scholarly journals Erratum: clinical and molecular characteristics of patients with 46,xy dsd due to nr5a1 gene mutations (Probl Endokrinol (Mosk). 2020 Sep 16;66(3):62-69. Russian. doi: 10.14341/probl12445)

2021 ◽  
Vol 67 (6) ◽  
pp. 124-126
Author(s):  
N. Yu. Kalinchenko ◽  
A. A. Kolodkina ◽  
N. Yu. Raygorodskaya ◽  
A. N. Tiulpakov
Keyword(s):  
Stop Codon ◽  
Premature Stop Codon ◽  
Gene Mutations ◽  
Synonymous Substitution ◽  
Molecular Characteristics ◽  
Missense Mutations ◽  
Reading Frame ◽  
Splicing Site

n the article some corrections were needed. Abstract: “Heterozygous SF1 variants were found in 36 out of 310 (11.6%) of cases, among them 15 were not previously described”. has been corrected to read “Heterozygous SF1 variants were found in 36 out of 310 (11.6%) of cases, among them 22 were not previously described”. Results: “Heterozygous SF1 variants were found in 36 out of 310 (11.6%) of cases, among them 15 were not previously described”, has been corrected to read “Heterozygous SF1 variants were found in 36 out of 310 (11.6%) of cases, among them 22 were not previously described”. Among the newly identified variants in the NR1A1 gene, two lead to the premature stop codon -p. Y197X and p. Y25X, two lead to a shift in the reading frame-p. N385fs and p. L245fs, which does not allow us to doubt their pathogenicityAmong the previously undescribed variant changes, 5 missense mutations (p. C283Y, p. C283B, p.H24Q, p.M126K, p.E81K) and 1  synonymous substitution affecting the splicing site (E330E) were evaluated as pathogenic, and 5 others as probably pathogenic.Has been corrected to read: Among the newly identified variants in the NR1A1 gene, two lead to the premature stop codon -p. Y197X and p. Y25X, two lead to a shift in the reading frame — p.N385SfsX10 and p.L245AfsX53, which does not allow us to doubt their pathogenicity Among the previously undescribed variants, 5 missense mutations (p.C283Y, p.С283F, p.H24Q, p.M126K, p.A82T) and 1 synonymous substitution affecting the splicing site (E330E) were predicted as pathogenic, and 5 others as probably pathogenic by calculating pathogenicity. The authors apologize for these errors. 

Abstract 293: Tcf7l2 Expression And Isoform Switching In Mouse Hearts

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
LU XIAO ◽  
Haiqing Bai ◽  
James Boyer ◽  
Bo Ye ◽  
Ning Hou ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Wnt Signaling ◽  
Stop Codon ◽  
Medical Center ◽  
Premature Stop Codon ◽  
Beta Catenin ◽  
Canonical Wnt Signaling ◽  
Cardiovascular Research ◽  
Reading Frame ◽  
Canonical Wnt

Lu Xiao, Haiqing Bai, James Boyer, Bo Ye, Ning Hou, Haodong Xu, and Faqian Li Department of Pathology and Laboratory Medicine and Cardiovascular Research Institute, University of Rochester Medical Center, Rochester, NY, USA Backgrounds: Canonical Wnt signaling appears to have multiphasic and often antagonistic roles in cardiac development. The molecular mechanism for these opposing actions is not clear. We hypothesized that alternative splicing of TCF7L2, a nuclear interaction partner of beta-catenin is involved in the specificity of canonical Wnt signaling. Methods: RT-PCR were performed on embryonic (E16.5) and neonatal (day 8) hearts with primers spanning the end of first exon and the beginning of last exon and the products were cloned and sequenced. Result: There are totally 18 exons identified so far in TCF7L2. We sequenced 56 clones and 53 clones (29 from day 8) and (24 from E16.5) contained TCF7L2 sequences. No exon 6 or exon 17 was found in TCF7L2 transcripts of mouse hearts. Most clones (more than 80%) from E16.5 and day 8 hearts excluded exon 4. Both E16.5 and day 8 hearts had one clone with exon 9 deletion which does not change reading frame and another with alterations in exon 3 that lead to reading frame shift and premature stop codon. As reported in other organs, there were extensive alternative splicing in the C-terminal exons 14, 15 and 16. The inclusion of exon 14 was more frequently in day 8 (18 of 29, 62%) than in E16.5 (8 of 24, 33%) hearts. The peptide encoded by exon 14 has conserved functional motif. Additionally, this alternative exon usage can change the C-terminus of TCF7L2 to include or exclude the so-called E tail with two binding motifs for C-terminal binding protein. Conclusion: The isoform switch of TCF7L2 occurs in neonatal mouse hearts and may have a role in the terminal differentiation of cardiac myocytes during this period.

