scholarly journals Clinically silent LINE 1 insertion in the PNPLA3 gene may impede genotyping of the p.I148M variant

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Martin Leníček ◽  
Václav Šmíd ◽  
Petr Pajer ◽  
Anna Nazarova ◽  
Karel Dvořák ◽  
...  
Keyword(s):  
Dna Analysis ◽  
Risk Allele ◽  
The Novel ◽  
Terminal Sequence ◽  
Nonalcoholic Fatty Liver ◽  
Rna Analysis ◽  
Novel Variant ◽  
Liver Biopsies ◽  
Long Interspersed Element ◽  
Careful Design

AbstractThe patatin-like phospholipase domain containing 3 (PNPLA3) gene (viz. its I148M variant) is one of the key players in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). We have identified a novel insertion/deletion variant of 1114 bp, localized in the second intron of the PNPLA3 gene, which corresponds to the 3′ terminal sequence of the long-interspersed element (LINE-1). DNA analysis of 122 NAFLD patients and 167 control subjects as well as RNA analysis of 19 liver biopsies revealed that the novel variant is very common (frequency = 0.41), fully linked to the clinically important I148M variant, and clinically silent. Although the LINE-1 insertion does not seem to have any biological effect, it can impede genotyping of the I148M variant. If insertion prevents the attachment of the diagnostic primer, then the non-insertion allele will be selectively amplified; and thus the frequency of the 148M "risk" allele will be significantly overestimated due to the complete linkage of the LINE-1 insertion and the 148I allele of the PNPLA3 gene. Therefore, our findings underline the importance of careful design and consistent documentation of the methodology, including primer sequences. Critical revisions of the results of some studies that have already been reported may therefore be needed.

scholarly journals Motion – All Patients with NASH Need to Have a Liver Biopsy: Arguments against the Motion

2002 ◽  
Vol 16 (10) ◽  
pp. 722-726 ◽  
Author(s):  
Jacqueline Laurin
Keyword(s):  
Liver Disease ◽  
Liver Biopsy ◽  
Chronic Liver Disease ◽  
Chronic Liver ◽  
Nonalcoholic Fatty Liver ◽  
Histological Assessment ◽  
Clinical Benefits ◽  
Liver Biopsies ◽  
Alpha 1 Antitrypsin ◽  
Iron Profile

Most cases of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are suspected on the basis of the exclusion of viral, autoimmune, metabolic and genetic causes of chronic liver disease in patients with chronic elevation of aminotransferase enzymes. However, the definitive diagnosis of NASH requires liver biopsy. Valuable blood tests include hepatitis B and C serology, iron profile, alpha 1-antitrypsin phenotype, ceruloplasmin, antinuclear antibody and antismooth muscle antibody, and serum protein electrophoresis. If these tests are negative or normal, and if there are no symptoms or signs of chronic liver disease, it is unlikely that a specifically treatable liver disease would be discovered at biopsy. The prevalence of NAFLD in the general population appears to be approximately 20%, and 2% to 3% of people have NASH. There is no proven specific therapy for the spectrum of nonalcoholic liver disease; therefore, the management of the patient with NASH is not likely to be changed after histological assessment. Bleeding, sometimes fatal, and other complications requiring hospitalization can occur, and liver biopsies should not be undertaken without clear clinical indications. The high cost of undertaking histological assessment of all persons with asymptomatic elevations of liver enzymes cannot be justified in view of the risks and limited clinical benefits.

scholarly journals A novel multi-word paradigm for investigating semantic context effects in language production

2019 ◽  
Author(s):  
Cornelia van Scherpenberg ◽  
Rasha Abdel Rahman ◽  
Hellmuth Obrig
Keyword(s):  
Eye Tracking ◽  
Picture Naming ◽  
Language Production ◽  
Context Effects ◽  
Semantic Context ◽  
The Novel ◽  
Target Picture ◽  
Novel Variant ◽  
Lexical Interference ◽  
Respective Category

