Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Hussain, Muhammad Sajid UNSPECIFIED orcid.org/0000-0002-1353-8809 UNSPECIFIED Battaglia, Agatino UNSPECIFIED orcid.org/0000-0002-7128-7606 UNSPECIFIED Szczepanski, Sandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Kaygusuz, Emrah UNSPECIFIED UNSPECIFIED UNSPECIFIED Toliat, Mohammad Reza UNSPECIFIED UNSPECIFIED UNSPECIFIED Sakakibara, Shin-ichi UNSPECIFIED orcid.org/0000-0001-8983-2249 UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Gudrun UNSPECIFIED UNSPECIFIED UNSPECIFIED Moosa, Shahida UNSPECIFIED orcid.org/0000-0002-4463-3067 UNSPECIFIED Yigit, Goekhan UNSPECIFIED UNSPECIFIED UNSPECIFIED Beleggia, Filippo UNSPECIFIED orcid.org/0000-0003-0234-7094 UNSPECIFIED Tinschert, Sigrid UNSPECIFIED UNSPECIFIED UNSPECIFIED Clayton-Smith, Jill UNSPECIFIED UNSPECIFIED UNSPECIFIED Vasudevan, Pradeep UNSPECIFIED UNSPECIFIED UNSPECIFIED Urquhart, Jill E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Donnai, Dian UNSPECIFIED UNSPECIFIED UNSPECIFIED Fryer, Alan UNSPECIFIED UNSPECIFIED UNSPECIFIED Percin, Ferda UNSPECIFIED orcid.org/0000-0001-9317-8155 UNSPECIFIED Brancati, Francesco UNSPECIFIED UNSPECIFIED UNSPECIFIED Dobbie, Angus UNSPECIFIED UNSPECIFIED UNSPECIFIED Smigiel, Robert UNSPECIFIED UNSPECIFIED UNSPECIFIED Gillessen-Kaesbach, Gabriele UNSPECIFIED UNSPECIFIED UNSPECIFIED Wollnik, Bernd UNSPECIFIED UNSPECIFIED UNSPECIFIED Noegel, Angelika Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Newman, William G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED
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:	Keywords Language MENTAL-RETARDATION; PHENOTYPE; PATIENT Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/42356