title: Deletions and point mutations of LRRC50 cause primary ciliary dyskinesia due to dynein arm defects.
abstract: Genetic defects affecting motility of cilia and flagella cause chronic destructive airway disease, randomization of left-right body asymmetry, and, frequently, male infertility in primary ciliary dyskinesia (PCD). 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. Here, we demonstrate that large genomic deletions, as well as point mutations involving LRRC50, are responsible for a distinct PCD variant that is characterized by a combined defect involving assembly of the ODAs and IDAs. Functional analyses showed that LRRC50 deficiency disrupts assembly of distally and proximally DNAH5- and DNAI2-containing ODA complexes, as well as DNALI1-containing IDA complexes, resulting in immotile cilia. On the basis of these findings, we assume that LRRC50 plays a role in assembly of distinct dynein-arm complexes.
authors: Department of Paediatrics and Adolescent Medicine, University Hospital 79106 Freiburg, Germany.
authors: Niki Tomas
authors: NT
authors: Loges
authors: Heike
authors: H
authors: Olbrich
authors: Anita
authors: A
authors: Becker-Heck
authors: Karsten
authors: K
authors: Häffner
authors: Angelina
authors: A
authors: Heer
authors: Christina
authors: C
authors: Reinhard
authors: Miriam
authors: M
authors: Schmidts
authors: Andreas
authors: A
authors: Kispert
authors: Maimoona A
authors: MA
authors: Zariwala
authors: Margaret W
authors: MW
authors: Leigh
authors: Michael R
authors: MR
authors: Knowles
authors: Hanswalter
authors: H
authors: Zentgraf
authors: Horst
authors: H
authors: Seithe
authors: Gudrun
authors: G
authors: Nürnberg
authors: Peter
authors: P
authors: Nürnberg
authors: Richard
authors: R
authors: Reinhardt
authors: Heymut
authors: H
authors: Omran
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D000818:Animals; D002875:Chromosomes / Q000648:ultrastructure; D004252:DNA Mutational Analysis; D004398:Dyneins / Q000235:genetics*; D005260:Female; D005407:Flagella; D017353:Gene Deletion; D023281:Genomics; D006801:Humans; D007619:Kartagener Syndrome / Q000235:genetics*; D008297:Male; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000502:physiology*; D008957:Models, Genetic; D009154:Mutation; D017354:Point Mutation; D011506:Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C546358:DNAAF1 protein, human; D008869:Microtubule-Associated Proteins; D011506:Proteins; D004398:Dyneins