Semantic context modulates precision and speed of language production. Using different experimental designs including the Picture-Word-Interference (PWI) paradigm, it has consistently been shown that categorically related distractor words (e.g., cat) inhibit retrieval of the target picture name (dog). Here we introduce a novel variant of the PWI paradigm in which we present 8 words prior to a to be named target picture. Within this set, the number of words categorically related was varied between 3 and 5, and the picture to be named was either related or unrelated to the respective category. To disentangle interacting effects of semantic context we combined different naming paradigms manipulating the number of competitors, and assessing the effect of repeated naming instances. Evaluating processing of the cohort by eye-tracking provided us with a metric of the (implicit) recognition of the semantic cohort. Results replicate the interference effect in that overall naming of pictures categorically related to the distractor set was slower compared to unrelated pictures. However, interference did not increase with increasing number of distractors. Tracking this effect across naming repetitions, we found that interference is prominent at the first naming instance of every picture only, whereby it is stable across distractor conditions, but dissipates across the experiment. Regarding eye-tracking our data show that participants fixated longer on semantically related items, indicating the identification of the lexico-semantic cohort. Our findings confirm the validity of the novel paradigm and indicate that besides interference during first exposure, repeated exposure to the semantic context may facilitate picture naming and counteract lexical interference.

The association of FKBP5 polymorphism with asthma susceptibility in asthmatic patients

2021 ◽  
Vol 32 (4) ◽  
pp. 479-484
Author(s):  
Sura F. Alsaffar ◽  
Haider A. Rasheed ◽  
Jabbar H. Yenzeel ◽  
Haider F. Ghazi
Keyword(s):  
Allele Frequency ◽  
Risk Allele ◽  
Inhaled Corticosteroids ◽  
Control Group ◽  
The Novel ◽  
Nucleotide Polymorphisms ◽  
Asthmatic Patients ◽  
Asthma Susceptibility ◽  
Group Members ◽  
Novel Snp

Abstract Objectives Inhaled corticosteroids are the most effective controllers of asthma, although asthmatics vary in their response. FKBP51 is a major component of the glucocorticoid receptor which regulates its responses to corticosteroids. Therefore, the present study aims to identify the role of FKBP5 gene polymorphism in asthma susceptibility and corticosteroid resistance. Methods DNA was extracted from the blood of 68 asthmatic and 40 control subjects. FKBP5 gene fragments were amplified by PCR and sequenced by the Sanger method. The sequencing results were aligned by mapping on the reference sequences of National center of Biotechnology Information (NCBI) and single nucleotide polymorphisms (SNPs) which were checked. Finally, the genotype, allele frequency and odds ratio (OR) were calculated. Results The FKBP5 fragment sequencing revealed the presence of rs1360780 and one novel SNP found in 17 samples taken from asthmatic patients as compared to db SNP data in the NCBI database. The FKBP5 variant (rs1360780) indicated that the allele frequency of risk allele T was 41.18% in patients and 20% in control group members p<0.001 and OR=2.8 when compared to a wild C allele frequency of 58.82% in patients and 64% in the control group members. The novel SNP FKBP5 was compared to the SNP database in the NCBI database in which wild T allele was substituted with G. The novel SNP was submitted to the ClinVar Submission Portal at NCBI with accession number: rs1581842283 and confirmed an asthma susceptibility risk factor with allele G frequency of 11.76% in asthmatics and 2.5% in the control group members (OR=5.2, p<0.05), as compared to a wild T allele frequency of 88.24% in asthmatics and 97.5% in the control group members. Conclusions The risk allele T of rs1360780 and the novel SNP rs1581842283 risk allele G predict asthma susceptibility but show no association with corticosteroid resistant.

Novel somatic mutations in UBA1 as a cause of VEXAS syndrome

Blood ◽  
2021 ◽  
Author(s):  
James A Poulter ◽  
Jason Charles Collins ◽  
Catherine Cargo ◽  
Ruth M de Tute ◽  
Paul Evans ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Somatic Mutations ◽  
Clinical Phenotype ◽  
Splice Acceptor Site ◽  
Acceptor Site ◽  
The Novel ◽  
Disease Mechanism ◽  
Bone Marrow Biopsies ◽  
Novel Variant

