrest. They also showed low levels of tyr15-phosphorylated CDK1 (CDC2; 116940) in S and G2 phase, which correlated with elevated frequency of G2-like cells displaying premature chromosome condensation. Alderton et al. (2006) concluded that MCPH1 has a role in maintaining inhibitory CDK1 phosphorylation, which prevents premature entry into mitosis.
By genomic sequence analysis, Jackson et al. (2002) determined that the MCPH1 gene contains 14 exons.
By positional cloning, Jackson et al. (2002) mapped the MCPH1 gene to the primary microcephaly-1 critical region on chromosome 8p23. Jackson et al. (2002) mapped the mouse Mcph1 gene to chromosome 8A2, a region that also contains the Angpt2 gene and thus shows homology of synteny to human chromosome 8p23.
Jackson et al. (2002) identified a homozygous mutation in the microcephalin gene (S25X; 607117.0001) in 2 families with primary microcephaly-1 (MCPH1; 251200) sharing an ancestral 8p23 haplotype. All 7 affected individuals were homozygous for the mutation, and their 8 parents (obligate carriers) were heterozygous for this mutation. The S25X mutation occurred in the first BRCT domain and considerably truncated the microcephalin protein.
In 2 sibs, born of consanguineous parents, with microcephaly and premature chromosome condensation syndrome originally reported by Neitzel et al. (2002), Trimborn et al. (2004) identified a homozygous 1-bp insertion (427insA; 607117.0002) in exon 5 of the MCPH1 gene. The cellular phenotype showed premature chromosome condensation in the early G2 phase of the cell cycle, which may be a useful diagnostic marker for individuals with mutation in the MCPH1 gene. Trimborn et al. (2004) demonstrated that siRNA-mediated depletion of MCPH1 is sufficient to reproduce this cellular phenotype, and also showed that MCPH1-deficient cells exhibit delayed decondensation postmitosis. These findings implicated microcephalin as a regulator of chromosome condensation and linked the apparently disparate fields of neurogenesis and chromosome biology.
Darvish et al. (2010) identified 8 different homozygous mutations in the MCPH1 gene (see, e.g., 607117.0004-607117.0006) in 8 (8.7%) of 112 Iranian families with primary microcephaly, mental retardation, and premature chromosome condensation. Six of the mutations were predicted to result in a truncated protein. One of the families and the corresponding mutation had been reported by Garshasbi et al. (2006).
Human evolution is characterized by a dramatic increase in brain size and complexity. To probe its genetic basis, Dorus et al. (2004) examined the evolution of genes involved in diverse aspects of nervous system biology. These genes, including MCPH1, displayed significantly higher rates of protein evolution in primates than in rodents. This trend was most pronounced for the subset of genes implicated in nervous system development. Moreover, within primates, the acceleration of protein evolution was most prominent in the lineage leading from ancestral primates to humans. Dorus et al. (2004) concluded that the phenotypic evolution of the human nervous system has a salient molecular correlate, i.e., accelerated evolution of the underlying genes, particularly those linked to nervous system development.
Similarly, Evans et al. (2004) showed that the evolution of microcephalin's protein sequence was highly accelerated throughout the lineage from simian ancestors to humans and chimpanzees, with the most pronounced acceleration seen in the early periods of this lineage. This accelerated evolution was coupled with signatures of positive selection. Statistical analysis suggested that about 45 advantageous amino acid changes in microcephalin might have fixed during the 25 to 30 million years of evolution from early simian progenitors to modern humans. These observations supported the notion that the molecular evolution of microcephalin may have contributed to brain expansion in the simian lineage leading to humans.
Wang and Su (2004) sequenced the coding region of microcephalin gene in humans and 12 representative nonhuman primate species covering great apes, lesser apes, Old World monkeys, and New World monkeys. Microcephalin was highly polymorphic in human populations. Among 22 substitutions in the coding region of microcephalin gene in human populations, 15 caused amino acid changes. Neutrality tests and phylogenetic analysis indicated that the sequence variations of microcephalin in humans were likely caused by the combination of recent population expansion and Darwinian positive selection. Synonymous/nonsynonymous analyses in primates revealed positive selection on microcephalin during the origin of the last common ancestor of humans and great apes, which coincides with the drastic brain enlargement from lesser apes to great apes. A codon-based neutrality test also indicated the signal of positive selection on 5 individual amino acid sites of microcephalin, which may contribute to brain enlargement during primate evolution and human origin.
