title: Mutations in PIH1D3 Cause X-Linked Primary Ciliary Dyskinesia with Outer and Inner Dynein Arm Defects.
abstract: Defects in motile cilia and sperm flagella cause primary ciliary dyskinesia (PCD), characterized by chronic airway disease, infertility, and left-right body axis disturbance. Here we report maternally inherited and de novo mutations in PIH1D3 in four men affected with PCD. PIH1D3 is located on the X chromosome and is involved in the preassembly of both outer (ODA) and inner (IDA) dynein arms of cilia and sperm flagella. Loss-of-function mutations in PIH1D3 lead to absent ODAs and reduced to absent IDAs, causing ciliary and flagellar immotility. Further, PIH1D3 interacts and co-precipitates with cytoplasmic ODA/IDA assembly factors DNAAF2 and DNAAF4. This result has clinical and genetic counseling implications for genetically unsolved male case subjects with a classic PCD phenotype that lack additional phenotypes such as intellectual disability or retinitis pigmentosa.
authors.affiliation: Department of Pulmonary Diseases, VU University Medical Center, 1007 MB Amsterdam, the Netherlands; Department of Paediatric Pulmonology, VU University Medical Center, 1007 MB Amsterdam, the Netherlands; Department of Clinical Genetics, VU University Medical Center, 1007 MB Amsterdam, the Netherlands.
authors.forename: Tamara
authors.initials: T
authors.lastname: Paff
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Niki T
authors.initials: NT
authors.lastname: Loges
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Isabella
authors.initials: I
authors.lastname: Aprea
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, the Netherlands.
authors.forename: Kaman
authors.initials: K
authors.lastname: Wu
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, the Netherlands.
authors.forename: Zeineb
authors.initials: Z
authors.lastname: Bakey
authors.affiliation: Department of Paediatric Pulmonology, VU University Medical Center, 1007 MB Amsterdam, the Netherlands.
authors.forename: Eric G
authors.initials: EG
authors.lastname: Haarman
authors.affiliation: Department of Pulmonary Diseases, VU University Medical Center, 1007 MB Amsterdam, the Netherlands.
authors.forename: Johannes M A
authors.initials: JMA
authors.lastname: Daniels
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, 1007 MB Amsterdam, the Netherlands.
authors.forename: Erik A
authors.initials: EA
authors.lastname: Sistermans
authors.affiliation: Department of Surgery and Physiology, Amsterdam Cardiovascular Sciences, VU University Medical Center, 1007 MB Amsterdam, the Netherlands.
authors.forename: Natalija
authors.initials: N
authors.lastname: Bogunovic
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Gerard W
authors.initials: GW
authors.lastname: Dougherty
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Inga M
authors.initials: IM
authors.lastname: Höben
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Große-Onnebrink
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Matter
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Olbrich
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Claudius
authors.initials: C
authors.lastname: Werner
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, 1007 MB Amsterdam, the Netherlands.
authors.forename: Gerard
authors.initials: G
authors.lastname: Pals
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, the Netherlands; Pediatric Genetics Division, Center for Pediatrics and Adolescent Medicine, University Hospital Freiburg, 79110 Freiburg, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Schmidts
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Heymut
authors.initials: H
authors.lastname: Omran
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, 1007 MB Amsterdam, the Netherlands. Electronic address: d.micha@vumc.nl.
authors.forename: Dimitra
authors.initials: D
authors.lastname: Micha
mesh_terms: D002923:Cilia / Q000378:metabolism / Q000473:pathology*; D002925:Ciliary Motility Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003593:Cytoplasm / Q000378:metabolism; D004398:Dyneins / Q000378:metabolism*; D005260:Female; D050172:Genes, X-Linked; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D013081:Sperm Motility / Q000235:genetics; D013082:Sperm Tail / Q000378:metabolism / Q000473:pathology*
chemical_list: D004398:Dyneins