Somatic mutations at methionine 41 (Met41) in UBA1, encoding the major E1 enzyme responsible for initiating ubiquitylation, were recently identified as the cause of a novel autoinflammatory disease, named VEXAS (Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic). We sought to determine the prevalence of UBA1 mutations in a UK cohort of patients matching the VEXAS clinical phenotype. We identified 10 new patients with somatic mutations in UBA1, but only 8 had altered p.Met41. A novel variant, c.167C&gt;T; p.Ser56Phe was identified, which was present in myeloid, and not lymphoid lineages and led to preferential loss of the catalytic activity of cytoplasmic UBA1. An additional novel variant, c.118-1G&gt;C was identified at the splice acceptor site of exon 3 leading to altered splicing in vitro. Bone marrow biopsies from two patients with a Met41 substitution and the novel splice site variant were consistent with previously reported features of VEXAS. The bone marrow of the patient with the p.Ser56Phe variant was less similar, likely driven by a distinct but overlapping disease mechanism. Our study therefore confirms somatic p.Met41 substitutions in UBA1 as a major cause of VEXAS syndrome and identifies two new disease causing mutations.

A novel variant in PAX6 as the cause of aniridia in a Chinese family

2020 ◽  
Author(s):  
Xin Jin ◽  
Wei Liu ◽  
HouBin Huang
Keyword(s):  
Nonsense Mutation ◽  
Novel Mutation ◽  
Causative Mutation ◽  
Chinese Family ◽  
The Novel ◽  
Targeted Next Generation Sequencing ◽  
Iris Defect ◽  
The Family ◽  
Novel Variant ◽  
Pax6 Mutation

Abstract Background: Aniridia is a kind of congenital human panocular anomaly, which is related to PAX6 commonly. Methods: A Chinese Aniridia pedigree underwent ophthalmic examinations, including visual acuity, slit lamp and fundoscopy examination. The targeted next-generation sequencing of Aniridia genes was used to identify the causative mutation. Results: A novel heterozygous PAX6 nonsense mutation c.619A>T (p.K207*) was identified in the Chinese autosomal dominant family with aniridia. Phenotypes related to the novel mutation include nystagmus, iris defect, cataract and absence of macular fovea. Conclusion: The novel nonsense mutation in PAX6 was responsible for aniridia phenotype in the family. which expands the spectrum of the PAX6 mutation and its associated phenotype.

scholarly journals Identification of a Modified HOXB9 mRNA in Breast Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Ayako Nakashoji ◽  
Tetsu Hayashida ◽  
Yuko Kawai ◽  
Masayuki Kikuchi ◽  
Rurina Watanuki ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Human Breast Cancer ◽  
Cancer Cell Line ◽  
Clinical Samples ◽  
The Novel ◽  
Rna Seq ◽  
Human Breast ◽  
Aberrant Expression ◽  
Novel Variant

First identified as a developmental gene, HOXB9 is also known to be involved in tumor biological processes, and its aberrant expression correlates with poor prognosis of various cancers. In this study, we isolated a homeodomain-less, novel HOXB9 variant (HOXB9v) from human breast cancer cell line-derived mRNA. We confirmed that the novel variant was produced from variationless HOXB9 genomic DNA. RT-PCR of mRNA isolated from clinical samples and reanalysis of publicly available RNA-seq data proved that the new transcript is frequently expressed in human breast cancer. Exogenous HOXB9v expression significantly enhanced the proliferation of breast cancer cells, and gene ontology analysis indicated that apoptotic signaling was suppressed in these cells. Considering that HOXB9v lacks key domains of homeobox proteins, its behavior could be completely different from that of the previously described variationless HOXB9. Because none of the previous studies on HOXB9 have considered the presence of HOXB9v, further research analyzing the two transcripts individually is warranted to re-evaluate the true role of HOXB9 in cancer.

scholarly journals Sa1618 – Characteristics of Nonalcoholic Fatty Liver Disease in Patients with Severe Obesity: Insights from 3077 Consecutive Liver Biopsies

2019 ◽  
Vol 156 (6) ◽  
pp. S-1256
Author(s):  
Tavankit Singh ◽  
Neal Mehta ◽  
Catherine F. Vozzo ◽  
Philip R. Schauer ◽  
Arthur McCullough ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Severe Obesity ◽  
Nonalcoholic Fatty Liver ◽  
Liver Biopsies
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