Biallelic Mutations in LRRC56, Encoding a Protein Associated with Intraflagellar Transport, Cause Mucociliary Clearance and Laterality Defects

Am J Hum Genet. 2018 Nov 1;103(5):727-739. doi: 10.1016/j.ajhg.2018.10.003.

Serge Bonnefoy ¹, Christopher M Watson ², Kristin D Kernohan ³, Moara Lemos ¹, Sebastian Hutchinson ¹, James A Poulter ⁴, Laura A Crinnion ², Ian Berry ⁵, Jennifer Simmonds ⁵, Pradeep Vasudevan ⁶, Chris O'Callaghan ⁷, Robert A Hirst ⁶, Andrew Rutman ⁶, Lijia Huang ³, Taila Hartley ³, David Grynspan ⁸, Eduardo Moya ⁹, Chunmei Li ¹⁰, Ian M Carr ⁴, David T Bonthron ², Michel Leroux ¹⁰, Care4Rare Canada Consortium ³, Kym M Boycott ³, Philippe Bastin ¹¹, Eamonn G Sheridan ¹²

Affiliations

1 Trypanosome Cell Biology Unit & INSERM U1201, Institut Pasteur, 25, rue du Docteur Roux, 75015 Paris, France.
2 Yorkshire Regional Genetics Service, St. James's University Hospital, Leeds LS9 7TF, UK; School of Medicine, University of Leeds, St. James's University Hospital, Leeds LS9 7TF, UK.
3 Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
4 School of Medicine, University of Leeds, St. James's University Hospital, Leeds LS9 7TF, UK.
5 Yorkshire Regional Genetics Service, St. James's University Hospital, Leeds LS9 7TF, UK.
6 Centre for PCD Diagnosis and Research, Department of Infection, Immunity and Inflammation, RKCSB, University of Leicester, Leicester LE2 7LX, UK.
7 Centre for PCD Diagnosis and Research, Department of Infection, Immunity and Inflammation, RKCSB, University of Leicester, Leicester LE2 7LX, UK; Respiratory, Critical Care & Anaesthesia, Institute of Child Health, University College London & Great Ormond Street Children's Hospital, 30 Guilford Street, London WC1N 1EH, UK.
8 Department of Pathology, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, ON K1H 8L1, Canada.
9 Bradford Royal Infirmary, Bradford, West Yorkshire BD9 6R, UK.
10 Department of Molecular Biology and Biochemistry, and Centre for Cell Biology, Development and Disease, Simon Fraser University, Burnaby, BC, Canada.
11 Trypanosome Cell Biology Unit & INSERM U1201, Institut Pasteur, 25, rue du Docteur Roux, 75015 Paris, France. Electronic address: philippe.bastin@pasteur.fr.
12 Yorkshire Regional Genetics Service, St. James's University Hospital, Leeds LS9 7TF, UK; School of Medicine, University of Leeds, St. James's University Hospital, Leeds LS9 7TF, UK. Electronic address: e.sheridan@leeds.ac.uk.

PMID: 30388400 DOI: 10.1016/j.ajhg.2018.10.003

Abstract

Primary defects in motile cilia result in dysfunction of the apparatus responsible for generating fluid flows. Defects in these mechanisms underlie disorders characterized by poor mucus clearance, resulting in susceptibility to chronic recurrent respiratory infections, often associated with infertility; laterality defects occur in about 50% of such individuals. Here we report biallelic variants in LRRC56 (known as oda8 in Chlamydomonas) identified in three unrelated families. The phenotype comprises laterality defects and chronic pulmonary infections. High-speed video microscopy of cultured epithelial cells from an affected individual showed severely dyskinetic cilia but no obvious ultra-structural abnormalities on routine transmission electron microscopy (TEM). Further investigation revealed that LRRC56 interacts with the intraflagellar transport (IFT) protein IFT88. The link with IFT was interrogated in Trypanosoma brucei. In this protist, LRRC56 is recruited to the cilium during axoneme construction, where it co-localizes with IFT trains and is required for the addition of dynein arms to the distal end of the flagellum. In T. brucei carrying LRRC56-null mutations, or a variant resulting in the p.Leu259Pro substitution corresponding to the p.Leu140Pro variant seen in one of the affected families, we observed abnormal ciliary beat patterns and an absence of outer dynein arms restricted to the distal portion of the axoneme. Together, our findings confirm that deleterious variants in LRRC56 result in a human disease and suggest that this protein has a likely role in dynein transport during cilia assembly that is evolutionarily important for cilia motility.

Keywords

cilia; ciliopathies; dynein arms; flagella; intraflagellar transport; left-right asymmetry; leucine-rich repeat protein; trypanosome.

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