ALBERT

Description: 〈p〉Publication date: 1 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 The American Journal of Human Genetics, Volume 103, Issue 5〈/p〉 〈p〉Author(s): Serge Bonnefoy, Christopher M. Watson, Kristin D. Kernohan, Moara Lemos, Sebastian Hutchinson, James A. Poulter, Laura A. Crinnion, Ian Berry, Jennifer Simmonds, Pradeep Vasudevan, Chris O’Callaghan, Robert A. Hirst, Andrew Rutman, Lijia Huang, Taila Hartley, David Grynspan, Eduardo Moya, Chunmei Li, Ian M. Carr, David T. Bonthron〈/p〉 〈div〉〈p〉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 〈em〉LRRC56〈/em〉 (known as 〈em〉oda8〈/em〉 in 〈em〉Chlamydomonas〈/em〉) 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 〈em〉Trypanosoma brucei.〈/em〉 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 〈em〉T. brucei〈/em〉 carrying 〈em〉LRRC56〈/em〉-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 〈em〉LRRC56〈/em〉 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.〈/p〉〈/div〉