title: Mutations in CDK5RAP2 cause Seckel syndrome.
abstract: Seckel syndrome is a heterogeneous, autosomal recessive disorder marked by prenatal proportionate short stature, severe microcephaly, intellectual disability, and characteristic facial features. Here, we describe the novel homozygous splice-site mutations c.383+1G>C and c.4005-9A>G in CDK5RAP2 in two consanguineous families with Seckel syndrome. CDK5RAP2 (CEP215) encodes a centrosomal protein which is known to be essential for centrosomal cohesion and proper spindle formation and has been shown to be causally involved in autosomal recessive primary microcephaly. We establish CDK5RAP2 as a disease-causing gene for Seckel syndrome and show that loss of functional CDK5RAP2 leads to severe defects in mitosis and spindle organization, resulting in cells with abnormal nuclei and centrosomal pattern, which underlines the important role of centrosomal and mitotic proteins in the pathogenesis of the disease. Additionally, we present an intriguing case of possible digenic inheritance in Seckel syndrome: A severely affected child of nonconsanguineous German parents was found to carry heterozygous mutations in CDK5RAP2 and CEP152. This finding points toward a potential additive genetic effect of mutations in CDK5RAP2 and CEP152.
authors.affiliation: Institute of Human Genetics, University of Cologne Cologne, Germany ; Center for Molecular Medicine Cologne (CMMC), University of Cologne Cologne, Germany ; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne Cologne, Germany.
authors.forename: Gökhan
authors.initials: G
authors.lastname: Yigit
authors.affiliation: Chromosome Biology Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital London, W12 0NN, UK.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Brown
authors.affiliation: Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University Istanbul, Turkey.
authors.forename: Hülya
authors.initials: H
authors.lastname: Kayserili
authors.affiliation: Institute of Human Genetics, University of Cologne Cologne, Germany ; Center for Molecular Medicine Cologne (CMMC), University of Cologne Cologne, Germany ; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne Cologne, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Pohl
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University of Kiel Kiel, Germany.
authors.forename: Almuth
authors.initials: A
authors.lastname: Caliebe
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander University Erlangen-Nuremberg Erlangen, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Zahnleiter
authors.affiliation: Department of Clinical Genetics, Great Ormond Street Hospital for Children London, WC1N 3EH, UK.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Rosser
authors.affiliation: Institute of Human Genetics, University of Cologne Cologne, Germany ; Center for Molecular Medicine Cologne (CMMC), University of Cologne Cologne, Germany ; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne Cologne, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Bögershausen
authors.affiliation: Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University Istanbul, Turkey.
authors.forename: Zehra Oya
authors.initials: ZO
authors.lastname: Uyguner
authors.affiliation: Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University Istanbul, Turkey.
authors.forename: Umut
authors.initials: U
authors.lastname: Altunoglu
authors.affiliation: Center for Molecular Medicine Cologne (CMMC), University of Cologne Cologne, Germany ; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne Cologne, Germany ; Cologne Center for Genomics, University of Cologne Cologne, Germany.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.affiliation: Center for Molecular Medicine Cologne (CMMC), University of Cologne Cologne, Germany ; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne Cologne, Germany ; Cologne Center for Genomics, University of Cologne Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Institute of Medical Genetics, University of Zurich Schwerzenbach-Zurich, Switzerland.
authors.forename: Anita
authors.initials: A
authors.lastname: Rauch
authors.affiliation: Institute of Human Genetics, University of Cologne Cologne, Germany ; Center for Molecular Medicine Cologne (CMMC), University of Cologne Cologne, Germany ; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne Cologne, Germany.
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander University Erlangen-Nuremberg Erlangen, Germany.
authors.forename: Christian Thomas
authors.initials: CT
authors.lastname: Thiel
authors.affiliation: Institute of Human Genetics, University of Cologne Cologne, Germany ; Center for Molecular Medicine Cologne (CMMC), University of Cologne Cologne, Germany ; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne Cologne, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Wollnik
keywords: CDK5RAP2; CEP215; Seckel syndrome; microcephaly; primordial dwarfism