Mutations in TP73 cause impaired mucociliary clearance and lissencephaly

• Published in: American journal of human genetics Vol. 108; no. 7; pp. 1318 - 1329
• Main Authors: Wallmeier, Julia, Bracht, Diana, Alsaif, Hessa S., Dougherty, Gerard W., Olbrich, Heike, Cindric, Sandra, Dzietko, Mark, Heyer, Christoph, Teig, Norbert, Thiels, Charlotte, Faqeih, Eissa, Al-Hashim, Aqeela, Khan, Sameena, Mogarri, Ibrahim, Almannai, Mohammed, Al Otaibi, Wadha, Alkuraya, Fowzan S., Koerner-Rettberg, Cordula, Omran, Heymut
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2021; Elsevier
• Subjects: Cell Differentiation - genetics; Cells, Cultured; cilia; ciliogenesis; Ciliopathies - genetics; Genes, Recessive; Homozygote; Humans; lissencephaly; Lissencephaly - genetics; Loss of Function Mutation; Microscopy, Video; motile ciliopathy; Mucociliary Clearance - genetics; PCD; primary ciliary dyskinesia; reduced generation of multiple motile cilia; Respiratory Mucosa - cytology; Respiratory Mucosa - metabolism; Respiratory Mucosa - ultrastructure; RGMC; TP73; Tumor Protein p73 - genetics; Whole Exome Sequencing; PCD; lissencephaly; ciliogenesis; motile ciliopathy; reduced generation of multiple motile cilia; cilia; RGMC; primary ciliary dyskinesia; TP73
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2021.05.002

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.