PKD1L1 Is Involved in Congenital Chylothorax

Author:

Whitchurch Jonathan B.1ORCID,Schneider Sophia23ORCID,Hilger Alina C.4,Köllges Ricarda23,Stegmann Jil D.23,Waffenschmidt Lea35,Dyer Laura1,Thiele Holger6,Dhabhai Bhanupriya7,Dakal Tikam Chand7ORCID,Müller Andreas2,Norris Dominic P.1,Reutter Heiko M.35ORCID

Affiliation:

1. Mammalian Genetics Unit, MRC Harwell Institute, Harwell Campus, Oxfordshire OX11 0RD, UK

2. Department of Neonatology and Paediatric Intensive Care, University Hospital Bonn Center of Paediatrics, 53127 Bonn, Germany

3. Institute of Human Genetics, University Hospital Bonn, 53127 Bonn, Germany

4. Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, 91054 Erlangen, Germany

5. Division of Neonatology and Pediatric Intensive Care, Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, 91054 Erlangen, Germany

6. Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany

7. Genome & Computational Biology Lab, Department of Biotechnology, Mohanlal Sukhadia University, Udaipur 313001, India

Abstract

Besides visceral heterotaxia, Pkd1l1 null mouse embryos exhibit general edema and perinatal lethality. In humans, congenital chylothorax (CCT) is a frequent cause of fetal hydrops. In 2021, Correa and colleagues reported ultrarare compound heterozygous variants in PKD1L1 exhibiting in two consecutive fetuses with severe hydrops, implicating a direct role of PKD1L1 in fetal hydrops formation. Here, we performed an exome survey and identified ultrarare compound heterozygous variants in PKD1L1 in two of the five case–parent trios with CCT. In one family, the affected carried the ultrarare missense variants c.1543G>A(p.Gly515Arg) and c.3845T>A(p.Val1282Glu). In the other family, the affected carried the ultrarare loss-of-function variant (LoF) c.863delA(p.Asn288Thrfs*3) and the ultrarare missense variant c.6549G>T(p.Gln2183His). Investigation of the variants’ impact on PKD1L1 protein localization suggests the missense variants cause protein dysfunction and the LoF variant causes protein mislocalization. Further analysis of Pkd1l1 mutant mouse embryos revealed about 20% of Pkd1l1−/− embryos display general edema and pleural effusion at 14.5 dpc. Immunofluorescence staining at 14.5 dpc in Pkd1l1−/− embryos displayed both normal and massively altered lymphatic vessel morphologies. Together, our studies suggest the implication of PKD1L1 in congenital lymphatic anomalies, including CCTs.

Funder

German Research Foundation

Deutsche Forschungsgemeinschaft and Friedrich-Alexander-Universität Erlangen-Nürnberg within the funding program “Open Access Publication Funding”

Publisher

MDPI AG

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