Recessive HYDIN mutations cause primary ciliary dyskinesia without randomization of left-right body asymmetry. Olbrich, H., Schmidts, M., Werner, C., Onoufriadis, A., Loges, N. T., Raidt, J., Banki, N. F., Shoemark, A., Burgoyne, T., Al Turki, S., Hurles, M. E., UK10K Consortium, Köhler, G., Schroeder, J., Nürnberg, G., Nürnberg, P., Chung, E. M. K., Reinhardt, R., Marthin, J. K., Nielsen, K. G., Mitchison, H. M., & Omran, H. American Journal of Human Genetics, 91(4):672–684, October, 2012.
doi  abstract   bibtex   
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\textgreaterT 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\textgreaterT (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.
@article{olbrich_recessive_2012,
	title = {Recessive {HYDIN} mutations cause primary ciliary dyskinesia without randomization of left-right body asymmetry},
	volume = {91},
	issn = {1537-6605},
	doi = {10.1016/j.ajhg.2012.08.016},
	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{\textgreater}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{\textgreater}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.},
	language = {eng},
	number = {4},
	journal = {American Journal of Human Genetics},
	author = {Olbrich, Heike and Schmidts, Miriam and Werner, Claudius and Onoufriadis, Alexandros and Loges, Niki T. and Raidt, Johanna and Banki, Nora Fanni and Shoemark, Amelia and Burgoyne, Tom and Al Turki, Saeed and Hurles, Matthew E. and {UK10K Consortium} and Köhler, Gabriele and Schroeder, Josef and Nürnberg, Gudrun and Nürnberg, Peter and Chung, Eddie M. K. and Reinhardt, Richard and Marthin, June K. and Nielsen, Kim G. and Mitchison, Hannah M. and Omran, Heymut},
	month = oct,
	year = {2012},
	pmid = {23022101},
	pmcid = {PMC3484652},
	keywords = {Adult, Base Sequence, Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 16, Cilia, DNA Mutational Analysis, Female, Genes, Recessive, Genetic Loci, Genetic Predisposition to Disease, Haplotypes, Homozygote, Humans, Hydrocephalus, Kartagener Syndrome, Male, Microfilament Proteins, Molecular Sequence Data, Mutation, Pedigree, RNA Splicing, Siblings, Situs Inversus},
	pages = {672--684}
}

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