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Identification and Analysis of Axonemal Dynein Light Chain 1 in Primary Ciliary Dyskinesia Patients

Department of Pediatrics and Adolescent Medicine, Albert-Ludwigs-University, Freiburg; Institut für Molekularbiologie, Medizinische Hochschule Hannover, Hannover; ⁶Max-Planck Institut for Molecular Genetics, Berlin; and Institute of Human Genetics, University of Goettingen, Goettingen, Germany; Department of Biochemistry, University of Connecticut Health Center, Farmington, Connecticut; Department of Medicine, University of North Carolina, Chapel Hill, North Carolina; Department of Paediatrics and Child Health, Royal Free and University College Medical School London, London, United Kingdom; and Second Department of Pediatrics, School of Medicine, Semmelweis University, Budapest, Hungary

Correspondence and requests for reprints should be addressed to Heymut Omran, M.D., Department of Pediatrics and Adolescent Medicine, Mathildenstrasse 1, 79106 Freiburg, Germany. E-mail: omran{at}kikli.ukl.uni-freiburg.de

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder characterized by chronic infections of the upper and lower airways, randomization of left/right body asymmetry, and reduced fertility. The phenotype results from dysfunction of motile cilia of the respiratory epithelium, at the embryonic node and of sperm flagella. Ultrastructural defects often involve outer dynein arms (ODAs), that are composed of several light (LCs), intermediate, and heavy (HCs) dynein chains. We recently showed that recessive mutations of DNAH5, the human ortholog of the biflagellate Chlamydomonas ODA -HC, cause PCD. In Chlamydomonas, motor protein activity of the -ODA-HC is regulated by binding of the axonemal LC1. We report the identification of the human (DNAL1) and murine (Dnal1) orthologs of the Chlamydomonas LC1-gene. Northern blot and in situ hybridization analyses revealed specific expression in testis, embryonic node, respiratory epithelium, and ependyma, resembling the DNAH5 expression pattern. In silico protein analysis showed complete conservation of the LC1/-HC binding motif in DNAL1. Protein interaction studies demonstrated binding of DNAL1 and DNAH5. Based on these findings, we considered DNAL1 a candidate for PCD and sequenced all exons of DNAL1 in 86 patients. Mutational analysis was negative, excluding a major role of DNAL1 in the pathogenesis of PCD.

Key Words: cilia • primary ciliary dyskinesia • light chain • dynein

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