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Exome sequencing in large CHD cohorts has been performed to provide insights into the genetic aetiology of CHD. This includes a study of 1891 probands by our group in collaboration with others, which identified three novel genes\u2014<jats:italic>CDK13, PRKD1<\/jats:italic>, and <jats:italic>CHD4<\/jats:italic>, in patients with syndromic CHD. <jats:italic>PRKD1<\/jats:italic> encodes a serine\/threonine protein kinase, which is important in a variety of fundamental cellular functions. Individuals with a heterozygous mutation in <jats:italic>PRKD1<\/jats:italic> may have facial dysmorphism, ectodermal dysplasia and may have CHDs such as pulmonary stenosis, atrioventricular septal defects, coarctation of the aorta and bicuspid aortic valve. To obtain a greater appreciation for the role that this essential protein kinase plays in cardiogenesis and CHD, we have analysed a <jats:italic>Prkd1<\/jats:italic> transgenic mouse model (<jats:italic>Prkd1<\/jats:italic><jats:sup><jats:italic>em1<\/jats:italic><\/jats:sup>) carrying deletion of exon 2, causing loss of function. High\u2010resolution episcopic microscopy affords detailed morphological 3D analysis of the developing heart and provides evidence for an essential role of <jats:italic>Prkd1<\/jats:italic> in both normal cardiac development and CHD. We show that homozygous deletion of <jats:italic>Prkd1<\/jats:italic> is associated with complex forms of CHD such as atrioventricular septal defects, and bicuspid aortic and pulmonary valves, and is lethal. Even in heterozygotes, cardiac differences occur. However, given that 97% of <jats:italic>Prkd1<\/jats:italic> heterozygous mice display normal heart development, it is likely that one normal allele is sufficient, with the defects seen most likely to represent sporadic events. Moreover, mRNA and protein expression levels were investigated by RT\u2010qPCR and western immunoblotting, respectively. A significant reduction in <jats:italic>Prkd1<\/jats:italic> mRNA levels was seen in homozygotes, but not heterozygotes, compared to WT littermates. While a trend towards lower PRKD1 protein expression was seen in the heterozygotes, the difference was only significant in the homozygotes. There was no compensation by the related <jats:italic>Prkd2<\/jats:italic> and <jats:italic>Prkd3<\/jats:italic> at transcript level, as evidenced by RT\u2010qPCR. Overall, we demonstrate a vital role of <jats:italic>Prkd1<\/jats:italic> in heart development and the aetiology of CHD.<\/jats:p>","DOI":"10.1111\/joa.14033","type":"journal-article","created":{"date-parts":[[2024,2,29]],"date-time":"2024-02-29T05:09:37Z","timestamp":1709183377000},"page":"70-83","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Effect of deletion of the protein kinase <scp>PRKD1<\/scp> on development of the mouse embryonic heart"],"prefix":"10.1111","volume":"245","author":[{"given":"Qazi","family":"Waheed\u2010Ullah","sequence":"first","affiliation":[{"name":"School of Life Sciences, Faculty of Medicine and Health Sciences University of Nottingham  Nottingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Wilsdon","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Faculty of Medicine and Health Sciences University of Nottingham  Nottingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aseel","family":"Abbad","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Faculty of Medicine and Health Sciences University of Nottingham  Nottingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Rochette","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Faculty of Medicine and Health Sciences University of Nottingham  Nottingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frances","family":"Bu'Lock","sequence":"additional","affiliation":[{"name":"East Midlands Congenital Heart Centre University Hospitals of Leicester NHS Trust  Leicester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc\u2010Phillip","family":"Hitz","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics Carl von Ossietzky University Oldenburg  Oldenburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregor","family":"Dombrowsky","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics Carl von Ossietzky University Oldenburg  Oldenburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Friederike","family":"Cuello","sequence":"additional","affiliation":[{"name":"Institute of Experimental Pharmacology and Toxicology, Cardiovascular Research Center University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"},{"name":"DZHK (German Center for Cardiovascular Research), partner site Hamburg\/Kiel\/L\u00fcbeck University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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