Monoallelic Mutation

2020 ◽  
Author(s):  
Keyword(s):  
Monoallelic Mutation

Kallmann syndrome due to a mutation in ANOS1 gene and monoallelic mutation in GNRHR gene

2021 ◽  
Author(s):  
Catarina Cidade-Rodrigues ◽  
Catarina Chaves ◽  
Mariana Martinho ◽  
Filipe Cunha ◽  
Margarida Almeida
Keyword(s):  
Kallmann Syndrome ◽  
Monoallelic Mutation

Clinical Implications of the Colorectal Cancer Risk Associated With MUTYH Mutation

2009 ◽  
Vol 27 (24) ◽  
pp. 3975-3980 ◽  
Author(s):  
Steven J. Lubbe ◽  
Maria Chiara Di Bernardo ◽  
Ian P. Chandler ◽  
Richard S. Houlston
Keyword(s):  
Colorectal Cancer ◽  
Mutation Screening ◽  
Biallelic Mutation ◽  
Repair Gene ◽  
Detection Rates ◽  
Mutation Status ◽  
Dna Repair Gene ◽  
Monoallelic Mutation ◽  
Mutyh Mutation ◽  
Biallelic Mutations

Purpose Biallelic mutations in the base excision DNA repair gene MUTYH predispose to colorectal cancer (CRC). Evidence that monoallelic mutations also confer an elevated CRC risk is controversial. Precise quantification of the CRC risk and the phenotype associated with MUTYH mutations is relevant to the counseling, surveillance, and clinical management of at-risk individuals. Methods We analyzed a population-based series of 9,268 patients with CRC and 5,064 controls for the Y179C and G396D MUTYH mutations. We related genotypes to phenotype and calculated genotype-specific CRC risks. Results Overall, biallelic mutation status conferred a 28-fold increase in CRC risk (95% CI,17.66 to 44.06); this accounted for 0.3% of CRCs in the cohort. Genotype relative risks of CRC were strongly age dependent, but penetrance was incomplete at age 60 years. CRC that developed in the context of biallelic mutations were microsatellite stable. Biallelic mutation carriers were more likely to have proximal CRC (P = 4.0 × 10−4) and synchronous polyps (P = 5.7 × 10−9) than noncarriers. The performance characteristics of clinicopathologic criteria for the identification of biallelic mutations are poor. Monoallelic mutation was not associated with an increased CRC risk (odds ratio, 1.07; 95% CI, 0.87 to 1.31). Conclusion The high risk and the propensity for proximal disease associated with biallielic MUTYH mutation justify colonoscopic surveillance. Although mutation screening should be directed to patients with APC-negative polyposis and early-onset proximal MSS CRC in whom detection rates will be highest, the expanded phenotype associated with MUTYH mutation needs to be recognized. There is no evidence than monoallelic mutation status per se is clinically important.

scholarly journals TSC1 loss-of-function increases risk for tauopathy by inducing tau acetylation and preventing autophagy-mediated tau clearance

2020 ◽  
Author(s):  
Carolina Alquezar ◽  
Kathleen M Schoch ◽  
Ethan G Geier ◽  
Eliana Marisa Ramos ◽  
Aurora Scrivo ◽  
...  
Keyword(s):  
Genetic Model ◽  
Loss Of Function ◽  
Therapeutic Modalities ◽  
Risk Variants ◽  
Lysine Residues ◽  
Monoallelic Mutation ◽  
Mutant Forms ◽  
Chaperone Mediated Autophagy ◽  
Tau Acetylation

