Biallelic disruption of PKDCC is associated with a skeletal disorder characterised by rhizomelic shortening of extremities and dysmorphic features

2018 ◽  
Vol 56 (12) ◽  
pp. 850-854
Author(s):  
Samin A Sajan ◽  
Jaya Ganesh ◽  
Deepali N Shinde ◽  
Zöe Powis ◽  
Maria I Scarano ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Sanger Sequencing ◽  
Kinase Domain ◽  
Long Bones ◽  
Splice Donor ◽  
Protein Kinase Domain ◽  
Nonsense Mediated Decay ◽  
Dysmorphic Features ◽  
Branchial Arches ◽  
Skeletal Disorder

BackgroundDuring mouse embryonic development the protein kinase domain containing, cytoplasmic (Pkdcc) gene, also known as Vlk, is expressed in several tissues including the ventral midbrain, with particularly strong expression in branchial arches and limb buds. Homozygous Pkdcc knockout mice have dysmorphic features and shortened long bones as the most obvious morphological abnormalities. The human PKDCC gene has currently not been associated with any disorders.ObjectiveTo use clinical diagnostic exome sequencing (DES) for providing genetic diagnoses to two apparently unrelated patients with similar skeletal abnormalities comprising rhizomelic shortening of limbs and dysmorphic features.MethodsPatient–parents trio DES was carried out and the identified candidate variants were confirmed by Sanger sequencing.ResultsEach patient had a homozygous gene disrupting variant in PKDCC considered to explain the skeletal phenotypes shared by both. The first patient was homozygous for the nonsense variant p.(Tyr217*) (NM_1 38 370 c.651C>A) expected to result in nonsense-mediated decay of the mutant transcripts, whereas the second patient was homozygous for the splice donor variant c.639+1G>T predicted to abolish the donor splice site by three in silico splice prediction algorithms.ConclusionsBiallelic gene disrupting variants in PKDCC in humans, just like in mice, cause dysmorphic features and rhizomelic shortening of limbs.

In silico profiling and structural insights of missense mutations in RET protein kinase domain by molecular dynamics and docking approach

2014 ◽  
Vol 10 (3) ◽  
pp. 421-436 ◽  
Author(s):  
C. George Priya Doss ◽  
B. Rajith ◽  
Chiranjib Chakraboty ◽  
V. Balaji ◽  
R. Magesh ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Protein Kinase ◽  
In Silico ◽  
Kinase Domain ◽  
Missense Mutations ◽  
Protein Kinase Domain ◽  
Docking Approach ◽  
Structural Insights

The Eukaryotic Protein Kinase Domain

2005 ◽  
pp. 181-209 ◽  
Author(s):  
Arvin C. Dar ◽  
Leanne E. Wybenga-Groot ◽  
Frank Sicheri
Keyword(s):  
Protein Kinase ◽  
Kinase Domain ◽  
Protein Kinase Domain ◽  
Eukaryotic Protein Kinase ◽  
Eukaryotic Protein

scholarly journals Heterozygous mutations affecting the protein kinase domain of CDK13 cause a syndromic form of developmental delay and intellectual disability

2017 ◽  
Vol 55 (1) ◽  
pp. 28-38 ◽  
Author(s):  
Mark J Hamilton ◽  
Richard C Caswell ◽  
Natalie Canham ◽  
Trevor Cole ◽  
Helen V Firth ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Intellectual Disability ◽  
Protein Kinase ◽  
Developmental Delay ◽  
Congenital Heart ◽  
Kinase Domain ◽  
Dominant Negative ◽  
Missense Mutations ◽  
Protein Kinase Domain

IntroductionRecent evidence has emerged linking mutations in CDK13 to syndromic congenital heart disease. We present here genetic and phenotypic data pertaining to 16 individuals with CDK13 mutations.MethodsPatients were investigated by exome sequencing, having presented with developmental delay and additional features suggestive of a syndromic cause.ResultsOur cohort comprised 16 individuals aged 4–16 years. All had developmental delay, including six with autism spectrum disorder. Common findings included feeding difficulties (15/16), structural cardiac anomalies (9/16), seizures (4/16) and abnormalities of the corpus callosum (4/11 patients who had undergone MRI). All had craniofacial dysmorphism, with common features including short, upslanting palpebral fissures, hypertelorism or telecanthus, medial epicanthic folds, low-set, posteriorly rotated ears and a small mouth with thin upper lip vermilion. Fifteen patients had predicted missense mutations, including five identical p.(Asn842Ser) substitutions and two p.(Gly717Arg) substitutions. One patient had a canonical splice acceptor site variant (c.2898–1G>A). All mutations were located within the protein kinase domain of CDK13. The affected amino acids are highly conserved, and in silico analyses including comparative protein modelling predict that they will interfere with protein function. The location of the missense mutations in a key catalytic domain suggests that they are likely to cause loss of catalytic activity but retention of cyclin K binding, resulting in a dominant negative mode of action. Although the splice-site mutation was predicted to produce a stable internally deleted protein, this was not supported by expression studies in lymphoblastoid cells. A loss of function contribution to the underlying pathological mechanism therefore cannot be excluded, and the clinical significance of this variant remains uncertain.ConclusionsThese patients demonstrate that heterozygous, likely dominant negative mutations affecting the protein kinase domain of the CDK13 gene result in a recognisable, syndromic form of intellectual disability, with or without congenital heart disease.

