Recessive HYDIN Mutations Cause Primary Ciliary Dyskinesia without Randomization of Left-Right Body Asymmetry

被引:220
作者
Olbrich, Heike [1 ]
Schmidts, Miriam [2 ]
Werner, Claudius [1 ]
Onoufriadis, Alexandros [2 ]
Loges, Niki T. [1 ]
Raidt, Johanna [1 ]
Banki, Nora Fanni [3 ]
Shoemark, Amelia [4 ]
Burgoyne, Tom [4 ]
Al Turki, Saeed [5 ]
Hurles, Matthew E. [5 ]
Koehler, Gabriele [6 ]
Schroeder, Josef [7 ]
Nuernberg, Gudrun [8 ,9 ,10 ]
Nuernberg, Peter [8 ,9 ,10 ]
Chung, Eddie M. K. [11 ]
Reinhardt, Richard [12 ]
Marthin, June K. [13 ,14 ]
Nielsen, Kim G. [13 ,14 ]
Mitchison, Hannah M. [2 ]
Omran, Heymut [1 ]
机构
[1] Univ Childrens Hosp Muenster, Dept Gen Pediat, D-48149 Munster, Germany
[2] UCL, Inst Child Hlth, Mol Med Unit, London WC1N 1EH, England
[3] Semmelweis Univ, Dept Pediat, H-1085 Budapest, Hungary
[4] Royal Brompton & Harefield NHS Trust, Dept Paediat Resp Med, London, England
[5] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England
[6] Univ Childrens Hosp Muenster, Dept Pathol, D-48149 Munster, Germany
[7] Univ Regensburg, Dept Pathol, D-93053 Regensburg, Germany
[8] Univ Cologne, Cologne Ctr Genom, D-50931 Cologne, Germany
[9] Univ Cologne, Ctr Mol Med Cologne, D-50931 Cologne, Germany
[10] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, D-50931 Cologne, Germany
[11] Univ London Univ Coll, Gen & Adolescent Paediat Unit, Inst Child Hlth, London WC1E 6JJ, England
[12] Max Planck Inst Plant Breeding Res, Genome Ctr Cologne, D-50829 Cologne, Germany
[13] Copenhagen Univ Hosp, Cyst Fibrosis Ctr, DK-2100 Copenhagen, Denmark
[14] Copenhagen Univ Hosp, Pediat Pulm Serv, DK-2100 Copenhagen, Denmark
基金
英国惠康基金;
关键词
OF-FUNCTION MUTATIONS; GENE-PRODUCT; MICE LACKING; PROTEIN; DEFECTS; HYDROCEPHALUS; COMPLEX; FLOW; DNA; DYSFUNCTION;
D O I
10.1016/j.ajhg.2012.08.016
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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(star)), 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.
引用
收藏
页码:672 / 684
页数:13
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