Mutations in Microcephalin Cause Aberrant Regulation of Chromosome Condensation

Abstract

Microcephalin (MCPH1) is a gene mutated in primary microcephaly, an autosomal recessive neurodevelopmental disorder in which there is a marked reduction in brain size. PCC syndrome is a recently described disorder of microcephaly, short stature, and misregulated chromosome condensation. Here, we report the finding that MCPH1 primary microcephaly and PCC syndrome are allelic disorders, both having mutations in the MCPH1 gene. The two conditions share a common cellular phenotype of premature chromosome condensation in the early G2 phase of the cell cycle, which, therefore, appears to be a useful diagnostic marker for individuals with MCPH1 gene mutations. We demonstrate that an siRNA-mediated depletion of MCPH1 is sufficient to reproduce this phenotype and also show that MCPH1-deficient cells exhibit delayed decondensation postmitosis. These findings implicate microcephalin as a novel regulator of chromosome condensation and link the apparently disparate fields of neurogenesis and chromosome biology. Further characterization of MCPH1 is thus likely to lead to fundamental insights into both the regulation of chromosome condensation and neurodevelopment.

Brain shape in human microcephalics and Homo floresiensis

“…4). Virtual endocasts of microcephalics, on the other hand, appear flatter on their orbital surfaces, which is consistent with images of actual brains (21,29), even when the sulci and gyri appear superficially normal (SI Fig. 4).…”

“…The relatively smaller frontal breadths of microcephalics (Fig. 3) are consistent with their typically sloping foreheads, frontal lobes that are more pointed rostrally in dorsal views, and hypothetically smaller forebrains (15,21,26,27,29). In brains of normal humans, the orbital surface of the frontal lobes (in lateral view) is expanded due to ventral protrusion of the cortex medially (underneath the paths of the olfactory tracts) (33) (Fig.…”

“…MCPH has been distinguished from microcephaly that is acquired or ''secondary'' to degenerative brain disorders. Since 1998, however, at least seven autosomal recessive microcephalic loci and five associated genes have been identified [see supporting information (SI) (13,20,29). Even the signature sloping forehead of primary microcephalics is occasionally lacking in affected individuals (17, 24) (SI Fig.…”

Rare copy number variation in cerebral palsy

“…Microcephalin, the product of MCPH1, highly expressed in the foetal cerebral cortex 41 is involved in neurogenesis and regulation of cerebral cortex size. Homozygous loss of function mutations of the MCPH1 gene (OMIM 607117, 606858, and 251200) cause autosomal recessive disorders including premature chromosome condensation syndrome, 42 intellectual disability, 42 and microcephaly. 43 Heterozygous deletions and duplications of MCPH1 have been reported in families with autism spectrum disorders, supporting the concept that MCPH1 is a dosage-sensitive gene, with considerable mutation pleiotropy.…”

Interkinetic Nuclear Movement in the Ventricular Zone of the Cortex

“…Additional links between regulation of mitosis, microcephaly, and DNA damage response have been noted. Microcephalin, an additional gene implicated in human microcephaly, has a role in the initiation of chromosome condensation during mitosis and DNA damage-induced cellular responses (Trimborn et al 2004;Xu et al 2004;O'Driscoll et al 2006). Furthermore, patients with mutations in microcephalin can be more readily diagnosed by the finding of increased numbers of "prophaselike cells" on routine cytogenetic investigation (Cox et al 2006).…”