Deletions and point mutations of LRRC50 cause primary ciliary dyskinesia due to dynein arm defects.
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.
Loges
Niki Tomas
NT
Department of Paediatrics and Adolescent Medicine, University Hospital 79106 Freiburg, Germany.
Olbrich
Heike
H
Becker-Heck
Anita
A
Häffner
Karsten
K
Heer
Angelina
A
Reinhard
Christina
C
Schmidts
Miriam
M
Kispert
Andreas
A
Zariwala
Maimoona A
MA
Leigh
Margaret W
MW
Knowles
Michael R
MR
Zentgraf
Hanswalter
H
Seithe
Horst
H
Nürnberg
Gudrun
G
Nürnberg
Peter
P
Reinhardt
Richard
R
Omran
Heymut
H
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
C546358:DNAAF1 protein, human; D008869:Microtubule-Associated Proteins; D011506:Proteins; D004398:Dyneins