title: RTTN mutations link primary cilia function to organization of the human cerebral cortex.
abstract: Polymicrogyria is a malformation of the developing cerebral cortex caused by abnormal organization and characterized by many small gyri and fusion of the outer molecular layer. We have identified autosomal-recessive mutations in RTTN, encoding Rotatin, in individuals with bilateral diffuse polymicrogyria from two separate families. Rotatin determines early embryonic axial rotation, as well as anteroposterior and dorsoventral patterning in the mouse. Human Rotatin has recently been identified as a centrosome-associated protein. The Drosophila melanogaster homolog of Rotatin, Ana3, is needed for structural integrity of centrioles and basal bodies and maintenance of sensory neurons. We show that Rotatin colocalizes with the basal bodies at the primary cilium. Cultured fibroblasts from affected individuals have structural abnormalities of the cilia and exhibit downregulation of BMP4, WNT5A, and WNT2B, which are key regulators of cortical patterning and are expressed at the cortical hem, the cortex-organizing center that gives rise to Cajal-Retzius (CR) neurons. Interestingly, we have shown that in mouse embryos, Rotatin colocalizes with CR neurons at the subpial marginal zone. Knockdown experiments in human fibroblasts and neural stem cells confirm a role for RTTN in cilia structure and function. RTTN mutations therefore link aberrant ciliary function to abnormal development and organization of the cortex in human individuals.
authors.affiliation: Department of Clinical Genetics, Erasmus University Medical Center (Erasmus MC), P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Sima
authors.initials: S
authors.lastname: Kheradmand Kia
authors.forename: Elly
authors.initials: E
authors.lastname: Verbeek
authors.forename: Erik
authors.initials: E
authors.lastname: Engelen
authors.forename: Rachel
authors.initials: R
authors.lastname: Schot
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Poot
authors.forename: Irenaeus F M
authors.initials: IF
authors.lastname: de Coo
authors.forename: Maarten H
authors.initials: MH
authors.lastname: Lequin
authors.forename: Cathryn J
authors.initials: CJ
authors.lastname: Poulton
authors.forename: Farzin
authors.initials: F
authors.lastname: Pourfarzad
authors.forename: Frank G
authors.initials: FG
authors.lastname: Grosveld
authors.forename: António
authors.initials: A
authors.lastname: Brehm
authors.forename: Marie Claire Y
authors.initials: MC
authors.lastname: de Wit
authors.forename: Renske
authors.initials: R
authors.lastname: Oegema
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
authors.forename: Frans W
authors.initials: FW
authors.lastname: Verheijen
authors.forename: Grazia M S
authors.initials: GM
authors.lastname: Mancini
mesh_terms: D000293:Adolescent; D002352:Carrier Proteins / Q000235:genetics*; D018797:Cell Cycle Proteins; D002460:Cell Line; D002540:Cerebral Cortex / Q000196:embryology* / Q000502:physiology*; D002648:Child; D002923:Cilia / Q000502:physiology*; D005260:Female; D055786:Gene Knockout Techniques; D005808:Genes, Recessive; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D054220:Malformations of Cortical Development / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C576561:RTTN protein, human