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SPEF2- And HYDIN-mutant cilia lack the central pair-associated protein SPEF2, aiding primary ciliary dyskinesia diagnostics

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Harvard

Cindrić, S, Dougherty, GW, Olbrich, H, Hjeij, R, Loges, NT, Amirav, I, Philipsen, MC, Marthin, JK, Nielsen, KG, Sutharsan, S, Raidt, J, Werner, C, Pennekamp, P, Dworniczak, B & Omran, H 2020, 'SPEF2- And HYDIN-mutant cilia lack the central pair-associated protein SPEF2, aiding primary ciliary dyskinesia diagnostics' American Journal of Respiratory Cell and Molecular Biology, bind 62, nr. 3, s. 382-396. https://doi.org/10.1165/rcmb.2019-0086OC

APA

CBE

Cindrić S, Dougherty GW, Olbrich H, Hjeij R, Loges NT, Amirav I, Philipsen MC, Marthin JK, Nielsen KG, Sutharsan S, Raidt J, Werner C, Pennekamp P, Dworniczak B, Omran H. 2020. SPEF2- And HYDIN-mutant cilia lack the central pair-associated protein SPEF2, aiding primary ciliary dyskinesia diagnostics. American Journal of Respiratory Cell and Molecular Biology. 62(3):382-396. https://doi.org/10.1165/rcmb.2019-0086OC

MLA

Vancouver

Author

Cindrić, Sandra ; Dougherty, Gerard W ; Olbrich, Heike ; Hjeij, Rim ; Loges, Niki Tomas ; Amirav, Israel ; Philipsen, Maria C ; Marthin, June K ; Nielsen, Kim G ; Sutharsan, Sivagurunathan ; Raidt, Johanna ; Werner, Claudius ; Pennekamp, Petra ; Dworniczak, Bernd ; Omran, Heymut. / SPEF2- And HYDIN-mutant cilia lack the central pair-associated protein SPEF2, aiding primary ciliary dyskinesia diagnostics. I: American Journal of Respiratory Cell and Molecular Biology. 2020 ; Bind 62, Nr. 3. s. 382-396.

Bibtex

@article{c45c56dc920c43d48a2fce718275c912,
title = "SPEF2- And HYDIN-mutant cilia lack the central pair-associated protein SPEF2, aiding primary ciliary dyskinesia diagnostics",
abstract = "Primary ciliary dyskinesia (PCD) is a genetically heterogeneous chronic destructive airway disease. PCD is traditionally diagnosed by nasal nitric oxide measurement, analysis of ciliary beating, transmission electron microscopy (TEM), and/or genetic testing. In most genetic PCD variants, laterality defects can occur. However, it is difficult to establish a diagnosis in individuals with PCD and central pair (CP) defects, and alternative strategies are required because of very subtle ciliary beating abnormalities, a normal ciliary ultrastructure, and normal situs composition. Mutations in HYDIN are known to cause CP defects, but the genetic analysis of HYDIN variants is confounded by the pseudogene HYDIN2, which is almost identical in terms of intron/exon structure. We have previously shown that several types of PCD can be diagnosed via immunofluorescence (IF) microscopy analyses. Here, using IF microscopy, we demonstrated that in individuals with PCD and CP defects, the CP-associated protein SPEF2 is absent inHYDIN-mutant cells, revealing its dependence on functional HYDIN. Next, we performed IF analyses of SPEF2 in respiratory cells from 189 individuals with suspected PCD and situs solitus. Forty-one of the 189 individuals had undetectable SPEF2 and were subjected to a genetic analysis, which revealed one novel loss-of-function mutation in SPEF2 and three reported and 13 novel HYDIN mutations in 15 individuals. The remaining 25 individuals are good candidates for new, as-yet uncharacterized PCD variants that affect the CP apparatus. SPEF2 mutations have been associated with male infertility but have not previously been identified to cause PCD. We identified a mutation of SPEF2 that is causative for PCD with a CP defect. We conclude that SPEF2 IF analyses can facilitate the detection of CP defects and evaluation of the pathogenicity of HYDIN variants, thus aiding the molecular diagnosis of CP defects.",
keywords = "Cilia, HYDIN2, Immunofluorescence microscopy analysis, Situs solitus, Test sensitivity and specificity",
author = "Sandra Cindrić and Dougherty, {Gerard W} and Heike Olbrich and Rim Hjeij and Loges, {Niki Tomas} and Israel Amirav and Philipsen, {Maria C} and Marthin, {June K} and Nielsen, {Kim G} and Sivagurunathan Sutharsan and Johanna Raidt and Claudius Werner and Petra Pennekamp and Bernd Dworniczak and Heymut Omran",
year = "2020",
month = "3",
doi = "10.1165/rcmb.2019-0086OC",
language = "English",
volume = "62",
pages = "382--396",
journal = "American Journal of Respiratory Cell and Molecular Biology",
issn = "1044-1549",
publisher = "American Thoracic Society",
number = "3",

