Mutations in Citron Kinase Cause Recessive Microlissencephaly with Multinucleated Neurons.
Am J Hum Genet
; 99(2): 511-20, 2016 Aug 04.
Article
em En
| MEDLINE
| ID: mdl-27453579
ABSTRACT
Primary microcephaly is a neurodevelopmental disorder that is caused by a reduction in brain size as a result of defects in the proliferation of neural progenitor cells during development. Mutations in genes encoding proteins that localize to the mitotic spindle and centrosomes have been implicated in the pathogenicity of primary microcephaly. In contrast, the contractile ring and midbody required for cytokinesis, the final stage of mitosis, have not previously been implicated by human genetics in the molecular mechanisms of this phenotype. Citron kinase (CIT) is a multi-domain protein that localizes to the cleavage furrow and midbody of mitotic cells, where it is required for the completion of cytokinesis. Rodent models of Cit deficiency highlighted the role of this gene in neurogenesis and microcephaly over a decade ago. Here, we identify recessively inherited pathogenic variants in CIT as the genetic basis of severe microcephaly and neonatal death. We present postmortem data showing that CIT is critical to building a normally sized human brain. Consistent with cytokinesis defects attributed to CIT, multinucleated neurons were observed throughout the cerebral cortex and cerebellum of an affected proband, expanding our understanding of mechanisms attributed to primary microcephaly.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Serina-Treonina Quinases
/
Peptídeos e Proteínas de Sinalização Intracelular
/
Genes Recessivos
/
Microcefalia
/
Neurônios
Tipo de estudo:
Prognostic_studies
Limite:
Child
/
Female
/
Humans
/
Infant
/
Male
/
Newborn
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article