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, Shinichi 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

    Research output: Contribution to journalArticle

    16 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

    Fingerprint

    Cytoskeleton
    Mutation
    Genes
    Proteins
    Tooth Abnormalities
    Spindle Poles
    Syndactyly
    Exome
    Cell Line
    Microcephaly
    Chromosome Segregation
    Frameshift Mutation
    Spindle Apparatus
    human CKAP2 protein
    Filippi syndrome
    Nose
    Microtubules
    Intellectual Disability
    Cell Division
    Hair

    ASJC Scopus subject areas

    • Genetics
    • Genetics(clinical)

    Cite this

    Hussain, M. S., Battaglia, A., Szczepanski, S., Kaygusuz, E., Toliat, M. R., Sakakibara, S., ... 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

    Mutations in CKAP2L, the human homolog of the mouse radmis gene, cause filippi syndrome. / Hussain, Muhammad Sajid; Battaglia, Agatino; Szczepanski, Sandra; Kaygusuz, Emrah; Toliat, Mohammad Reza; Sakakibara, Shinichi; Altmüller, Janine; Thiele, Holger; Nürnberg, Gudrun; Moosa, Shahida; Yigit, Gökhan; Beleggia, Filippo; Tinschert, Sigrid; Clayton-Smith, Jill; Vasudevan, Pradeep; Urquhart, Jill E.; Donnai, Dian; Fryer, Alan; Percin, Ferda; Brancati, Francesco; Dobbie, Angus; ͆migiel, Robert; Gillessen-Kaesbach, Gabriele; Wollnik, Bernd; Anna Noegel, Angelika; Newman, William G.; Nürnberg, Peter.

    In: American Journal of Human Genetics, Vol. 95, No. 5, 2014, p. 622-632.

    Research output: Contribution to journalArticle

    Hussain, MS, Battaglia, A, Szczepanski, S, Kaygusuz, E, Toliat, MR, Sakakibara, S, Altmüller, J, Thiele, H, Nürnberg, G, Moosa, S, Yigit, G, Beleggia, F, Tinschert, S, Clayton-Smith, J, Vasudevan, P, Urquhart, JE, Donnai, D, Fryer, A, Percin, F, Brancati, F, Dobbie, A, ͆migiel, R, Gillessen-Kaesbach, G, Wollnik, B, Anna Noegel, A, Newman, WG & Nürnberg, P 2014, 'Mutations in CKAP2L, the human homolog of the mouse radmis gene, cause filippi syndrome', American Journal of Human Genetics, vol. 95, no. 5, pp. 622-632. https://doi.org/10.1016/j.ajhg.2014.10.008
    Hussain, Muhammad Sajid ; Battaglia, Agatino ; Szczepanski, Sandra ; Kaygusuz, Emrah ; Toliat, Mohammad Reza ; Sakakibara, Shinichi ; Altmüller, Janine ; Thiele, Holger ; Nürnberg, Gudrun ; Moosa, Shahida ; Yigit, Gökhan ; Beleggia, Filippo ; Tinschert, Sigrid ; Clayton-Smith, Jill ; Vasudevan, Pradeep ; Urquhart, Jill E. ; Donnai, Dian ; Fryer, Alan ; Percin, Ferda ; Brancati, Francesco ; Dobbie, Angus ; ͆migiel, Robert ; Gillessen-Kaesbach, Gabriele ; Wollnik, Bernd ; Anna Noegel, Angelika ; Newman, William G. ; Nürnberg, Peter. / Mutations in CKAP2L, the human homolog of the mouse radmis gene, cause filippi syndrome. In: American Journal of Human Genetics. 2014 ; Vol. 95, No. 5. pp. 622-632.
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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.",
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    AU - Hussain, Muhammad Sajid

    AU - Battaglia, Agatino

    AU - Szczepanski, Sandra

    AU - Kaygusuz, Emrah

    AU - Toliat, Mohammad Reza

    AU - Sakakibara, Shinichi

    AU - Altmüller, Janine

    AU - Thiele, Holger

    AU - Nürnberg, Gudrun

    AU - Moosa, Shahida

    AU - Yigit, Gökhan

    AU - Beleggia, Filippo

    AU - Tinschert, Sigrid

    AU - Clayton-Smith, Jill

    AU - Vasudevan, Pradeep

    AU - Urquhart, Jill E.

    AU - Donnai, Dian

    AU - Fryer, Alan

    AU - Percin, Ferda

    AU - Brancati, Francesco

    AU - Dobbie, Angus

    AU - ͆migiel, Robert

    AU - Gillessen-Kaesbach, Gabriele

    AU - Wollnik, Bernd

    AU - Anna Noegel, Angelika

    AU - Newman, William G.

    AU - Nürnberg, Peter

    PY - 2014

    Y1 - 2014

    N2 - 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.

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