Premature Chromosome Condensation in Humans Associated with Microcephaly and Mental Retardation: A Novel Autosomal Recessive Condition

Neitzel, Heidemarie; Neumann, Luitgard M.; Schindler, Detlev; Wirges, Andreas; Tönnies, Holger; Trimborn, Marc; Krebsová, Alice; Richter, Reyk; Sperling, Karl

doi:10.1086/339518

Cited by 82 publications

(106 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent reports show that microcephalin is involved in regulation of unperturbed mitotic cell cycles such as proper execution of the intra-S phase and G2/M checkpoints in response to genotoxic stress such as ionizing radiation (Lin et al 2005;Xu et al 2004). Microcephalindeficient cells exhibit abnormal G2-like lymphocytes that show elevated number of cells with prematurely-condensed chromosomes (Neitzel et al 2002) which have not progressed normally into mitosis. Microcephalin has also recently been shown to be involved in centrosomal function potentially modulating the number of neurons generated by neuronal precursor cells (Zhong et al 2006).…”

Section: Discussionmentioning

confidence: 99%

Viral regulation of aquaporin 4, connexin 43, microcephalin and nucleolin

Fatemi¹,

Folsom²,

Reutiman³

et al. 2008

Schizophrenia Research

View full text Add to dashboard Cite

The current study investigated whether human influenza viral infection in midpregnancy leads to alterations in proteins involved in brain development. Human influenza viral infection was administered to E9 pregnant Balb/c mice. Brains of control and virally exposed littermates were subjected to microarray analysis, SDS-PAGE and western blotting at three postnatal stages. Microarray analysis of virally-exposed mouse brains showed significant, two-fold change in expression of multiple genes in both neocortex and cerebellum when compared to sham-infected controls. Levels of mRNA and protein levels of four selected genes were examined in brains of exposed mice. Nucleolin mRNA was significantly decreased in day 0 and day 35 neocortex and significantly increased in day 35 cerebellum. Protein levels were significantly upregulated at days 35 and 56 in neocortex and at day 56 in cerebellum. Connexin 43 protein levels were significantly decreased at day 56 in neocortex. Aquaporin 4 mRNA was significantly decreased in day 0 neocortex. Aquaporin 4 protein levels decreased in neocortex significantly at day 35. Finally, microcephalin mRNA was significantly decreased in day 56 neocortex and protein levels were significantly decreased at 56 cerebellum. These data suggest that influenza viral infection in midpregnancy in mice leads to long term changes in brain markers for enhanced ribosome genesis (nucleolin), increased production of immature neurons (microcephalin), and abnormal glial-neuronal communication (connexin 43 and aquaporin 4).

show abstract

Section: Discussionmentioning

confidence: 99%

Viral regulation of aquaporin 4, connexin 43, microcephalin and nucleolin

Fatemi¹,

Folsom²,

Reutiman³

et al. 2008

Schizophrenia Research

View full text Add to dashboard Cite

show abstract

“…Subsequently microcephalin has been found to have multiple roles in cell cycle and DNA repair. Microcephalin has been implicated in the timing of cell cycle events and specifically in the regulation of chromosome condensation (Neitzel et al, 2002;Trimborn et al, 2004) and Cdk1 phosphorylation (Alderton et al, 2006). Both RNAi depletion and mutation of microcephalin result in a cellular phenotype of premature chromosome condensation (Neitzel et al, 2002;Trimborn et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Microcephalin coordinates mitosis in the syncytialDrosophilaembryo

Brunk

Vernay

Griffith

et al. 2007

Journal of Cell Science

View full text Add to dashboard Cite

Microcephalin (MCPH1) is mutated in primary microcephaly, an autosomal recessive human disorder of reduced brain size. It encodes a protein with three BRCT domains that has established roles in DNA damage signalling and the cell cycle, regulating chromosome condensation. Significant adaptive evolutionary changes in primate MCPH1 sequence suggest that changes in this gene could have contributed to the evolution of the human brain. To understand the developmental role of microcephalin we have studied its function in Drosophila. We report here that Drosophila MCPH1 is cyclically localised during the cell cycle, co-localising with DNA during interphase, but not with mitotic chromosomes. mcph1 mutant flies have a maternal effect lethal phenotype, due to mitotic arrest occurring in early syncytial cell cycles. Mitotic entry is slowed from the very first mitosis in such embryos, with prolonged prophase and metaphase stages; and frequent premature separation as well as detachment of centrosomes. As a consequence, centrosome and nuclear cycles become uncoordinated, resulting in arrested embryonic development. Phenotypic similarities with abnormal spindle (asp) and centrosomin (cnn) mutants (whose human orthologues are also mutated in primary microcephaly), suggest that further studies in the Drosophila embryo may establish a common developmental and cellular pathway underlying the human primary microcephaly phenotype.

show abstract

“…This highly characteristic cellular phenotype is due to premature chromosome condensation in the early G2 phase of the cell cycle (hence, "premature chromosome condensation" = PCC syndrome) and delayed decondensation postmitosis. This aberrant regulation thus causes the large numbers of prophase-like cells (PLCs) that are seen (Neitzel et al, 2002;Trimborn et al, 2004). The MCPH1 gene encodes an 835 amino acid protein, microcephalin, which contains one N-terminal and two C-terminal BRCT domains (BRCA1 C-terminus).…”

Section: Introductionmentioning

confidence: 99%

The first missense alteration in the MCPH1 gene causes autosomal recessive microcephaly with an extremely mild cellular and clinical phenotype

et al. 2005

Self Cite

View full text Add to dashboard Cite

Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental disorder characterized by mental retardation and congenital microcephaly with a head circumference at least 4 SD below age and sex means, in the absence of other significant malformations or neurological deficits. Truncating alterations in the MCPH1 gene have previously been shown to exhibit a distinct cellular phenotype, with a high proportion of prophase-like cells (>10%) due to premature chromosome condensation in early G2-and delayed decondensation in early G1-phase of the cell cycle. 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. The cellular and clinical phenotype of this patient is much less pronounced than that of previously described patients with truncating alterations in the MCPH1 gene. Firstly, the fraction of prophase-like cells accounts for just 3-4% of the cell population. Secondly, clinically, he has only a very mild mental retardation with predominantly delayed motor skills but normal verbal IQ attainment. Additionally, head circumference was less severely affected, being -2.4 SD at birth and -3 SD at the age of six years. This justifies reconsideration and widening of the clinical phenotype definition of MCPH1.

show abstract

Premature Chromosome Condensation in Humans Associated with Microcephaly and Mental Retardation: A Novel Autosomal Recessive Condition

Cited by 82 publications

References 24 publications

Viral regulation of aquaporin 4, connexin 43, microcephalin and nucleolin

Viral regulation of aquaporin 4, connexin 43, microcephalin and nucleolin

Microcephalin coordinates mitosis in the syncytialDrosophilaembryo

The first missense alteration in the MCPH1 gene causes autosomal recessive microcephaly with an extremely mild cellular and clinical phenotype

Contact Info

Product

Resources

About