Evans et al. (2005) presented evidence that haplotype 49 of microcephalin, corresponding to the C allele of the G37995C SNP, increased its frequency too rapidly to be compatible with neutral drift. This indicates that it has spread under strong positive selection. The G37995C SNP occurs in exon 8 and changes amino acid 314 from an ancestral aspartate to a histidine (D314H). Position 37995 of the genomic sequence corresponds to position 940 of the open reading frame.
Currat et al. (2006) commented on the paper by Evans et al. (2005), stating that they had developed models of human history including both population growth and spatial structure that could generate the observed pattern of microcephalin haplotypes without selection. Mekel-Bobrov et al. (2006) responded that the demographic models adopted by Currat et al. (2006) strongly contradicted a decade of empirical research on human demographic history and did not account for the critical features of the data on which Mekel-Bobrov et al. (2006) had developed their argument for selection.
In a study of 5 independent population-based samples comprising 2,393 individuals, Mekel-Bobrov et al. (2007) did not find a detectable association between the recent adaptive evolution of either the ASPM (605481) or microcephalin genes and normal variation in IQ.
Maghirang-Rodriguez et al. (2009) found no association between the 940G variant of MCPH1 and microcephaly or mental retardation among 1,054 affected individuals compared to 401 controls. However, in controls the frequency of the 940G allele was significantly higher among African Americans (66%) compared to Caucasians (17%).
Jackson et al. (2002) identified a C-to-G transversion at nucleotide 74 in exon 2 of the microcephalin gene, resulting in a ser25-to-ter (S25X) substitution, in 2 families with primary microcephaly (251200) sharing an ancestral 8p23 haplotype. All 7 affected individuals were homozygous for the mutation, and their 8 parents (obligate carriers) were heterozygous for this mutation. The S25X mutation occurred in the first BRCT domain of microcephalin and considerably truncated the protein.
Alderton et al. (2006) found that cells expressing the S25X mutation had reduced, but residual, MCPH1 protein expression. The mutant protein would result in loss of the N-terminal BRCT domain.
In 2 sibs, born to consanguineous parents, with microcephaly (251200) and premature chromosome condensation originally reported by Neitzel et al. (2002), Trimborn et al. (2004) sequenced the entire coding region of the MCPH1 gene; they identified a homozygous 1-bp insertion in exon 5, 427insA, resulting in a frameshift with a premature stop codon in exon 6 and, thus, a markedly truncated protein of 146 amino acids encoding only the N-terminal BRCT domain of the protein. The insertion, which occurred within a run of 6 adenines, was heterozygous in both unaffected parents and not present in 220 control alleles. Trimborn et al. (2004) concluded that the cellular phenotype was due to functional loss of the microcephalin protein.
Alderton et al. (2006) found that cells expressing the 427insA mutant lacked detectable MCPH1 protein. The mutant transcript underwent nonsense-mediated decay, but residual mutant mRNA was detectable.
In 6 affected members of a consanguineous Iranian family with mental retardation, mild microcephaly (-3 SD), and premature chromosome condensation in at least 10 to 15% of cells (251200), Garshasbi et al. (2006) identified a homozygous 150- to 200-kb deletion encompassing the promoter and the first 6 exons of the MCPH1 gene.
In 3 affected members of a consanguineous Iranian family with microcephaly (-6 SD), moderate mental retardation, and premature chromosome condensation (251200), Darvish et al. (2010) identified a homozygous 1-bp insertion (566insA) in exon 6 of the MCPH1 gene, predicted to result in a frameshift. The mutation was not found in 160 German and 190 Iranian controls.
In 4 affected members of a consanguineous Iranian family with microcephaly (-7 to -9 SD), moderate mental retardation, and premature chromosome condensation (251200), Darvish et al. (2010) identified a homozygous 147C-G transversion in exon 3 of the MCPH1 gene, predicted to result in his49-to-gln (H49Q) substitution in the BRCT1 domain. The mutation was not found in 160 German and 190 Iranian controls.
