title: Recessive HYDIN mutations cause primary ciliary dyskinesia without randomization of left-right body asymmetry.
abstract: Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder characterized by defective cilia and flagella motility. Chronic destructive-airway disease is caused by abnormal respiratory-tract mucociliary clearance. Abnormal propulsion of sperm flagella contributes to male infertility. Genetic defects in most individuals affected by PCD cause randomization of left-right body asymmetry; approximately half show situs inversus or situs ambiguous. Almost 70 years after the hy3 mouse possessing Hydin mutations was described as a recessive hydrocephalus model, we report HYDIN mutations in PCD-affected persons without hydrocephalus. By homozygosity mapping, we identified a PCD-associated locus, chromosomal region 16q21-q23, which contains HYDIN. However, a nearly identical 360 kb paralogous segment (HYDIN2) in chromosomal region 1q21.1 complicated mutational analysis. In three affected German siblings linked to HYDIN, we identified homozygous c.3985G>T mutations that affect an evolutionary conserved splice acceptor site and that subsequently cause aberrantly spliced transcripts predicting premature protein termination in respiratory cells. Parallel whole-exome sequencing identified a homozygous nonsense HYDIN mutation, c.922A>T (p.Lys307(∗)), in six individuals from three Faroe Island PCD-affected families that all carried an 8.8 Mb shared haplotype across HYDIN, indicating an ancestral founder mutation in this isolated population. We demonstrate by electron microscopy tomography that, consistent with the effects of loss-of-function mutations, HYDIN mutant respiratory cilia lack the C2b projection of the central pair (CP) apparatus; similar findings were reported in Hydin-deficient Chlamydomonas and mice. High-speed videomicroscopy demonstrated markedly reduced beating amplitudes of respiratory cilia and stiff sperm flagella. Like the hy3 mouse model, all nine PCD-affected persons had normal body composition because nodal cilia function is apparently not dependent on the function of the CP apparatus.
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Olbrich
authors.forename: Miriam
authors.initials: M
authors.lastname: Schmidts
authors.forename: Claudius
authors.initials: C
authors.lastname: Werner
authors.forename: Alexandros
authors.initials: A
authors.lastname: Onoufriadis
authors.forename: Niki T
authors.initials: NT
authors.lastname: Loges
authors.forename: Johanna
authors.initials: J
authors.lastname: Raidt
authors.forename: Nora Fanni
authors.initials: NF
authors.lastname: Banki
authors.forename: Amelia
authors.initials: A
authors.lastname: Shoemark
authors.forename: Tom
authors.initials: T
authors.lastname: Burgoyne
authors.forename: Saeed
authors.initials: S
authors.lastname: Al Turki
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Hurles
authors.forename: Gabriele
authors.initials: G
authors.lastname: Köhler
authors.forename: Josef
authors.initials: J
authors.lastname: Schroeder
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Eddie M K
authors.initials: EM
authors.lastname: Chung
authors.forename: Richard
authors.initials: R
authors.lastname: Reinhardt
authors.forename: June K
authors.initials: JK
authors.lastname: Marthin
authors.forename: Kim G
authors.initials: KG
authors.lastname: Nielsen
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Mitchison
authors.forename: Heymut
authors.initials: H
authors.lastname: Omran
mesh_terms: D000328:Adult; D001483:Base Sequence; D002878:Chromosomes, Human, Pair 1; D002885:Chromosomes, Human, Pair 16; D002923:Cilia / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D005808:Genes, Recessive; D056426:Genetic Loci / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D006849:Hydrocephalus / Q000235:genetics; D007619:Kartagener Syndrome / Q000235:genetics*; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D012326:RNA Splicing / Q000235:genetics; D035781:Siblings; D012857:Situs Inversus / Q000235:genetics
chemical_list: D008840:Microfilament Proteins