Mutations in CIT, encoding citron rho-interacting serine/threonine kinase, cause severe primary microcephaly in humans

Primary microcephaly is a clinical phenotype in which the head circumference is significantly reduced at birth due to abnormal brain development, primarily at the cortical level. Despite the marked genetic heterogeneity, most primary microcephaly-linked genes converge on mitosis regulation. Two cons...

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Bibliographic Details
Published in:Human genetics 2016-10, Vol.135 (10), p.1191-1197
Main Authors: Shaheen, Ranad, Hashem, Amal, Abdel-Salam, Ghada M. H., Al-Fadhli, Fatima, Ewida, Nour, Alkuraya, Fowzan S.
Format: Article
Language:English
Subjects:
Animals
Biomedical and Life Sciences
Biomedicine
Brain - growth & development
Brain - pathology
Brain research
Child
Cytokinesis - genetics
Female
Gene Function
Genetic Heterogeneity
Genetic Predisposition to Disease
Genetics
Genomes
Genotype & phenotype
Human Genetics
Humans
Infant, Newborn
Intracellular Signaling Peptides and Proteins - genetics
Kinases
Metabolic Diseases
Mice
Mice, Knockout
Microcephaly
Microcephaly - genetics
Microcephaly - pathology
Mitosis - genetics
Molecular Medicine
Mutation
Original Investigation
Protein-Serine-Threonine Kinases - genetics
Rats
Saudi Arabia
Signal Transduction
Ultrasonic imaging
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Summary:Primary microcephaly is a clinical phenotype in which the head circumference is significantly reduced at birth due to abnormal brain development, primarily at the cortical level. Despite the marked genetic heterogeneity, most primary microcephaly-linked genes converge on mitosis regulation. Two consanguineous families segregating the phenotype of severe primary microcephaly, spasticity and failure to thrive had overlapping autozygomes in which exome sequencing identified homozygous splicing variants in CIT that segregate with the phenotype within each family. CIT encodes citron, an effector of the Rho signaling that is required for cytokinesis specifically in proliferating neuroprogenitors, as well as for postnatal brain development. In agreement with the critical role assigned to the kinase domain in effecting these biological roles, we show that both splicing variants predict variable disruption of this domain. The striking phenotypic overlap between CIT -mutated individuals and the knockout mice and rats that are specifically deficient in the kinase domain supports the proposed causal link between CIT mutation and primary microcephaly in humans.
ISSN:0340-6717
1432-1203
DOI:10.1007/s00439-016-1722-2