title: Mutations in CIT, encoding citron rho-interacting serine/threonine kinase, cause severe primary microcephaly in humans.
abstract: 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.
authors: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors: Ranad
authors: R
authors: Shaheen
authors: Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
authors: Amal
authors: A
authors: Hashem
authors: Department of Clinical Genetics, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
authors: Ghada M H
authors: GM
authors: Abdel-Salam
authors: Medical Genetics, Madina Maternity Hospital, Madina, Saudi Arabia.
authors: Fatima
authors: F
authors: Al-Fadhli
authors: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors: Nour
authors: N
authors: Ewida
authors: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa.|Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa.
authors: Fowzan S
authors: FS
authors: Alkuraya
mesh_terms: D000818:Animals; D001921:Brain / Q000254:growth & development / Q000473:pathology; D002648:Child; D048749:Cytokinesis / Q000235:genetics; D005260:Female; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D006801:Humans; D007231:Infant, Newborn; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008831:Microcephaly / Q000235:genetics* / Q000473:pathology; D008938:Mitosis / Q000235:genetics; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D051381:Rats; D012529:Saudi Arabia; D015398:Signal Transduction
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C115635:citron-kinase; D017346:Protein Serine-Threonine Kinases