TY - JOUR
T1 - De Novo Mutations in FOXJ1 Result in a Motile Ciliopathy with Hydrocephalus and Randomization of Left/Right Body Asymmetry
AU - Wallmeier, Julia
AU - Frank, Diana
AU - Shoemark, Amelia
AU - Nöthe-Menchen, Tabea
AU - Cindric, Sandra
AU - Olbrich, Heike
AU - Loges, Niki T.
AU - Aprea, Isabella
AU - Dougherty, Gerard W.
AU - Pennekamp, Petra
AU - Kaiser, Thomas
AU - Mitchison, Hannah M.
AU - Hogg, Claire
AU - Carr, Siobhán B.
AU - Zariwala, Maimoona A.
AU - Ferkol, Thomas
AU - Leigh, Margaret W.
AU - Davis, Stephanie D.
AU - Atkinson, Jeffrey
AU - Dutcher, Susan K.
AU - Knowles, Michael R.
AU - Thiele, Holger
AU - Altmüller, Janine
AU - Krenz, Henrike
AU - Wöste, Marius
AU - Brentrup, Angela
AU - Ahrens, Frank
AU - Vogelberg, Christian
AU - Morris-Rosendahl, Deborah J.
AU - Omran, Heymut
N1 - Funding Information:
We thank the PCD-affected individuals and their families for their participation and acknowledge the German PCD support group Kartagener Syndrom und Primaere Ciliaere Dyskinesie e.V, UK PCD Family Support Group, and North American PCD Foundation. The University Children's Hospital Muenster and the Royal Brompton and Harefield NHS Trust are part of ERN-Lung, the European Reference Network for Rare Diseases. We would like to thank K.-P. Schlingmann for the discussion and A. Borgscheiper, A. Dorißen, D. Ernst, S. Helms, M. Herting, J. Quante, A. Robbers, L. Schwiddessen, F.J. Seesing, S. Sivalingam, M. Tekaat, K. Wohlgemuth, C. Westermann, and S. Wilkinson for excellent clinical and technical work. We thank the investigators and coordinators of Genetics Disorders of Mucociliary Clearance Consortium (GDMCC); Drs. J. Stonebraker and H. Dang of UNC for technical and bioinformatics assistance, respectively; Ms. Kimberly Burns of UNC for electron microscopy support; McDonnell Genome Institute (Washington University); and Drs. S. Mane, F. Lopez-Giraldez, and W. Dong from Yale Center for Mendelian Genomics (UM1 HG006504) for providing whole-exome sequencing and bioinformatics support. We thank Sayyid Hasan (RBHT) as WL GMC Validation Coordinator of results from the UK 100K Project, Dr. Anne Schmidt for the clinical workup of subject RBH II-1 as well as Mitali P. Patel for the IF stainings. This work was funded by the Deutsche Forschungsgemeinschaft (DFG), the National Institutes of Health (US), 100,000 Genomes Project National Institute for Health Research and NHS England (UK), IZKF Muenster, “Innovative Medical Research” of the University of Muenster Medical School, and Great Ormond Street Children's Charity. The authors participate in the COST action BEAT-PCD. The findings in subject RBH II1 were made possible through access to the data and findings generated by the 100,000 Genomes Project. Please find detailed funding information in the Supplemental Data.
