TY - JOUR
T1 - Recessive HYDIN mutations cause primary ciliary dyskinesia without randomization of left-right body asymmetry
AU - Olbrich, Heike
AU - Schmidts, Miriam
AU - Werner, Claudius
AU - Onoufriadis, Alexandros
AU - Loges, Niki T.
AU - Raidt, Johanna
AU - Banki, Nora Fanni
AU - Shoemark, Amelia
AU - Burgoyne, Tom
AU - Al Turki, Saeed
AU - Hurles, Matthew E.
AU - Köhler, Gabriele
AU - Schroeder, Josef
AU - Nürnberg, Gudrun
AU - Nürnberg, Peter
AU - Chung, Eddie M.K.
AU - Reinhardt, Richard
AU - Marthin, June K.
AU - Nielsen, Kim G.
AU - Mitchison, Hannah M.
AU - Omran, Heymut
N1 - Funding Information:
We are grateful to the affected persons and their families for their participation in this study. We thank the German patient support group “Kartagener Syndrom und Primaere Ciliaere Dyskinesie e.V.” We thank Angelina Heer, Martina Herting, Denise Nergenau, Carmen Kopp, and Dinu Antony for excellent technical assistance. The UK10K project ( http://www.uk10k.org/ ) is funded by the Wellcome Trust. Contributing investigators of the UK10K project are listed in the Supplemental Data . H.M.M. thanks R. Mark Gardiner and Maggie Meeks for originating the Faroe Island project and Peter J. Scambler and Philip L. Beales for their work on the UK10K project. This work was supported by grants from the Newlife Foundation for Disabled Children and Action Medical Research (to H.M.M.), the Kindness for Kids Foundation, Deutsche Forschungsgemeinschaft (DFG Om 6/4), GRK 1104, SFB 592, and the Cell Dynamics and Disease graduate program, as well as the European Community’s SYSCILIA project (to H.O.). The manuscript has been seen and approved by all authors.
Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.
PY - 2012/10/5
Y1 - 2012/10/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84867244938&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2012.08.016
DO - 10.1016/j.ajhg.2012.08.016
M3 - Article
C2 - 23022101
AN - SCOPUS:84867244938
SN - 0002-9297
VL - 91
SP - 672
EP - 684
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 4
ER -