Telangiectasia-ectodermal dysplasia-brachydactyly-cardiac anomaly syndrome is caused by de novo mutations in protein kinase D1

2020 ◽  
pp. jmedgenet-2019-106564
Author(s):  
Svenja Alter ◽  
Andreas David Zimmer ◽  
Misun Park ◽  
Jianli Gong ◽  
Almuth Caliebe ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Congenital Heart Disease ◽  
Protein Kinase ◽  
Recombinant Proteins ◽  
Congenital Heart ◽  
Ectodermal Dysplasia ◽  
De Novo ◽  
De Novo Mutations ◽  
Protein Kinase D1

BackgroundWe describe two unrelated patients who display similar clinical features including telangiectasia, ectodermal dysplasia, brachydactyly and congenital heart disease.MethodsWe performed trio whole exome sequencing and functional analysis using in vitro kinase assays with recombinant proteins.ResultsWe 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.ConclusionThe 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.

scholarly journals De novo mutations in histone-modifying genes in congenital heart disease

Nature ◽  
2013 ◽  
Vol 498 (7453) ◽  
pp. 220-223 ◽  
Author(s):  
Samir Zaidi ◽  
Murim Choi ◽  
Hiroko Wakimoto ◽  
Lijiang Ma ◽  
Jianming Jiang ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Congenital Heart ◽  
De Novo ◽  
De Novo Mutations ◽  
Modifying Genes

scholarly journals Molecular Genetics and Complex Inheritance of Congenital Heart Disease

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 1020
Author(s):  
Nicholas S. Diab ◽  
Syndi Barish ◽  
Weilai Dong ◽  
Shujuan Zhao ◽  
Garrett Allington ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
High Throughput ◽  
Congenital Heart ◽  
High Throughput Sequencing ◽  
De Novo ◽  
Copy Number Variations ◽  
De Novo Mutations ◽  
Genomic Technologies ◽  
Chd Risk

Congenital heart disease (CHD) is the most common congenital malformation and the leading cause of mortality therein. Genetic etiologies contribute to an estimated 90% of CHD cases, but so far, a molecular diagnosis remains unsolved in up to 55% of patients. Copy number variations and aneuploidy account for ~23% of cases overall, and high-throughput genomic technologies have revealed additional types of genetic variation in CHD. The first CHD risk genotypes identified through high-throughput sequencing were de novo mutations, many of which occur in chromatin modifying genes. Murine models of cardiogenesis further support the damaging nature of chromatin modifying CHD mutations. Transmitted mutations have also been identified through sequencing of population scale CHD cohorts, and many transmitted mutations are enriched in cilia genes and Notch or VEGF pathway genes. While we have come a long way in identifying the causes of CHD, more work is required to end the diagnostic odyssey for all CHD families. Complex genetic explanations of CHD are emerging but will require increasingly sophisticated analysis strategies applied to very large CHD cohorts before they can come to fruition in providing molecular diagnoses to genetically unsolved patients. In this review, we discuss the genetic architecture of CHD and biological pathways involved in its pathogenesis.

scholarly journals De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies

Science ◽  
2015 ◽  
Vol 350 (6265) ◽  
pp. 1262-1266 ◽  
Author(s):  
J. Homsy ◽  
S. Zaidi ◽  
Y. Shen ◽  
J. S. Ware ◽  
K. E. Samocha ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Congenital Anomalies ◽  
Congenital Heart ◽  
De Novo ◽  
De Novo Mutations

scholarly journals Case report: adult onset diabetes with partial pancreatic agenesis and congenital heart disease due to a de novo GATA6 mutation

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Begona Sanchez-Lechuga ◽  
Muhammad Saqlain ◽  
Nicholas Ng ◽  
Kevin Colclough ◽  
Conor Woods ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Case Report ◽  
Congenital Heart ◽  
De Novo ◽  
Adult Onset ◽  
Onset Diabetes ◽  
Adult Onset Diabetes ◽  
Pancreatic Agenesis

Genetics of Chondroectodermal Dysplasia

PEDIATRICS ◽  
1958 ◽  
Vol 22 (4) ◽  
pp. 777-777
Author(s):  
JULIUS D. METRAKOS ◽  
F. CLARKE FRASER
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Congenital Heart ◽  
Ectodermal Dysplasia ◽  
Case Histories ◽  
Statistical Probability ◽  
Ellis Van Creveld Syndrome

We read with great interest the two excellent case histories of chondroectodermal dysplasia (Ellis-van Creveld syndrome) that were reported recently by Smith and Hand (Pediatrics, 21:298, 1958). We must take issue, however, with the conclusion that "The statistical probability of siblings having the complete tetrad of defects is rather remote...." This conclusion appears to be based on the assumptions that the four members of the tetrad (chondrodysplasia, ectodermal dysplasia, polydactylism and congenital heart disease) are caused by four different genes, and that the characteristic association of abnormalities to form a syndrome is due to linkage.

scholarly journals Activation of Hematopoietic Progenitor Kinase 1 Involves Relocation, Autophosphorylation, and Transphosphorylation by Protein Kinase D1

2005 ◽  
Vol 25 (6) ◽  
pp. 2364-2383 ◽  
Author(s):  
Rüdiger Arnold ◽  
Irene M. Patzak ◽  
Brit Neuhaus ◽  
Sadia Vancauwenbergh ◽  
André Veillette ◽  
...  
Keyword(s):  
T Cell ◽  
Protein Kinase ◽  
Adaptor Protein ◽  
Cell Receptor ◽  
Hematopoietic Progenitor ◽  
Kinase Activation ◽  
Protein Kinase D1 ◽  
Enzymatic Activation ◽  
Antigen Presenting

ABSTRACT Adaptive immune signaling can be coupled to stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK) and NF-κB activation by the hematopoietic progenitor kinase 1 (HPK1), a mammalian hematopoiesis-specific Ste20 kinase. To gain insight into the regulation of leukocyte signal transduction, we investigated the molecular details of HPK1 activation. Here we demonstrate the capacity of the Src family kinase Lck and the SLP-76 family adaptor protein Clnk (cytokine-dependent hematopoietic cell linker) to induce HPK1 tyrosine phosphorylation and relocation to the plasma membrane, which in lymphocytes results in recruitment of HPK1 to the contact site of antigen-presenting cell (APC)-T-cell conjugates. Relocation and clustering of HPK1 cause its enzymatic activation, which is accompanied by phosphorylation of regulatory sites in the HPK1 kinase activation loop. We show that full activation of HPK1 is dependent on autophosphorylation of threonine 165 and phosphorylation of serine 171, which is a target site for protein kinase D (PKD) in vitro. Upon T-cell receptor stimulation, PKD robustly augments HPK1 kinase activity in Jurkat T cells and enhances HPK1-driven SAPK/JNK and NF-κB activation; conversely, antisense down-regulation of PKD results in reduced HPK1 activity. Thus, activation of major lymphocyte signaling pathways via HPK1 involves (i) relocation, (ii) autophosphorylation, and (iii) transphosphorylation of HPK1 by PKD.

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