title: Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome.
abstract: Filippi syndrome is a rare, presumably autosomal-recessive disorder characterized by microcephaly, pre- and postnatal growth failure, syndactyly, and distinctive facial features, including a broad nasal bridge and underdeveloped alae nasi. Some affected individuals have intellectual disability, seizures, undescended testicles in males, and teeth and hair abnormalities. We performed homozygosity mapping and whole-exome sequencing in a Sardinian family with two affected children and identified a homozygous frameshift mutation, c.571dupA (p.Ile191Asnfs(∗)6), in CKAP2L, encoding the protein cytoskeleton-associated protein 2-like (CKAP2L). The function of this protein was unknown until it was rediscovered in mice as Radmis (radial fiber and mitotic spindle) and shown to play a pivotal role in cell division of neural progenitors. Sanger sequencing of CKAP2L in a further eight unrelated individuals with clinical features consistent with Filippi syndrome revealed biallelic mutations in four subjects. In contrast to wild-type lymphoblastoid cell lines (LCLs), dividing LCLs established from the individuals homozygous for the c.571dupA mutation did not show CKAP2L at the spindle poles. Furthermore, in cells from the affected individuals, we observed an increase in the number of disorganized spindle microtubules owing to multipolar configurations and defects in chromosome segregation. The observed cellular phenotypes are in keeping with data from in vitro and in vivo knockdown studies performed in human cells and mice, respectively. Our findings show that loss-of-function mutations in CKAP2L are a major cause of Filippi syndrome.
authors.affiliation: Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany; Institute of Biochemistry I, Medical Faculty, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany.
authors.forename: Muhammad Sajid
authors.initials: MS
authors.lastname: Hussain
authors.affiliation: Stella Maris Clinical Research Institute for Child and Adolescent Neurology and Psychiatry, 56128 Calambrone, Pisa, Italy.
authors.forename: Agatino
authors.initials: A
authors.lastname: Battaglia
authors.affiliation: Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany; Institute of Biochemistry I, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Szczepanski
authors.affiliation: Institute of Biochemistry I, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
authors.forename: Emrah
authors.initials: E
authors.lastname: Kaygusuz
authors.affiliation: Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany.
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Toliat
authors.affiliation: Laboratory for Molecular Neurobiology, Graduate School of Human Sciences, Waseda University, Tokorozawa, Saitama 359-1192, Japan.
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Sakakibara
authors.affiliation: Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany; Institute of Human Genetics, University of Cologne, Cologne, 50931, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.affiliation: Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.affiliation: Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.affiliation: Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Institute of Human Genetics, University of Cologne, Cologne, 50931, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany.
authors.forename: Shahida
authors.initials: S
authors.lastname: Moosa
authors.affiliation: Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Institute of Human Genetics, University of Cologne, Cologne, 50931, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany.
authors.forename: Gökhan
authors.initials: G
authors.lastname: Yigit
authors.affiliation: Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Institute of Human Genetics, University of Cologne, Cologne, 50931, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany.
authors.forename: Filippo
authors.initials: F
authors.lastname: Beleggia
authors.affiliation: Division of Human Genetics, Innsbruck Medical University, Innsbruck 6020, Austria; Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Tinschert
authors.affiliation: Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester Academic Health Sciences Centre, School of Biomedicine, University of Manchester, Manchester M13 9WL, UK.
authors.forename: Jill
authors.initials: J
authors.lastname: Clayton-Smith
authors.affiliation: Department of Clinical Genetics, University Hospitals of Leicester NHS Foundation Trust, Leicester LE1 5WW, UK.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Vasudevan
authors.affiliation: Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester Academic Health Sciences Centre, School of Biomedicine, University of Manchester, Manchester M13 9WL, UK.
authors.forename: Jill E
authors.initials: JE
authors.lastname: Urquhart
authors.affiliation: Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester Academic Health Sciences Centre, School of Biomedicine, University of Manchester, Manchester M13 9WL, UK.
authors.forename: Dian
authors.initials: D
authors.lastname: Donnai
authors.affiliation: Department of Clinical Genetics, Alder Hey Children's Hospital, Liverpool L12 2AP, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Fryer
authors.affiliation: Department of Medical Genetics, Faculty of Medicine, Gazi University, 06500 Ankara, Turkey.
authors.forename: Ferda
authors.initials: F
authors.lastname: Percin
authors.affiliation: Department of Medical, Oral, and Biotechnological Sciences, Gabriele D'Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; Medical Genetics Unit, Policlinico Tor Vergata University Hospital, 00133 Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Brancati
authors.affiliation: Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds LS7 4SA, UK.
authors.forename: Angus
authors.initials: A
authors.lastname: Dobbie
authors.affiliation: Genetics Department, Wroclaw Medical University, 50-368 Wroclaw, Poland.
authors.forename: Robert
authors.initials: R
authors.lastname: Smigiel
authors.affiliation: Institut für Humangenetik Lübeck, Universität zu Lübeck, 23538 Lübeck, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gillessen-Kaesbach
authors.affiliation: Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Institute of Human Genetics, University of Cologne, Cologne, 50931, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Wollnik
authors.affiliation: Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany; Institute of Biochemistry I, Medical Faculty, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany.
authors.forename: Angelika Anna
authors.initials: AA
authors.lastname: Noegel
authors.affiliation: Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester Academic Health Sciences Centre, School of Biomedicine, University of Manchester, Manchester M13 9WL, UK.
authors.forename: William G
authors.initials: WG
authors.lastname: Newman
authors.affiliation: Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany. Electronic address: nuernberg@uni-koeln.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
mesh_terms: D000818:Animals; D001483:Base Sequence; D020732:Cytogenetic Analysis; D003598:Cytoskeletal Proteins / Q000235:genetics*; D019066:Facies; D016368:Frameshift Mutation / Q000235:genetics; D040461:Gene Components; D005808:Genes, Recessive / Q000235:genetics; D006130:Growth Disorders / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology; D007558:Italy; D008297:Male; D051379:Mice; D008831:Microcephaly / Q000235:genetics* / Q000473:pathology; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D017422:Sequence Analysis, DNA; D013576:Syndactyly / Q000235:genetics* / Q000473:pathology
chemical_list: C114988:CKAP2 protein, human; D003598:Cytoskeletal Proteins