dc.contributor.author |
Olbrich H |
|
dc.contributor.author |
Schmidts M |
|
dc.contributor.author |
Werner C |
|
dc.contributor.author |
Onoufriadis A |
|
dc.contributor.author |
Loges NT |
|
dc.contributor.author |
Bánki, Nóra Fanni |
|
dc.contributor.author |
Shoemark, A |
|
dc.contributor.author |
Burgoyne, T |
|
dc.contributor.author |
Turki, S A |
|
dc.contributor.author |
Hurles, M E |
|
dc.contributor.author |
UK10K Consortium |
|
dc.contributor.author |
Köhler, G |
|
dc.contributor.author |
Schroeder, J |
|
dc.contributor.author |
Nürnberg, G |
|
dc.contributor.author |
Nürnberg, P |
|
dc.contributor.author |
Chung, E M |
|
dc.contributor.author |
Reinhardt, R |
|
dc.contributor.author |
Marthin, J K |
|
dc.contributor.author |
Nielsen, K G |
|
dc.contributor.author |
Mitchison, M H |
|
dc.contributor.author |
Omran, H |
|
dc.date.accessioned |
2016-08-25T07:19:42Z |
|
dc.date.available |
2016-08-25T07:19:42Z |
|
dc.date.issued |
2012 |
|
dc.identifier.citation |
pagination=672-684;journalVolume=91;journalIssueNumber=4;journalTitle=AMERICAN JOURNAL OF HUMAN GENETICS; |
hu |
dc.identifier.issn |
0002-9297 |
|
dc.identifier.uri |
http://repo.lib.semmelweis.hu//handle/123456789/2257 |
|
dc.identifier.uri |
doi:10.1016/j.ajhg.2012.08.016 |
|
dc.description.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. |
hu |
dc.relation.ispartof |
urn:issn:0002-9297 |
|
dc.title |
Recessive HYDIN Mutations Cause Primary Ciliary Dyskinesia without Randomization of Left-Right Body Asymmetry |
hu |
dc.type |
Journal Article |
hu |
dc.date.updated |
2015-11-03T11:13:06Z |
|
dc.language.rfc3066 |
en |
hu |
dc.identifier.mtmt |
2105053 |
|
dc.identifier.wos |
000309568500009 |
|
dc.identifier.pubmed |
23022101 |
|
dc.contributor.department |
SE/AOK/K/I. Sz. Gyermekgyógyászati Klinika |
|
dc.contributor.institution |
Semmelweis Egyetem |
|