Universität zu Köln

Olbrich, Heike, Schmidts, Miriam ORCID: 0000-0002-1714-6749, Werner, Claudius, Onoufriadis, Alexandros, Loges, Niki T., Raidt, Johanna, Banki, Nora Fanni, Shoemark, Amelia ORCID: 0000-0001-7360-6060, Burgoyne, Tom, Al Turki, Saeed, Hurles, Matthew E., Koehler, Gabriele, Schroeder, Josef, Nuernberg, Gudrun, Nuernberg, Peter, Chung, Eddie M. K., Reinhardt, Richard ORCID: 0000-0001-9376-2132, Marthin, June K., Nielsen, Kim G., Mitchison, Hannah M. and Omran, Heymut (2012). Recessive HYDIN Mutations Cause Primary Ciliary Dyskinesia without Randomization of Left-Right Body Asymmetry. Am. J. Hum. Genet., 91 (4). S. 672 - 685. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

Full text not available from this repository.

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(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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Olbrich, Heike UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmidts, Miriam UNSPECIFIED orcid.org/0000-0002-1714-6749 UNSPECIFIED Werner, Claudius UNSPECIFIED UNSPECIFIED UNSPECIFIED Onoufriadis, Alexandros UNSPECIFIED UNSPECIFIED UNSPECIFIED Loges, Niki T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Raidt, Johanna UNSPECIFIED UNSPECIFIED UNSPECIFIED Banki, Nora Fanni UNSPECIFIED UNSPECIFIED UNSPECIFIED Shoemark, Amelia UNSPECIFIED orcid.org/0000-0001-7360-6060 UNSPECIFIED Burgoyne, Tom UNSPECIFIED UNSPECIFIED UNSPECIFIED Al Turki, Saeed UNSPECIFIED UNSPECIFIED UNSPECIFIED Hurles, Matthew E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Koehler, Gabriele UNSPECIFIED UNSPECIFIED UNSPECIFIED Schroeder, Josef UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Gudrun UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Chung, Eddie M. K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Reinhardt, Richard UNSPECIFIED orcid.org/0000-0001-9376-2132 UNSPECIFIED Marthin, June K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Nielsen, Kim G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mitchison, Hannah M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Omran, Heymut UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-481140
DOI:	10.1016/j.ajhg.2012.08.016
Journal or Publication Title:	Am. J. Hum. Genet.
Volume:	91
Number:	4
Page Range:	S. 672 - 685
Date:	2012
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	1537-6605
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language OF-FUNCTION MUTATIONS; GENE-PRODUCT; MICE LACKING; PROTEIN; DEFECTS; HYDROCEPHALUS; COMPLEX; FLOW; DNA; DYSFUNCTION Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/48114