RESUMO
Compaction of chromosomes is essential for accurate segregation of the genome during mitosis. In vertebrates, two condensin complexes ensure timely chromosome condensation, sister chromatid disentanglement, and maintenance of mitotic chromosome structure. Here, we report that biallelic mutations in NCAPD2, NCAPH, or NCAPD3, encoding subunits of these complexes, cause microcephaly. In addition, hypomorphic Ncaph2 mice have significantly reduced brain size, with frequent anaphase chromatin bridge formation observed in apical neural progenitors during neurogenesis. Such DNA bridges also arise in condensin-deficient patient cells, where they are the consequence of failed sister chromatid disentanglement during chromosome compaction. This results in chromosome segregation errors, leading to micronucleus formation and increased aneuploidy in daughter cells. These findings establish "condensinopathies" as microcephalic disorders, with decatenation failure as an additional disease mechanism for microcephaly, implicating mitotic chromosome condensation as a key process ensuring mammalian cerebral cortex size.
Assuntos
Adenosina Trifosfatases/genética , Proteínas de Ligação a DNA/genética , Microcefalia/genética , Mitose/genética , Complexos Multiproteicos/genética , Mutação/genética , Aneuploidia , Animais , Catenanos/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Instabilidade Cromossômica/genética , Segregação de Cromossomos/genética , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Micronúcleos com Defeito Cromossômico , Neurônios/patologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Células-TroncoAssuntos
Células da Medula Óssea/citologia , Medula Óssea/metabolismo , Células Progenitoras Endoteliais/citologia , Células-Tronco/citologia , Adulto , Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/efeitos dos fármacos , Células Cultivadas , Células Progenitoras Endoteliais/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Células-Tronco/efeitos dos fármacosRESUMO
Centrioles are essential for ciliogenesis. However, mutations in centriole biogenesis genes have been reported in primary microcephaly and Seckel syndrome, disorders without the hallmark clinical features of ciliopathies. Here we identify mutations in the genes encoding PLK4 kinase, a master regulator of centriole duplication, and its substrate TUBGCP6 in individuals with microcephalic primordial dwarfism and additional congenital anomalies, including retinopathy, thereby extending the human phenotypic spectrum associated with centriole dysfunction. Furthermore, we establish that different levels of impaired PLK4 activity result in growth and cilia phenotypes, providing a mechanism by which microcephaly disorders can occur with or without ciliopathic features.