title: Identification and analysis of axonemal dynein light chain 1 in primary ciliary dyskinesia patients.
abstract: 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 gamma-HC, cause PCD. In Chlamydomonas, motor protein activity of the gamma-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/gamma-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.
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Albert-Ludwigs-University, Freiburg, Germany.
authors.forename: Judit
authors.initials: J
authors.lastname: Horváth
authors.forename: Manfred
authors.initials: M
authors.lastname: Fliegauf
authors.forename: Heike
authors.initials: H
authors.lastname: Olbrich
authors.forename: Andreas
authors.initials: A
authors.lastname: Kispert
authors.forename: Stephen M
authors.initials: SM
authors.lastname: King
authors.forename: Hannah
authors.initials: H
authors.lastname: Mitchison
authors.forename: Maimoona A
authors.initials: MA
authors.lastname: Zariwala
authors.forename: Michael R
authors.initials: MR
authors.lastname: Knowles
authors.forename: Ralf
authors.initials: R
authors.lastname: Sudbrak
authors.forename: György
authors.initials: G
authors.lastname: Fekete
authors.forename: Juergen
authors.initials: J
authors.lastname: Neesen
authors.forename: Richard
authors.initials: R
authors.lastname: Reinhardt
authors.forename: Heymut
authors.initials: H
authors.lastname: Omran
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D015152:Blotting, Northern; D002460:Cell Line; D002696:Chlamydomonas / Q000378:metabolism; D003001:Cloning, Molecular; D056445:Cytoplasmic Dyneins; D004252:DNA Mutational Analysis; D030541:Databases, Genetic; D004398:Dyneins / Q000096:biosynthesis / Q000737:chemistry*; D004622:Embryo, Mammalian / Q000378:metabolism; D004625:Embryo, Nonmammalian; D004805:Ependyma / Q000378:metabolism; D019143:Evolution, Molecular; D005091:Exons; D020224:Expressed Sequence Tags; D005407:Flagella / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D007438:Introns; D007619:Kartagener Syndrome / Q000378:metabolism*; D008168:Lung / Q000196:embryology / Q000473:pathology; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D016366:Open Reading Frames; D010641:Phenotype; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D012333:RNA, Messenger / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D013094:Spermatozoa / Q000378:metabolism; D013552:Swine; D013737:Testis / Q000378:metabolism; D014132:Trachea / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; C427758:DYNLL1 protein, human; D056445:Cytoplasmic Dyneins; D004398:Dyneins