Hussain, Muhammad Sajid ORCID: 0000-0002-1353-8809, Battaglia, Agatino ORCID: 0000-0002-7128-7606, Szczepanski, Sandra, Kaygusuz, Emrah, Toliat, Mohammad Reza, Sakakibara, Shin-ichi ORCID: 0000-0001-8983-2249, Altmueller, Janine, Thiele, Holger, Nuernberg, Gudrun, Moosa, Shahida ORCID: 0000-0002-4463-3067, Yigit, Goekhan, Beleggia, Filippo ORCID: 0000-0003-0234-7094, Tinschert, Sigrid, Clayton-Smith, Jill, Vasudevan, Pradeep, Urquhart, Jill E., Donnai, Dian, Fryer, Alan, Percin, Ferda ORCID: 0000-0001-9317-8155, Brancati, Francesco, Dobbie, Angus, Smigiel, Robert, Gillessen-Kaesbach, Gabriele, Wollnik, Bernd, Noegel, Angelika Anna, Newman, William G. and Nuernberg, Peter (2014). Mutations in CKAP2L, the Human Homo log of the Mouse Radmis Gene, Cause Filippi Syndrome. Am. J. Hum. Genet., 95 (5). S. 622 - 633. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Hussain, Muhammad SajidUNSPECIFIEDorcid.org/0000-0002-1353-8809UNSPECIFIED
Battaglia, AgatinoUNSPECIFIEDorcid.org/0000-0002-7128-7606UNSPECIFIED
Szczepanski, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kaygusuz, EmrahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Toliat, Mohammad RezaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sakakibara, Shin-ichiUNSPECIFIEDorcid.org/0000-0001-8983-2249UNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, GudrunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moosa, ShahidaUNSPECIFIEDorcid.org/0000-0002-4463-3067UNSPECIFIED
Yigit, GoekhanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beleggia, FilippoUNSPECIFIEDorcid.org/0000-0003-0234-7094UNSPECIFIED
Tinschert, SigridUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Clayton-Smith, JillUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vasudevan, PradeepUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Urquhart, Jill E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Donnai, DianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fryer, AlanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Percin, FerdaUNSPECIFIEDorcid.org/0000-0001-9317-8155UNSPECIFIED
Brancati, FrancescoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dobbie, AngusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Smigiel, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gillessen-Kaesbach, GabrieleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wollnik, BerndUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Noegel, Angelika AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Newman, William G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-423567
DOI: 10.1016/j.ajhg.2014.10.008
Journal or Publication Title: Am. J. Hum. Genet.
Volume: 95
Number: 5
Page Range: S. 622 - 633
Date: 2014
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1537-6605
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MENTAL-RETARDATION; PHENOTYPE; PATIENTMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/42356

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