Mutations in TP73 cause impaired mucociliary clearance and lissencephaly

Am J Hum Genet. 2021 Jul 1;108(7):1318-1329. doi: 10.1016/j.ajhg.2021.05.002.

Julia Wallmeier ¹, Diana Bracht ¹, Hessa S Alsaif ², Gerard W Dougherty ¹, Heike Olbrich ¹, Sandra Cindric ¹, Mark Dzietko ³, Christoph Heyer ⁴, Norbert Teig ⁵, Charlotte Thiels ⁶, Eissa Faqeih ⁷, Aqeela Al-Hashim ⁸, Sameena Khan ⁹, Ibrahim Mogarri ¹⁰, Mohammed Almannai ¹¹, Wadha Al Otaibi ¹¹, Fowzan S Alkuraya ¹², Cordula Koerner-Rettberg ¹³, Heymut Omran ¹⁴

Affiliations

1 Department of General Pediatrics, University Hospital Muenster, 48149 Muenster, Germany.
2 Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
3 Department for Pediatrics I, University Clinic Essen, Hufelandstrasse 55, 45147 Essen, Germany.
4 Institute of Radiology and Pediatric Radiology, University Hospital, Ruhr University Bochum, 44791 Bochum, Germany.
5 Department of Neonatology and Pediatric Intensive Care, University Children's Hospital, Ruhr University Bochum, 44791 Bochum, Germany.
6 Department of Neuropediatrics, University Children's Hospital, Ruhr University Bochum, 44791 Bochum, Germany.
7 Section of Medical Genetics, Children's Specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
8 National Neuroscience Institute, King Fahad Medical City, Riyadh 11211, Saudi Arabia.
9 Department of Neurosciences, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
10 Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
11 Department of Pediatric Subspecialties, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
12 Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11211, Saudi Arabia.
13 Children's Hospital Marienhospital Wesel, Pastor-Janssen-Str. 8-38, 46483 Wesel, Germany; Department of Pediatric Pneumology, University Children's Hospital, Ruhr University Bochum, 44791 Bochum, Germany.
14 Department of General Pediatrics, University Hospital Muenster, 48149 Muenster, Germany. Electronic address: heymut.omran@ukmuenster.de.

PMID: 34077761 DOI: 10.1016/j.ajhg.2021.05.002

Abstract

TP73 belongs to the TP53 family of transcription factors and has therefore been well studied in Cancer research. Studies in mice, however, have revealed non-oncogenic activities related to multiciliogenesis. Utilizing whole-exome Sequencing analysis in a cohort of individuals with a mucociliary clearance disorder and cortical malformation, we identified homozygous loss-of-function variants in TP73 in seven individuals from five unrelated families. All affected individuals exhibit a chronic airway disease as well as a brain malformation consistent with lissencephaly. We performed high-speed video microscopy, immunofluorescence analyses, and transmission electron microscopy in respiratory epithelial cells after spheroid or air liquid interface culture to analyze ciliary function, ciliary length, and number of multiciliated cells (MCCs). The respiratory epithelial cells studied display reduced ciliary length and basal bodies mislocalized within the cytoplasm. The number of MCCs is severely reduced, consistent with a reduced number of cells expressing the transcription factors crucial for multiciliogenesis (FOXJ1, RFX2). Our data demonstrate that autosomal-recessive deleterious variants in the TP53 family member TP73 cause a mucociliary clearance disorder due to a defect in MCC differentiation.

Keywords

PCD; RGMC; TP73; cilia; ciliogenesis; lissencephaly; motile ciliopathy; primary ciliary dyskinesia; reduced generation of multiple motile cilia.

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