AbstractAge-associated neurodegenerative disorders demonstrating tau-laden intracellular inclusions, including Alzheimer’s disease (AD), frontotemporal lobar degeneration (FTLD) and progressive supranuclear palsy (PSP), are collectively known as tauopathies. The vast majority of human tauopathies accumulate non-mutant tau rather than mutant forms of the protein, yet cell and animal models for non-mutant tauopathies are lacking. We previously linked a monoallelic mutation in the TSC1 gene to tau accumulation and FTLD. Now, we have identified new variants in TSC1 that predisposed to other tauopathies such as AD and PSP. These new TSC1 risk variants significantly decreased the half-life of TSC1/hamartin in vitro. Cellular and murine models of TSC1 haploinsufficiency (TSC1+/-) accumulated tau protein that exhibited aberrant acetylation on six lysine residues. Tau acetylation hindered its lysosomal degradation via chaperone-mediated autophagy leading to neuronal tau accumulation. Enhanced tau acetylation in TSC1+/- models was achieved through both an increase in p300 acetyltransferase activity and a decrease in SIRT1 deacetylase levels. Pharmacological modulation of either enzyme restored tau levels. Together, these studies substantiate TSC1 as a novel tauopathy risk gene and advance TSC1 haploinsufficiency as a new genetic model for tauopathy. In addition, these results promote acetylated tau as a rational target for diagnostic and therapeutic modalities in multiple tauopathies.

scholarly journals Case Report: Characterizing the Role of the STXBP2-R190C Monoallelic Mutation Found in a Patient With Hemophagocytic Syndrome and Langerhans Cell Histiocytosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Laura Viñas-Giménez ◽  
Rafael Rincón ◽  
Roger Colobran ◽  
Xavier de la Cruz ◽  
Verónica Paola Celis ◽  
...  
Keyword(s):  
Cell Line ◽  
Langerhans Cell Histiocytosis ◽  
Nk Cell ◽  
Adaptive Immune System ◽  
Langerhans Cell ◽  
Adaptive Immune ◽  
Life Threatening ◽  
Monoallelic Mutation ◽  
Nk Cell Cytotoxicity

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory disorder. HLH can be considered as a threshold disease depending on the trigger and the residual NK-cell cytotoxicity. In this study, we analyzed the molecular and functional impact of a novel monoallelic mutation found in a patient with two episodes of HLH. A 9-month-old child was diagnosed at 2 months of age with cutaneous Langerhans cell histiocytosis (LCH). After successful treatment, the patient developed an HLH episode. At 16 month of age, the patient went through an HSCT losing the engraftment 5 months later concomitant with an HLH relapse. The genetic study revealed a monoallelic mutation in the STXBP2 gene (.pArg190Cys). We transfected COS7 cells to analyze the STXBP2-R190C expression and to test the interaction with STX11. We used the RBL-2H3 cell line expressing STXBP2-WT-EGFP or R190C-EGFP for degranulation assays. Mutation STXBP2-R190C did not affect protein expression or interaction with syntaxin-11. However, we have demonstrated that STXBP2-R190C mutation diminishes degranulation in the RBL-2H3 cell line compared with the RBL-2H3 cell line transfected with STXBP2-WT or nontransfected. These results suggest that STXBP2-R190C mutation acts as a modifier of the degranulation process producing a decrease in degranulation. Therefore, under homeostatic conditions, the presence of one copy of STXBP2-R190 could generate sufficient degranulation capacity. However, it is likely that early in life when adaptive immune system functions are not sufficiently developed, an infection may not be resolved with this genetic background, leading to a hyperinflammation syndrome and eventually develop HLH. This analysis highlights the need for functional testing of new mutations to validate their role in genetic susceptibility and to establish the best possible treatment for these patients.

scholarly journals Efficient Generation of P53 Biallelic Mutations in Diannan Miniature Pigs Using RNA-Guided Base Editing

Life ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1417
Author(s):  
Honghui Li ◽  
Wenmin Cheng ◽  
Bowei Chen ◽  
Shaoxia Pu ◽  
Ninglin Fan ◽  
...  
Keyword(s):  
Disease Model ◽  
P53 Gene ◽  
P53 Mutation ◽  
P53 Mutations ◽  
P53 Expression ◽  
Base Editing ◽  
System A ◽  
Reconstructed Embryos ◽  
Monoallelic Mutation ◽  
Biallelic Mutations

