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Am J Hum Genet. 2016 Aug 4;99(2):511-20. doi: 10.1016/j.ajhg.2016.07.003. Epub 2016 Jul 21.

Mutations in Citron Kinase Cause Recessive Microlissencephaly with Multinucleated Neurons.

Author information

1
Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania and Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
2
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
3
Département de Génétique, Protect, Hôpital Robert Debré, Paris 75019, France; INSERM U1141, Hôpital Robert Debré, Paris 75019, France.
4
INSERM U1079, Institute for Research and Innovation in Biomedicine, University of Rouen, Normandy Centre for Genomic and Personalized Medicine, Rouen 76183, France.
5
INSERM U1079, Institute for Research and Innovation in Biomedicine, University of Rouen, Normandy Centre for Genomic and Personalized Medicine, Rouen 76183, France; Interactive Biosoftware, Rouen 76000, France.
6
Genetics and Genomic Medicine, UCL Institute of Child Health and Great Ormond Street NHS Foundation Trust, London WC1N 1EH, UK.
7
INSERM U1141, Hôpital Robert Debré, Paris 75019, France; Université Paris Diderot, Hôpital Robert Debré, Paris 75019, France; Center for Developing Brain, King's College, St. Thomas' Campus, London WC2R 2LS, UK.
8
INSERM U1141, Hôpital Robert Debré, Paris 75019, France.
9
Service de Neuropédiatrie, Centre Hospitalier Régional Universitaire de Lille, Lille 59037, France.
10
Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin 10126, Italy.
11
Interactive Biosoftware, Rouen 76000, France.
12
Département de Génétique, Protect, Hôpital Robert Debré, Paris 75019, France; INSERM U1141, Hôpital Robert Debré, Paris 75019, France; Université Paris Diderot, Hôpital Robert Debré, Paris 75019, France.
13
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: sbielas@umich.edu.

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.

KEYWORDS:

autosomal recessive; citron kinase; cytokinesis; lissencephaly; neurogenesis; primary microcephaly; splicing mutation

PMID:
27453579
PMCID:
PMC4974106
DOI:
10.1016/j.ajhg.2016.07.003
[Indexed for MEDLINE]
Free PMC Article

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