BRCA1 c.5181_5183delGTT (p.Val1688del) is a true pathogenic mutation that affects both protein stability and function: implications for genetic counseling.

2009 ◽  
Author(s):  
A De Nicolo ◽  
S Pathania ◽  
E Parisini ◽  
KJ Branda ◽  
K Stoeckert ◽  
...  
Keyword(s):  
Genetic Counseling ◽  
Protein Stability ◽  
Pathogenic Mutation ◽  
And Function

scholarly journals Hsp90 inhibition destabilizes Ezh2 protein in alloreactive T cells and reduces graft-versus-host disease in mice

Blood ◽  
2017 ◽  
Vol 129 (20) ◽  
pp. 2737-2748 ◽  
Author(s):  
Qingrong Huang ◽  
Shan He ◽  
Yuanyuan Tian ◽  
Yuting Gu ◽  
Pan Chen ◽  
...  
Keyword(s):  
T Cells ◽  
Protein Stability ◽  
Graft Versus Host Disease ◽  
Hsp90 Inhibition ◽  
Host Disease ◽  
Graft Versus Host ◽  
Alloreactive T Cells ◽  
Graft Versus Leukemia ◽  
Key Points ◽  
And Function

Key Points Ezh2 requires Hsp90 to maintain Ezh2 protein stability and function in alloreactive T cells. Pharmacological inhibition of Hsp90 destabilizes Ezh2 protein in alloreactive T cells and reduces GVHD but preserves graft-versus-leukemia effects.

scholarly journals The crystal structure of KSHV ORF57 reveals dimeric active sites important for protein stability and function

2018 ◽  
Vol 14 (8) ◽  
pp. e1007232 ◽  
Author(s):  
Fei Yuan ◽  
Zeng-Qiang Gao ◽  
Vladimir Majerciak ◽  
Lei Bai ◽  
Meng-Lu Hu ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Protein Stability ◽  
Active Sites ◽  
And Function

In Silico Analysis of Non Synonymous Single Nucleotide Polymorphisms (nsSNPs) of SMPX Gene in Hearing Impairment

2018 ◽  
Author(s):  
Md. Arifuzzaman ◽  
Sarmistha Mitra ◽  
Amir Hamza ◽  
Raju Das ◽  
Nurul Absar ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Protein Stability ◽  
In Silico Analysis ◽  
Normal Activity ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Binding Motifs ◽  
Stability Change ◽  
And Function ◽  
Dbsnp Database

ABSTRACTBackgroundMutations in SMPX gene can disrupt the normal activity of the SMPX protein which is involved in hearing process.ObjectiveIn this study, deleterious non-synonymous single nucleotide polymorphisms were isolated from the neutral variants by using several bioinformatics tools.MethodFirstly, dbSNP database hosted by NCBI was used to retrieve the SNPs of SMPX gene, secondly, SIFT was used primarily to screen the damaging SNPs. Further, for validation PROVEAN, PredictSNP and PolyPhen 2 were used. I-Mutant 3 was utilized to analyze the protein stability change and MutPred predicted the molecular mechanism of protein stability change. Finally evolutionary conservation was done to study their conservancy by using ConSurf server.ResultsA total of 26 missense (0.6517%) and 3 nonsense variants (0.075%) were retrieved and among them 4 mutations were found deleterious by all the tools of this experiment and are also highly conserved according to ConSurf server. rs772775896, rs759552778, rs200892029 and rs1016314772 are the reference IDs of deleterious mutations where the substitutions are S71L, N19D, A29T and K54N. Loss of Ubiquitination, loss of methylation, loss of glycosylation, and loss of MoRF binding motifs are the root causes of protein stability change.ConclusionThis is the first study regarding nsSNPs of SMPX gene where the most damaging SNPs were screened that are associated with the SMPX gene and can be used for further research to study their effect on protein structure and function, their dynamic behavior and how they actually affect protein’s flexibility.

scholarly journals Germline-activating mutations in PIK3CD compromise B cell development and function