The base editing 3 (BE3) system, a single-base gene editing technology developed using CRISPR/Cas9n, has a broad range of applications for human disease model construction and gene therapy, as it is highly efficient, accurate, and non-destructive. P53 mutations are present in more than 50% of human malignancies. Due to the similarities between humans and pigs at the molecular level, pig models carrying P53 mutations can be used to research the mechanism of tumorigenesis and improve tumor diagnosis and treatment. According to pathogenic mutations of the human P53 gene at W146* and Q100*, sgRNAs were designed to target exon 4 and exon 5 of the porcine P53 gene. The target editing efficiencies of the two sgRNAs were 61.9% and 50.0%, respectively. The editing efficiency of the BE3 system was highest (about 60%) when C (or G) was at the 5th base. Puromycin screening revealed that 75.0% (21/28) and 68.7% (22/32) of cell colonies contained a P53 mutation at sgRNA-Exon5 and sgRNA-Exon4, respectively. The reconstructed embryos from sgRNA-Exon5-5# were transferred into six recipient gilts, all of which aborted. The reconstructed embryos from sgRNA-Exon4-7# were transferred into 6 recipient gilts, 3 of which became pregnant, resulting in 14 live and 3 dead piglets. Sequencing analyses of the target site confirmed 1 P53 monoallelic mutation and 16 biallelic mutations. The qPCR analysis showed that the P53 mRNA expression level was significantly decreased in different tissues of the P53 mutant piglets (p < 0.05). Additionally, confocal microscopy and western blot analysis revealed an absence of P53 expression in the P53 mutant fibroblasts, livers, and lung tissues. In conclusion, a porcine cancer model with a P53 point mutation can be obtained via the BE3 system and somatic cell nuclear transfer (SCNT).

Overexpression of I Kappa B Alpha Without Inhibition of NF-κB Activity and Mutations in the I Kappa B Alpha Gene in Reed-Sternberg Cells

Blood ◽  
1999 ◽  
Vol 94 (9) ◽  
pp. 3129-3134 ◽  
Author(s):  
Florian Emmerich ◽  
Martina Meiser ◽  
Michael Hummel ◽  
Gudrun Demel ◽  
Hans-Dieter Foss ◽  
...  
Keyword(s):  
Hodgkin's Disease ◽  
Hodgkin’S Disease ◽  
Lymph Node Biopsy ◽  
Binding Activity ◽  
Nf Kappa B ◽  
Tissue Sections ◽  
I Kappa B Alpha ◽  
Dna Binding Activity ◽  
Constitutive Overexpression ◽  
Monoallelic Mutation

The transcription factor NF kappa B (NF-κB) mediates the expression of numerous genes involved in diverse functions such as inflammation, immune response, apoptosis, and cell proliferation. We recently identified constitutive activation of NF-κB (p50/p65) as a common feature of Hodgkin/Reed-Sternberg (HRS) cells preventing these cells from undergoing apoptosis and triggering proliferation. To examine possible alterations in the NF-κB/IκB system, which might be responsible for constitutive NF-κB activity, we have analyzed the inhibitor I kappa B alpha (IκB) in primary and cultured HRS cells on protein, mRNA, and genomic levels. In lymph node biopsy samples from Hodgkin’s disease patients, IκB mRNA proved to be strongly overexpressed in the HRS cells. In 2 cell lines (L428 and KM-H2), we detected mutations in the IκB gene, resulting in C-terminally truncated proteins, which are presumably not able to inhibit NF-κB–DNA binding activity. Furthermore, an analysis of the IκB gene in single HRS cells micromanipulated from frozen tissue sections showed a monoallelic mutation in 1 of 10 patients coding for a comparable C-terminally truncated IκB protein. We suggest that the observed IκB mutations contribute to constitutive NF-κB activity in cultured and primary HRS cells and are therefore involved in the pathogenesis of these Hodgkin’s disease (HD) patients. The demonstrated constitutive overexpression of IκB in HRS cells evidences a deregulation of the NF-κB/IκB system also in the remaining cases, probably due to defects in other members of the IκB family.