In 3 affected members of a consanguineous Iranian family with microcephaly (-6 to -7 SD), mild to moderate mental retardation, and premature chromosome condensation (251200), Darvish et al. (2010) identified a homozygous 215C-T transition in exon 3 of the MCPH1 gene, predicted to result in ser72-to-leu (S72L) substitution in the BRCT1 domain. The mutation was not found in 160 German and 190 Iranian controls.
In a Danish female with primary microcephaly-1 (251200), previously reported by Tommerup et al. (1993), Farooq et al. (2010) identified a homozygous 302C-G transversion in exon 4 of the MCPH1 gene, resulting in a ser101-to-ter (S101X) substitution. The truncated protein was predicted to retain the N-terminal BRCT domain but lack the 2 C-terminal BRCT domains. The patient also had craniosynostosis, ptosis, and bird-like facies with micrognathia. The cellular phenotype of chromosomal sensitivity to DNA damage was particularly severe, which the authors suggested may be related to presence of the N-terminal BRCT domain.
Alderton, G. K., Galbiati, L., Griffith, E., Surinya, K. H., Neitzel, H., Jackson, A. P., Jeggo, P. A., O'Driscoll, M. Regulation of mitotic entry by microcephalin and its overlap with ATR signalling. Nature Cell Biol. 8: 725-733, 2006. [PubMed: 16783362] [Full Text: https://doi.org/10.1038/ncb1431]
Currat, M., Excoffier, L., Maddison, W., Otto, S. P., Ray, N., Whitlock, M. C., Yeaman, S. Comment on 'Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens' and 'microcephalin, a gene regulating brain size, continues to evolve adaptively in humans.' (Abstract) Science 313: 172 only, 2006. [PubMed: 16840683] [Full Text: https://doi.org/10.1126/science.1122822]
Darvish, H., Esmaeeli-Nieh, S., Monajemi, G. B., Mohseni, M., Ghasemi-Firouzabadi, S., Abedini, S. S., Bahman, I., Jamali, P., Azimi, S., Mojahedi, F., Dehghan, A., Shafeghati, Y., and 14 others. A clinical and molecular genetic study of 112 Iranian families with primary microcephaly. J. Med. Genet. 47: 823-828, 2010. Note: Erratum: J. Med. Genet. 51: 70 only, 2014. [PubMed: 20978018] [Full Text: https://doi.org/10.1136/jmg.2009.076398]
Dorus, S., Vallender, E. J., Evans, P. D., Anderson, J. R., Gilbert, S. L., Mahowald, M., Wyckoff, G. J., Malcom, C. M., Lahn, B. T. Accelerated evolution of nervous system genes in the origin of Homo sapiens. Cell 119: 1027-1040, 2004. [PubMed: 15620360] [Full Text: https://doi.org/10.1016/j.cell.2004.11.040]
Evans, P. D., Anderson, J. R., Vallender, E. J., Choi, S. S., Lahn, B. T. Reconstructing the evolutionary history of microcephalin, a gene controlling human brain size. Hum. Molec. Genet. 13: 1139-1145, 2004. [PubMed: 15056607] [Full Text: https://doi.org/10.1093/hmg/ddh126]
Evans, P. D., Gilbert, S. L., Mekel-Bobrov, N., Vallender, E. J., Anderson, J. R., Vaez-Azizi, L. M., Tishkoff, S. A., Hudson, R. R., Lahn, B. T. Microcephalin, a gene regulating brain size, continues to evolve adaptively in humans. Science 309: 1717-1720, 2005. [PubMed: 16151009] [Full Text: https://doi.org/10.1126/science.1113722]
Farooq, M., Baig, S., Tommerup, N., Kjaer, K. W. Craniosynostosis-microcephaly with chromosomal breakage and other abnormalities is caused by a truncating MCPH1 mutation and is allelic to premature chromosomal condensation syndrome and primary autosomal recessive microcephaly type 1. Am. J. Med. Genet. 152A: 495-497, 2010. [PubMed: 20101680] [Full Text: https://doi.org/10.1002/ajmg.a.33234]