}

RIS

TY - JOUR

T1 - SPEF2- And HYDIN-mutant cilia lack the central pair-associated protein SPEF2, aiding primary ciliary dyskinesia diagnostics

AU - Cindrić, Sandra

AU - Dougherty, Gerard W

AU - Olbrich, Heike

AU - Hjeij, Rim

AU - Loges, Niki Tomas

AU - Amirav, Israel

AU - Philipsen, Maria C

AU - Marthin, June K

AU - Nielsen, Kim G

AU - Sutharsan, Sivagurunathan

AU - Raidt, Johanna

AU - Werner, Claudius

AU - Pennekamp, Petra

AU - Dworniczak, Bernd

AU - Omran, Heymut

PY - 2020/3

Y1 - 2020/3

N2 - Primary ciliary dyskinesia (PCD) is a genetically heterogeneous chronic destructive airway disease. PCD is traditionally diagnosed by nasal nitric oxide measurement, analysis of ciliary beating, transmission electron microscopy (TEM), and/or genetic testing. In most genetic PCD variants, laterality defects can occur. However, it is difficult to establish a diagnosis in individuals with PCD and central pair (CP) defects, and alternative strategies are required because of very subtle ciliary beating abnormalities, a normal ciliary ultrastructure, and normal situs composition. Mutations in HYDIN are known to cause CP defects, but the genetic analysis of HYDIN variants is confounded by the pseudogene HYDIN2, which is almost identical in terms of intron/exon structure. We have previously shown that several types of PCD can be diagnosed via immunofluorescence (IF) microscopy analyses. Here, using IF microscopy, we demonstrated that in individuals with PCD and CP defects, the CP-associated protein SPEF2 is absent inHYDIN-mutant cells, revealing its dependence on functional HYDIN. Next, we performed IF analyses of SPEF2 in respiratory cells from 189 individuals with suspected PCD and situs solitus. Forty-one of the 189 individuals had undetectable SPEF2 and were subjected to a genetic analysis, which revealed one novel loss-of-function mutation in SPEF2 and three reported and 13 novel HYDIN mutations in 15 individuals. The remaining 25 individuals are good candidates for new, as-yet uncharacterized PCD variants that affect the CP apparatus. SPEF2 mutations have been associated with male infertility but have not previously been identified to cause PCD. We identified a mutation of SPEF2 that is causative for PCD with a CP defect. We conclude that SPEF2 IF analyses can facilitate the detection of CP defects and evaluation of the pathogenicity of HYDIN variants, thus aiding the molecular diagnosis of CP defects.

AB - Primary ciliary dyskinesia (PCD) is a genetically heterogeneous chronic destructive airway disease. PCD is traditionally diagnosed by nasal nitric oxide measurement, analysis of ciliary beating, transmission electron microscopy (TEM), and/or genetic testing. In most genetic PCD variants, laterality defects can occur. However, it is difficult to establish a diagnosis in individuals with PCD and central pair (CP) defects, and alternative strategies are required because of very subtle ciliary beating abnormalities, a normal ciliary ultrastructure, and normal situs composition. Mutations in HYDIN are known to cause CP defects, but the genetic analysis of HYDIN variants is confounded by the pseudogene HYDIN2, which is almost identical in terms of intron/exon structure. We have previously shown that several types of PCD can be diagnosed via immunofluorescence (IF) microscopy analyses. Here, using IF microscopy, we demonstrated that in individuals with PCD and CP defects, the CP-associated protein SPEF2 is absent inHYDIN-mutant cells, revealing its dependence on functional HYDIN. Next, we performed IF analyses of SPEF2 in respiratory cells from 189 individuals with suspected PCD and situs solitus. Forty-one of the 189 individuals had undetectable SPEF2 and were subjected to a genetic analysis, which revealed one novel loss-of-function mutation in SPEF2 and three reported and 13 novel HYDIN mutations in 15 individuals. The remaining 25 individuals are good candidates for new, as-yet uncharacterized PCD variants that affect the CP apparatus. SPEF2 mutations have been associated with male infertility but have not previously been identified to cause PCD. We identified a mutation of SPEF2 that is causative for PCD with a CP defect. We conclude that SPEF2 IF analyses can facilitate the detection of CP defects and evaluation of the pathogenicity of HYDIN variants, thus aiding the molecular diagnosis of CP defects.

KW - Cilia

KW - HYDIN2

KW - Immunofluorescence microscopy analysis

KW - Situs solitus

KW - Test sensitivity and specificity

U2 - 10.1165/rcmb.2019-0086OC

DO - 10.1165/rcmb.2019-0086OC

M3 - Journal article

VL - 62

SP - 382

EP - 396

JO - American Journal of Respiratory Cell and Molecular Biology

JF - American Journal of Respiratory Cell and Molecular Biology

SN - 1044-1549

IS - 3

ER -

ID: 59079897