title: Primary ciliary dyskinesia caused by homozygous mutation in DNAL1, encoding dynein light chain 1.
abstract: In primary ciliary dyskinesia (PCD), genetic defects affecting motility of cilia and flagella cause chronic destructive airway disease, randomization of left-right body asymmetry, and, frequently, male infertility. The most frequent defects involve outer and inner dynein arms (ODAs and IDAs) that are large multiprotein complexes responsible for cilia-beat generation and regulation, respectively. Although it has long been suspected that mutations in DNAL1 encoding the ODA light chain1 might cause PCD such mutations were not found. We demonstrate here that a homozygous point mutation in this gene is associated with PCD with absent or markedly shortened ODA. The mutation (NM_031427.3: c.449A>G; p.Asn150Ser) changes the Asn at position150, which is critical for the proper tight turn between the β strand and the α helix of the leucine-rich repeat in the hydrophobic face that connects to the dynein heavy chain. The mutation reduces the stability of the axonemal dynein light chain 1 and damages its interactions with dynein heavy chain and with tubulin. This study adds another important component to understanding the types of mutations that cause PCD and provides clinical information regarding a specific mutation in a gene not yet known to be associated with PCD.
authors.affiliation: Department of Virology and Developmental Genetics, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Masha
authors.initials: M
authors.lastname: Mazor
authors.forename: Soliman
authors.initials: S
authors.lastname: Alkrinawi
authors.forename: Vered
authors.initials: V
authors.lastname: Chalifa-Caspi
authors.forename: Esther
authors.initials: E
authors.lastname: Manor
authors.forename: Val C
authors.initials: VC
authors.lastname: Sheffield
authors.forename: Micha
authors.initials: M
authors.lastname: Aviram
authors.forename: Ruti
authors.initials: R
authors.lastname: Parvari
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D056444:Axonemal Dyneins / Q000235:genetics*; D002923:Cilia / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005407:Flagella / Q000235:genetics; D005786:Gene Expression Regulation; D006720:Homozygote; D006801:Humans; D007248:Infertility, Male / Q000209:etiology / Q000378:metabolism; D007619:Kartagener Syndrome / Q000209:etiology* / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D010641:Phenotype; D017354:Point Mutation; D017433:Protein Structure, Secondary; D014404:Tubulin / Q000235:genetics
chemical_list: D014404:Tubulin; D056444:Axonemal Dyneins