Mutations in TP73 cause impaired mucociliary clearance and lissencephaly.

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.

Wallmeier J ，Bracht D ，Alsaif HS ，Dougherty GW ，Olbrich H ，Cindric S ，Dzietko M ，Heyer C ，Teig N ，Thiels C ，Faqeih E ，Al-Hashim A ，Khan S ，Mogarri I ，Almannai M ，Al Otaibi W ，Alkuraya FS ，Koerner-Rettberg C ，Omran H ... -  《-》

TAp73 is a central transcriptional regulator of airway multiciliogenesis.

Motile multiciliated cells (MCCs) have critical roles in respiratory health and disease and are essential for cleaning inhaled pollutants and pathogens from airways. Despite their significance for human disease, the transcriptional control that governs multiciliogenesis remains poorly understood. Here we identify TP73, a p53 homolog, as governing the program for airway multiciliogenesis. Mice with TP73 deficiency suffer from chronic respiratory tract infections due to profound defects in ciliogenesis and complete loss of mucociliary clearance. Organotypic airway cultures pinpoint TAp73 as necessary and sufficient for basal body docking, axonemal extension, and motility during the differentiation of MCC progenitors. Mechanistically, cross-species genomic analyses and complete ciliary rescue of knockout MCCs identify TAp73 as the conserved central transcriptional integrator of multiciliogenesis. TAp73 directly activates the key regulators FoxJ1, Rfx2, Rfx3, and miR34bc plus nearly 50 structural and functional ciliary genes, some of which are associated with human ciliopathies. Our results position TAp73 as a novel central regulator of MCC differentiation.

Nemajerova A ，Kramer D ，Siller SS ，Herr C ，Shomroni O ，Pena T ，Gallinas Suazo C ，Glaser K ，Wildung M ，Steffen H ，Sriraman A ，Oberle F ，Wienken M ，Hennion M ，Vidal R ，Royen B ，Alevra M ，Schild D ，Bals R ，Dönitz J ，Riedel D ，Bonn S ，Takemaru K ，Moll UM ，Lizé M ... -  《-》

MCIDAS mutations result in a mucociliary clearance disorder with reduced generation of multiple motile cilia.

Boon M ，Wallmeier J ，Ma L ，Loges NT ，Jaspers M ，Olbrich H ，Dougherty GW ，Raidt J ，Werner C ，Amirav I ，Hevroni A ，Abitbul R ，Avital A ，Soferman R ，Wessels M ，O'Callaghan C ，Chung EM ，Rutman A ，Hirst RA ，Moya E ，Mitchison HM ，Van Daele S ，De Boeck K ，Jorissen M ，Kintner C ，Cuppens H ，Omran H ... -  《Nature Communications》

A human ciliopathy reveals essential functions for NEK10 in airway mucociliary clearance.

Chivukula RR ，Montoro DT ，Leung HM ，Yang J ，Shamseldin HE ，Taylor MS ，Dougherty GW ，Zariwala MA ，Carson J ，Daniels MLA ，Sears PR ，Black KE ，Hariri LP ，Almogarri I ，Frenkel EM ，Vinarsky V ，Omran H ，Knowles MR ，Tearney GJ ，Alkuraya FS ，Sabatini DM ... -  《-》

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

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 ... -  《-》