Background We describe two unrelated patients who display similar clinical features including telangiectasia, ectodermal dysplasia, brachydactyly and congenital heart disease.
Methods We performed trio whole exome sequencing and functional analysis using in vitro kinase assays with recombinant proteins.
Results We identified two different de novo mutations in protein kinase D1 (PRKD1, NM_002742.2): c.1774G>C, p.(Gly592Arg) and c.1808G>A, p.(Arg603His), one in each patient. PRKD1 (PKD1, HGNC:9407) encodes a kinase that is a member of the protein kinase D (PKD) family of serine/threonine protein kinases involved in diverse cellular processes such as cell differentiation and proliferation and cell migration as well as vesicle transport and angiogenesis. Functional analysis using in vitro kinase assays with recombinant proteins showed that the mutation c.1808G>A, p.(Arg603His) represents a gain-of-function mutation encoding an enzyme with a constitutive, lipid-independent catalytic activity. The mutation c.1774G>C, p.(Gly592Arg) in contrast shows a defect in substrate phosphorylation representing a loss-of-function mutation.
Conclusion The present cases represent a syndrome, which associates symptoms from several different organ systems: skin, teeth, bones and heart, caused by heterozygous de novo mutations in PRKD1 and expands the clinical spectrum of PRKD1 mutations, which have hitherto been linked to syndromic congenital heart disease and limb abnormalities.
- protein kinase D1 (PRKD1)
- ectodermal dysplasia
- cardiac anomaly
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SFS and JF are joint senior authors.
Contributors SA, JF and SFS conceived the project. SA, ADZ, SFS and JF wrote the manuscript. SA, AC, RF-H, AT, IC, SFS and JF contributed to the acquisition and interpretation of data. SA, ADZ, MP, JG and SFS contributed to the analysis of data. All authors contributed to the critical revision of the manuscript and approved the manuscript.
Funding This work is supported by NIH, NHLBI grant HL112388, and by the faculty of Medicine of the University of Freiburg.
Competing interests None declared.
Patient consent for publication Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. Additional information is available from the corresponding authors on reasonable request.
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