2018 ◽  
Vol 215 (8) ◽  
pp. 2073-2095 ◽  
Author(s):  
Danielle T. Avery ◽  
Alisa Kane ◽  
Tina Nguyen ◽  
Anthony Lau ◽  
Akira Nguyen ◽  
...  
Keyword(s):  
B Cell ◽  
Cytidine Deaminase ◽  
Pathogenic Mutation ◽  
Gene Signature ◽  
Cell Development ◽  
B Cell Development ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Class Switch ◽  
And Function

Gain-of-function (GOF) mutations in PIK3CD, encoding the p110δ subunit of phosphatidylinositide 3-kinase (PI3K), cause a primary immunodeficiency. Affected individuals display impaired humoral immune responses following infection or immunization. To establish mechanisms underlying these immune defects, we studied a large cohort of patients with PIK3CD GOF mutations and established a novel mouse model using CRISPR/Cas9-mediated gene editing to introduce a common pathogenic mutation in Pik3cd. In both species, hyperactive PI3K severely affected B cell development and differentiation in the bone marrow and the periphery. Furthermore, PI3K GOF B cells exhibited intrinsic defects in class-switch recombination (CSR) due to impaired induction of activation-induced cytidine deaminase (AID) and failure to acquire a plasmablast gene signature and phenotype. Importantly, defects in CSR, AID expression, and Ig secretion were restored by leniolisib, a specific p110δ inhibitor. Our findings reveal key roles for balanced PI3K signaling in B cell development and long-lived humoral immunity and memory and establish the validity of treating affected individuals with p110δ inhibitors.

scholarly journals Hyperglycemia Regulates Hypoxia-Inducible Factor-1  Protein Stability and Function

Diabetes ◽  
2004 ◽  
Vol 53 (12) ◽  
pp. 3226-3232 ◽  
Author(s):  
S.-B. Catrina ◽  
K. Okamoto ◽  
T. Pereira ◽  
K. Brismar ◽  
L. Poellinger
Keyword(s):  
Protein Stability ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1 ◽  
And Function

scholarly journals Retroactive assessment for DNA mismatch repair deficiency in women with a history of endometrial cancer

2021 ◽  
Vol 9 (4) ◽  
Author(s):  
Y. Chen ◽  
Sushmita Gordhandas ◽  
Kelsey Musselman ◽  
Zhen Zhou ◽  
Brandon Maddy ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Genetic Counseling ◽  
Genetic Testing ◽  
Mismatch Repair ◽  
Gynecologic Oncology ◽  
Molecular Classification ◽  
Pathogenic Mutation ◽  
Mismatch Repair Deficiency ◽  
Repair Deficiency ◽  
Mismatch Repair Proteins

Objectives. Beginning in 2014, the Society of Gynecologic Oncology and the American College of Obstetricians and Gynecologists have recommended universal tumor testing for mismatch repair deficiency in endometrial cancer. Mismatch repair testing can triage patients who may benefit from genetic testing for Lynch syndrome. Many women previously diagnosed with endometrial cancer have not undergone mismatch repair tumor testing. We sought to determine the feasibility of retroactive assessment for mismatch repair deficiency among women with diagnosed with endometrial cancer prior to 2014. Methods. Between 2016 and 2018, we identified 36 patients presenting for gynecologic oncology follow-up visits who were previously diagnosed with endometrial cancer. The endometrial pathology underwent tumor assessment for loss of expression of mismatch repair proteins by immunohistochemistry. Patients with abnormal mismatch repair testing were referred to genetic counseling and, if indicated, for germline genetic testing. Results. Thirty-six patients underwent retroactive tumor immunohistochemistry, yielding 10 (28%) abnormal results, including nine (25%) with loss of one or more mismatch repair proteins and one with inconclusive staining (2.8%). All ten patients with abnormal immunohistochemistry were referred to genetic counseling; 9 (90%) accepted the referral and proceeded with genetic testing. One pathogenic mutation was identified in CHEK2 (11%). Five patients (56%) were found to have a variant of unknown significance. Conclusions. Implementation of universal retroactive tumor testing for mismatch repair deficiency in patients previously diagnosed with endometrial cancer is feasible. With the growing use of new molecular classification protocols for endometrial tumors, identification of mismatch repair deficiency may have significant clinicopathologic implications.

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