DYNC2LI1 mutations broaden the clinical spectrum of dynein-2 defects

Keßler K, Wunderlich I, Uebe S, Falk N, Gießl A, Brandstätter JH, Popp B, Klinger P, Ekici AB, Sticht H, Dörr HG, Reis A, Roepman R, Seemanova E, Thiel C (2015)

Publication Type: Journal article

Publication year: 2015

Journal

Scientific Reports Nature Publishing Group: Open Access Journals - Option B

Book Volume: 5

Pages Range: 11649

DOI: 10.1038/srep11649

Abstract

Skeletal ciliopathies are a heterogeneous group of autosomal recessive osteochondrodysplasias caused by defects in formation, maintenance and function of the primary cilium. Mutations in the underlying genes affect the molecular motors, intraflagellar transport complexes (IFT), or the basal body. The more severe phenotypes are caused by defects of genes of the dynein-2 complex, where mutations in DYNC2H1, WDR34 and WDR60 have been identified. In a patient with a Jeune-like phenotype we performed exome sequencing and identified compound heterozygous missense and nonsense mutations in DYNC2LI1 segregating with the phenotype. DYNC2LI1 is ubiquitously expressed and interacts with DYNC2H1 to form the dynein-2 complex important for retrograde IFT. Using DYNC2LI1 siRNA knockdown in fibroblasts we identified a significantly reduced cilia length proposed to affect cilia function. In addition, depletion of DYNC2LI1 induced altered cilia morphology with broadened ciliary tips and accumulation of IFT-B complex proteins in accordance with retrograde IFT defects. Our results expand the clinical spectrum of ciliopathies caused by defects of the dynein-2 complex.

Authors with CRIS profile

Kristin Keßler Lehrstuhl für Humangenetik Steffen Uebe Institute of Human Genetics Nathalie Falk Lehrstuhl für Tierphysiologie Andreas Gießl Lehrstuhl für Tierphysiologie Johann Helmut Brandstätter Lehrstuhl für Tierphysiologie Patricia Klinger Lehrstuhl für Funktionelle und Klinische Anatomie Arif Bülent Ekici Institute of Human Genetics Heinrich Sticht Professur für Bioinformatik Helmuth-Günther Dörr Professur für Kinderheilkunde mit dem Schwerpunkt Kinder-Endokrinologie und Diabetologie (Stiftungsprofessur) André Wiesmann da Silva Reis Lehrstuhl für Humangenetik Christian Thiel Medizinische Fakultät

Involved external institutions

Radboud University Nijmegen NL Netherlands (NL) Univerzita Karlova v Praze / Charles University in Prague CZ Czech Republic (CZ)

How to cite

APA:

Keßler, K., Wunderlich, I., Uebe, S., Falk, N., Gießl, A., Brandstätter, J.H.,... Thiel, C. (2015). DYNC2LI1 mutations broaden the clinical spectrum of dynein-2 defects. Scientific Reports, 5, 11649. https://dx.doi.org/10.1038/srep11649

MLA:

Keßler, Kristin, et al. "DYNC2LI1 mutations broaden the clinical spectrum of dynein-2 defects." Scientific Reports 5 (2015): 11649.

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