SPEF2- and HYDIN -Mutant Cilia Lack the Central Pair-associated Protein SPEF2, Aiding Primary Ciliary Dyskinesia Diagnostics

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...

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Published inAmerican journal of respiratory cell and molecular biology Vol. 62; no. 3; pp. 382 - 396
Main Authors 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
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LanguageEnglish
Published United States American Thoracic Society 01.03.2020
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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 are known to cause CP defects, but the genetic analysis of variants is confounded by the pseudogene , 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 in -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 . 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 and three reported and 13 novel mutations in 15 individuals. The remaining 25 individuals are good candidates for new, as-yet uncharacterized PCD variants that affect the CP apparatus. mutations have been associated with male infertility but have not previously been identified to cause PCD. We identified a mutation of 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 variants, thus aiding the molecular diagnosis of CP defects.
AbstractList 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. Here, Cindric et al. show that SPEF2- and HYDIN-Mutant Cilia lacks the central pair-associated protein SPEF2 to aide primary ciliary dyskinesia diagnostics.
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 are known to cause CP defects, but the genetic analysis of variants is confounded by the pseudogene , 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 in -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 . 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 and three reported and 13 novel mutations in 15 individuals. The remaining 25 individuals are good candidates for new, as-yet uncharacterized PCD variants that affect the CP apparatus. mutations have been associated with male infertility but have not previously been identified to cause PCD. We identified a mutation of 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 variants, thus aiding the molecular diagnosis of CP defects.
Author Omran, Heymut
Olbrich, Heike
Dworniczak, Bernd
Nielsen, Kim G
Marthin, June K
Philipsen, Maria C
Werner, Claudius
Dougherty, Gerard W
Raidt, Johanna
Sutharsan, Sivagurunathan
Cindrić, Sandra
Amirav, Israel
Pennekamp, Petra
Hjeij, Rim
Loges, Niki Tomas
Author_xml – sequence: 1
  givenname: Sandra
  orcidid: 0000-0002-8303-100X
  surname: Cindrić
  fullname: Cindrić, Sandra
  organization: Department of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany
– sequence: 2
  givenname: Gerard W
  surname: Dougherty
  fullname: Dougherty, Gerard W
  organization: Department of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany
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  givenname: Heike
  surname: Olbrich
  fullname: Olbrich, Heike
  organization: Department of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany
– sequence: 4
  givenname: Rim
  surname: Hjeij
  fullname: Hjeij, Rim
  organization: Department of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany
– sequence: 5
  givenname: Niki Tomas
  surname: Loges
  fullname: Loges, Niki Tomas
  organization: Department of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany
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  givenname: Israel
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  organization: Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
– sequence: 7
  givenname: Maria C
  surname: Philipsen
  fullname: Philipsen, Maria C
  organization: Danish PCD Centre, ERN Accredited, Pediatric Pulmonary Service, Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital, Copenhagen, Denmark
– sequence: 8
  givenname: June K
  surname: Marthin
  fullname: Marthin, June K
  organization: Danish PCD Centre, ERN Accredited, Pediatric Pulmonary Service, Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital, Copenhagen, Denmark
– sequence: 9
  givenname: Kim G
  surname: Nielsen
  fullname: Nielsen, Kim G
  organization: Danish PCD Centre, ERN Accredited, Pediatric Pulmonary Service, Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital, Copenhagen, Denmark
– sequence: 10
  givenname: Sivagurunathan
  surname: Sutharsan
  fullname: Sutharsan, Sivagurunathan
  organization: Department of Pulmonary Medicine, Ruhrlandklinik, Universitätsmedizin Essen, Essen, Germany; and
– sequence: 11
  givenname: Johanna
  surname: Raidt
  fullname: Raidt, Johanna
  organization: Department of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany
– sequence: 12
  givenname: Claudius
  surname: Werner
  fullname: Werner, Claudius
  organization: Department of Pediatrics, HELIOS Hospital Schwerin, Schwerin, Germany
– sequence: 13
  givenname: Petra
  surname: Pennekamp
  fullname: Pennekamp, Petra
  organization: Department of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany
– sequence: 14
  givenname: Bernd
  surname: Dworniczak
  fullname: Dworniczak, Bernd
  organization: Department of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany
– sequence: 15
  givenname: Heymut
  surname: Omran
  fullname: Omran, Heymut
  organization: Department of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany
BackLink https://www.ncbi.nlm.nih.gov/pubmed/31545650$$D View this record in MEDLINE/PubMed
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Keywords HYDIN2
situs solitus
test sensitivity and specificity
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immunofluorescence microscopy analysis
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Snippet Primary ciliary dyskinesia (PCD) is a genetically heterogeneous chronic destructive airway disease. PCD is traditionally diagnosed by nasal nitric oxide...
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pubmed
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StartPage 382
SubjectTerms Allergic diseases
Cilia
Genetic screening
Genetics
Lung diseases
Medical diagnosis
Mutants
Nitric oxide
Primary ciliary dyskinesia
Proteins
Respiratory tract diseases
Transmission electron microscopy
Ultrastructure
Title SPEF2- and HYDIN -Mutant Cilia Lack the Central Pair-associated Protein SPEF2, Aiding Primary Ciliary Dyskinesia Diagnostics
URI https://www.ncbi.nlm.nih.gov/pubmed/31545650
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