Garshasbi, M., Motazacker, M. M., Kahrizi, K., Behjati, F., Abedini, S. S., Nieh, S. E., Firouzabadi, S. G., Becker, C., Ruschendorf, F., Nurnberg, P., Tzschach, A., Vazifehmand, R., Erdogan, F., Ullmann, R., Lenzner, S., Kuss, A. W., Ropers, H. H., Najmabadi, H. SNP array-based homozygosity mapping reveals MCPH1 deletion in family with autosomal recessive mental retardation and mild microcephaly. Hum. Genet. 118: 708-715, 2006. [PubMed: 16311745] [Full Text: https://doi.org/10.1007/s00439-005-0104-y]
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. Identification of microcephalin, a protein implicated in determining the size of the human brain. Am. J. Hum. Genet. 71: 136-142, 2002. [PubMed: 12046007] [Full Text: https://doi.org/10.1086/341283]
Lin, S.-Y., Rai, R., Li, K., Xu, Z.-X., Elledge, S. J. BRIT1/MCPH1 is a DNA damage responsive protein that regulates the Brca1-Chk1 pathway, implicating checkpoint dysfunction in microcephaly. Proc. Nat. Acad. Sci. 102: 15105-15109, 2005. [PubMed: 16217032] [Full Text: https://doi.org/10.1073/pnas.0507722102]
Maghirang-Rodriguez, R., Archie, J. G., Schwarz, C. E., Collins, J. S. The c.940G variant of the microcephalin (MCPH1) gene is not associated with microcephaly or mental retardation. Am. J. Med. Genet. 149A: 622-625, 2009. [PubMed: 19267414] [Full Text: https://doi.org/10.1002/ajmg.a.32721]
Mekel-Bobrov, N., Evans, P. D., Gilbert, S. L., Vallender, E. J., Hudson, R. R., Lahn, B. T. Comment on 'Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens' and 'microcephalin, a gene regulating brain size, continues to evolve adaptively in humans.' (Abstract) Science 313: 172 only, 2006. [PubMed: 16840683] [Full Text: https://doi.org/10.1126/science.1122822]
Mekel-Bobrov, N., Posthuma, D., Gilbert, S. L., Lind, P., Gosso, M. F., Luciano, M., Harris, S. E., Bates, T. C., Polderman, T. J. C., Whalley, L. J., Fox, H., Starr, J. M., and 10 others. The ongoing adaptive evolution of ASPM and microcephalin is not explained by increased intelligence. Hum. Molec. Genet. 16: 600-608, 2007. [PubMed: 17220170] [Full Text: https://doi.org/10.1093/hmg/ddl487]
Neitzel, H., Neumann, L. M., Schindler, D., Wirges, A., Tonnies, H., Trimborn, M., Krebsova, A., Richter, R., Sperling, K. Premature chromosome condensation in humans associated with microcephaly and mental retardation: a novel autosomal recessive condition. Am. J. Hum. Genet. 70: 1015-1022, 2002. [PubMed: 11857108] [Full Text: https://doi.org/10.1086/339518]
Tommerup, N., Mortensen, E., Nielsen, M. H., Wegner, R.-D., Schindler, D., Mikkelsen, M. Chromosomal breakage, endomitosis, endoreduplication, and hypersensitivity toward radiomimetic and alkylating agents: a possible new autosomal recessive mutation in a girl with craniosynostosis and microcephaly. Hum. Genet. 92: 339-346, 1993. [PubMed: 7693575] [Full Text: https://doi.org/10.1007/BF01247331]
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. Mutations in microcephalin cause aberrant regulation of chromosome condensation. Am. J. Hum. Genet. 75: 261-266, 2004. [PubMed: 15199523] [Full Text: https://doi.org/10.1086/422855]
Wang, Y., Su, B. Molecular evolution of microcephalin, a gene determining human brain size. Hum. Molec. Genet. 13: 1131-1137, 2004. [PubMed: 15056608] [Full Text: https://doi.org/10.1093/hmg/ddh127]
Xu, X., Lee, J., Stern, D. F. Microcephalin is a DNA damage response protein involved in regulation of CHK1 and BRCA1. J. Biol. Chem. 279: 34091-34094, 2004. [PubMed: 15220350] [Full Text: https://doi.org/10.1074/jbc.C400139200]