Mutations in CKAP2L, the human homolog of the mouse radmis gene, cause filippi syndrome

Muhammad Sajid Hussain, Agatino Battaglia, Sandra Szczepanski, Emrah Kaygusuz, Mohammad Reza Toliat, Shin Ichi Sakakibara, Janine Altmüller, Holger Thiele, Gudrun Nürnberg, Shahida Moosa, Gökhan Yigit, Filippo Beleggia, Sigrid Tinschert, Jill Clayton-Smith, Pradeep Vasudevan, Jill E. Urquhart, Dian Donnai, Alan Fryer, Ferda Percin, Francesco BrancatiAngus Dobbie, Robert ͆migiel, Gabriele Gillessen-Kaesbach, Bernd Wollnik, Angelika Anna Noegel, William G. Newman, Peter Nürnberg

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19 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)622-632
Number of pages11
JournalAmerican Journal of Human Genetics
Volume95
Issue number5
DOIs
Publication statusPublished - 2014 Jan 1

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ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Hussain, M. S., Battaglia, A., Szczepanski, S., Kaygusuz, E., Toliat, M. R., Sakakibara, S. I., Altmüller, J., Thiele, H., Nürnberg, G., Moosa, S., Yigit, G., Beleggia, F., Tinschert, S., Clayton-Smith, J., Vasudevan, P., Urquhart, J. E., Donnai, D., Fryer, A., Percin, F., ... Nürnberg, P. (2014). Mutations in CKAP2L, the human homolog of the mouse radmis gene, cause filippi syndrome. American Journal of Human Genetics, 95(5), 622-632. https://doi.org/10.1016/j.ajhg.2014.10.008