scholarly journals Structural pathway for allosteric activation of the autophagic PI 3-kinase complex I

2019 ◽  
Vol 116 (43) ◽  
pp. 21508-21513 ◽  
Author(s):  
Lindsey N. Young ◽  
Felix Goerdeler ◽  
James H. Hurley
Keyword(s):  
Protein Kinase ◽  
Complex I ◽  
Structural Changes ◽  
Kinase Domain ◽  
Activation Loop ◽  
Class Iii ◽  
Lipid Kinase ◽  
Protein Kinase Domain ◽  
Autophagy Induction ◽  
Enzymatic Activation

Autophagy induction by starvation and stress involves the enzymatic activation of the class III phosphatidylinositol (PI) 3-kinase complex I (PI3KC3-C1). The inactive basal state of PI3KC3-C1 is maintained by inhibitory contacts between the VPS15 protein kinase and VPS34 lipid kinase domains that restrict the conformation of the VPS34 activation loop. Here, the proautophagic MIT domain-containing protein NRBF2 was used to map the structural changes leading to activation. Cryoelectron microscopy was used to visualize a 2-step PI3KC3-C1 activation pathway driven by NRFB2 MIT domain binding. Binding of a single NRBF2 MIT domain bends the helical solenoid of the VPS15 scaffold, displaces the protein kinase domain of VPS15, and releases the VPS34 kinase domain from the inhibited conformation. Binding of a second MIT stabilizes the VPS34 lipid kinase domain in an active conformation that has an unrestricted activation loop and is poised for access to membranes.

scholarly journals Sti1 and Cdc37 Can Stabilize Hsp90 in Chaperone Complexes with a Protein Kinase

2004 ◽  
Vol 15 (4) ◽  
pp. 1785-1792 ◽  
Author(s):  
Paul Lee ◽  
Arsalan Shabbir ◽  
Christopher Cardozo ◽  
Avrom J. Caplan
Keyword(s):  
Protein Kinase ◽  
Kinase Domain ◽  
Mitogen Activated Protein Kinase ◽  
Protein Kinase Domain ◽  
Relative Contribution ◽  
Expression Studies ◽  
Mitogen Activated Protein ◽  
Gene Expression Studies ◽  
Kinase Pathway

Hsp90 functions in association with several cochaperones for folding of protein kinases and transcription factors, although the relative contribution of each to the overall reaction is unknown. We assayed the role of nine different cochaperones in the activation of Ste11, a Saccharomyces cerevisiae mitogen-activated protein kinase kinase kinase. Studies on signaling via this protein kinase pathway was measured by α-factor-stimulated induction of FIG1 or lacZ, and repression of HHF1. Several cochaperone mutants tested had reduced FIG1 induction or HHF1 repression, although to differing extents. The greatest defects were in cpr7Δ, sse1Δ, and ydj1Δ mutants. Assays of Ste11 kinase activity revealed a pattern of defects in the cochaperone mutant strains that were similar to the gene expression studies. Overexpression of CDC37, a chaperone required for protein kinase folding, suppressed defects the sti1Δ mutant back to wild-type levels. CDC37 overexpression also restored stable Hsp90 binding to the Ste11 protein kinase domain in the sti1Δ mutant strain. These data suggest that Cdc37 and Sti1 have functional overlap in stabilizing Hsp90:client complexes. Finally, we show that Cns1 functions in MAP kinase signaling in association with Cpr7.

scholarly journals Receptor-mediated regulation of the TRPM7 channel through its endogenous protein kinase domain

2004 ◽  
Vol 101 (16) ◽  
pp. 6009-6014 ◽  
Author(s):  
R. Takezawa ◽  
C. Schmitz ◽  
P. Demeuse ◽  
A. M. Scharenberg ◽  
R. Penner ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Kinase Domain ◽  
Protein Kinase Domain ◽  
Endogenous Protein
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