A case report and literature review of monoallelic mutation of GHR

2019 ◽  
Vol 32 (4) ◽  
pp. 415-419
Author(s):  
Marie Mitani ◽  
Hirohito Shima ◽  
Takeshi Sato ◽  
Tomohiro Inoguchi ◽  
Tsutomu Kamimaki ◽  
...  
Keyword(s):  
Short Stature ◽  
Novel Mutation ◽  
Serum Insulin ◽  
The Novel ◽  
Gh Secretion ◽  
Old Japanese ◽  
Missense Variation ◽  
Normal Stature ◽  
Monoallelic Mutation ◽  
Severe Short Stature

Abstract Background Monoallelic mutations of GHR have been described in idiopathic short stature (ISS), although the significance of these remain unclear. We report a case of ISS with novel monoallelic S219L mutation of GHR and discuss the possible significance of monoallelic GHR mutation in ISS. Case presentation The proband, a 13.9-year-old Japanese boy, had severe short stature (−3.8 standard deviation [SD]). Serum insulin-like growth factor (IGF)-I level and growth hormone (GH) secretion was normal. His parents were nonconsanguineous and had normal stature. Genetic analyses revealed a novel monoallelic missense variation in exon 7 of GHR (S219L). The proband’s mother had the same variation. S219L might be the novel mutation judging from there being no registration of it as a single-nucleotide polymorphism (SNP) in any database, evolutional conservation of Ser219, in silico analyses, and computational molecular visualization analysis. Furthermore, a review of the literature showed that the median height of missense mutation carriers of GHR was relatively low. Conclusions We propose the possibility that monoallelic mutation of GHR increases the susceptibility to short stature.

Overexpression of I Kappa B Alpha Without Inhibition of NF-κB Activity and Mutations in the I Kappa B Alpha Gene in Reed-Sternberg Cells

Blood ◽  
1999 ◽  
Vol 94 (9) ◽  
pp. 3129-3134 ◽  
Author(s):  
Florian Emmerich ◽  
Martina Meiser ◽  
Michael Hummel ◽  
Gudrun Demel ◽  
Hans-Dieter Foss ◽  
...  
Keyword(s):  
Hodgkin's Disease ◽  
Hodgkin’S Disease ◽  
Lymph Node Biopsy ◽  
Binding Activity ◽  
Nf Kappa B ◽  
Tissue Sections ◽  
I Kappa B Alpha ◽  
Dna Binding Activity ◽  
Constitutive Overexpression ◽  
Monoallelic Mutation

Abstract The transcription factor NF kappa B (NF-κB) mediates the expression of numerous genes involved in diverse functions such as inflammation, immune response, apoptosis, and cell proliferation. We recently identified constitutive activation of NF-κB (p50/p65) as a common feature of Hodgkin/Reed-Sternberg (HRS) cells preventing these cells from undergoing apoptosis and triggering proliferation. To examine possible alterations in the NF-κB/IκB system, which might be responsible for constitutive NF-κB activity, we have analyzed the inhibitor I kappa B alpha (IκB) in primary and cultured HRS cells on protein, mRNA, and genomic levels. In lymph node biopsy samples from Hodgkin’s disease patients, IκB mRNA proved to be strongly overexpressed in the HRS cells. In 2 cell lines (L428 and KM-H2), we detected mutations in the IκB gene, resulting in C-terminally truncated proteins, which are presumably not able to inhibit NF-κB–DNA binding activity. Furthermore, an analysis of the IκB gene in single HRS cells micromanipulated from frozen tissue sections showed a monoallelic mutation in 1 of 10 patients coding for a comparable C-terminally truncated IκB protein. We suggest that the observed IκB mutations contribute to constitutive NF-κB activity in cultured and primary HRS cells and are therefore involved in the pathogenesis of these Hodgkin’s disease (HD) patients. The demonstrated constitutive overexpression of IκB in HRS cells evidences a deregulation of the NF-κB/IκB system also in the remaining cases, probably due to defects in other members of the IκB family.

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