Funding Information:
We thank the PCD-affected individuals and their families for their participation and acknowledge the German PCD support group Kartagener Syndrom und Primaere Ciliaere Dyskinesie e.V, UK PCD Family Support Group, and North American PCD Foundation. The University Children’s Hospital Muenster and the Royal Brompton and Harefield NHS Trust are part of ERN-Lung, the European Reference Network for Rare Diseases. We would like to thank K.-P. Schlingmann for the discussion and A. Borgscheiper, A. Dorißen, D. Ernst, S. Helms, M. Herting, J. Quante, A. Robbers, L. Schwiddessen, F.J. Seesing, S. Sivalingam, M. Tekaat, K. Wohlgemuth, C. Westermann, and S. Wilkinson for excellent clinical and technical work. We thank the investigators and coordinators of Genetics Disorders of Mucociliary Clearance Consortium (GDMCC); Drs. J. Stonebraker and H. Dang of UNC for technical and bioinformatics assistance, respectively; Ms. Kimberly Burns of UNC for electron microscopy support; McDonnell Genome Institute (Washington University); and Drs. S. Mane, F. Lopez-Giraldez, and W. Dong from Yale Center for Mendelian Genomics (UM1 HG006504) for providing whole-exome sequencing and bioinformatics support. We thank Sayyid Hasan (RBHT) as WL GMC Validation Coordinator of results from the UK 100K Project, Dr. Anne Schmidt for the clinical workup of subject RBH II-1 as well as Mitali P. Patel for the IF stainings. This work was funded by the Deutsche Forschungsgemeinschaft (DFG), the National Institutes of Health (US), 100,000 Genomes Project National Institute for Health Research and NHS England (UK), IZKF Muenster , “Innovative Medical Research” of the University of Muenster Medical School , and Great Ormond Street Children’s Charity . The authors participate in the COST action BEAT-PCD. The findings in subject RBH II1 were made possible through access to the data and findings generated by the 100,000 Genomes Project. Please find detailed funding information in the Supplemental Data .
Publisher Copyright:
© 2019 American Society of Human Genetics
PY - 2019/11/7
Y1 - 2019/11/7
N2 - Hydrocephalus is one of the most prevalent form of developmental central nervous system (CNS) malformations. Cerebrospinal fluid (CSF) flow depends on both heartbeat and body movement. Furthermore, it has been shown that CSF flow within and across brain ventricles depends on cilia motility of the ependymal cells lining the brain ventricles, which play a crucial role to maintain patency of the narrow sites of CSF passage during brain formation in mice. Using whole-exome and whole-genome sequencing, we identified an autosomal-dominant cause of a distinct motile ciliopathy related to defective ciliogenesis of the ependymal cilia in six individuals. Heterozygous de novo mutations in FOXJ1, which encodes a well-known member of the forkhead transcription factors important for ciliogenesis of motile cilia, cause a motile ciliopathy that is characterized by hydrocephalus internus, chronic destructive airway disease, and randomization of left/right body asymmetry. Mutant respiratory epithelial cells are unable to generate a fluid flow and exhibit a reduced number of cilia per cell, as documented by high-speed video microscopy (HVMA), transmission electron microscopy (TEM), and immunofluorescence analysis (IF). TEM and IF demonstrate mislocalized basal bodies. In line with this finding, the focal adhesion protein PTK2 displays aberrant localization in the cytoplasm of the mutant respiratory epithelial cells.
AB - Hydrocephalus is one of the most prevalent form of developmental central nervous system (CNS) malformations. Cerebrospinal fluid (CSF) flow depends on both heartbeat and body movement. Furthermore, it has been shown that CSF flow within and across brain ventricles depends on cilia motility of the ependymal cells lining the brain ventricles, which play a crucial role to maintain patency of the narrow sites of CSF passage during brain formation in mice. Using whole-exome and whole-genome sequencing, we identified an autosomal-dominant cause of a distinct motile ciliopathy related to defective ciliogenesis of the ependymal cilia in six individuals. Heterozygous de novo mutations in FOXJ1, which encodes a well-known member of the forkhead transcription factors important for ciliogenesis of motile cilia, cause a motile ciliopathy that is characterized by hydrocephalus internus, chronic destructive airway disease, and randomization of left/right body asymmetry. Mutant respiratory epithelial cells are unable to generate a fluid flow and exhibit a reduced number of cilia per cell, as documented by high-speed video microscopy (HVMA), transmission electron microscopy (TEM), and immunofluorescence analysis (IF). TEM and IF demonstrate mislocalized basal bodies. In line with this finding, the focal adhesion protein PTK2 displays aberrant localization in the cytoplasm of the mutant respiratory epithelial cells.
KW - FOXJ1
KW - cilia
KW - ciliogenesis
KW - ependyma
KW - hydrocephalus
KW - lung disease
UR - http://www.scopus.com/inward/record.url?scp=85074301064&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2019.09.022
DO - 10.1016/j.ajhg.2019.09.022
M3 - Article
C2 - 31630787
AN - SCOPUS:85074301064
SN - 0002-9297
VL - 105
SP - 1030
EP - 1039
JO - American journal of human genetics
JF - American journal of human genetics
IS - 5
ER -