A G-to-A mutation in IVS-3 of the human gamma fibrinogen gene causing afibrinogenemia due to abnormal RNA splicing

Blood ◽  
2000 ◽  
Vol 96 (7) ◽  
pp. 2501-2505 ◽  
Author(s):  
Maurizio Margaglione ◽  
Rosa Santacroce ◽  
Donatella Colaizzo ◽  
Davide Seripa ◽  
Gennaro Vecchione ◽  
...  
Keyword(s):  
Amino Acid ◽  
Rna Splicing ◽  
Messenger Rna ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Autosomal Recessive Disorder ◽  
Chain Gene ◽  
Hemorrhagic Diathesis ◽  
Reading Frame ◽  
Congenital Afibrinogenemia

Abstract Congenital afibrinogenemia is a rare autosomal recessive disorder characterized by a hemorrhagic diathesis of variable severity. Although more than 100 families with this disorder have been described, genetic defects have been characterized in few cases. An investigation of a young propositus, offspring of a consanguineous marriage, with undetectable levels of functional and quantitative fibrinogen, was conducted. Sequence analysis of the fibrinogen genes showed a homozygous G-to-A mutation at the fifth nucleotide (nt 2395) of the third intervening sequence (IVS) of the γ-chain gene. Her first-degree relatives, who had approximately half the normal fibrinogen values and showed concordance between functional and immunologic levels, were heterozygtes. The G-to-A change predicts the disappearance of a donor splice site. After transfection with a construct, containing either the wild-type or the mutated sequence, cells with the mutant construct showed an aberrant messenger RNA (mRNA), consistent with skipping of exon 3, but not the expected mRNA. Sequencing of the abnormal mRNA showed the complete absence of exon 3. Skipping of exon 3 predicts the deletion of amino acid sequence from residue 16 to residue 75 and shifting of reading frame at amino acid 76 with a premature stop codon within exon 4 at position 77. Thus, the truncated γ-chain gene product would not interact with other chains to form the mature fibrinogen molecule. The current findings show that mutations within highly conserved IVS regions of fibrinogen genes could affect the efficiency of normal splicing, giving rise to congenital afibrinogenemia.

Mutations of TET2 and JAK2 but Not CBL Are Detectable in a High Portion of Patients with Refractory Anemia with Ring Sideroblasts and Thrombocytosis (RARS-T).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1766-1766
Author(s):  
Johanna Flach ◽  
Sonja Schindela ◽  
Frank Dicker ◽  
Susanne Schnittger ◽  
Alexander Kohlmann ◽  
...  
Keyword(s):  
Microarray Analysis ◽  
Stop Codon ◽  
Myeloproliferative Neoplasms ◽  
Premature Stop Codon ◽  
Jak2v617f Mutation ◽  
Refractory Anemia ◽  
Missense Mutations ◽  
Myeloid Malignancies ◽  
Ring Sideroblasts ◽  
Equity Ownership

Abstract Abstract 1766 Poster Board I-792 Refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) forms a provisional entity within the category of MDS/MPN-U in the 2008 WHO classification. Although the identification of the JAK2V617F mutation was an important first step in distinguishing this entity from other hematological diseases, further genetic characterization is necessary. We performed comprehensive cytogenetic and molecular genetic investigations including targeted analysis of JAK2V617F, TET2, MPLW515 and CBL, markers known to be altered in MPN, as well as genome-wide single nucleotide polymorphism microarray analysis (SNP-A) in 23 RARS-T patients who fulfilled WHO 2008 diagnostic criteria. The JAK2V617F mutation was detectable in 15 out of 19 analyzed patients (78.9%), four of which were homozygous. However, our patients neither carried a MPLW515 mutation nor mutations in exons 8 or 9 of CBL genes. These genes were recently described to be mainly mutated in myeloproliferative neoplasms. In addition, conventional cytogenetic analysis did not reveal any recurrent cytogenetic abnormalities in RARS-T patients. We also performed SNP microarray analysis in a subset of 10 RARS-T patients. Although we did neither observe recurrent chromosomal gains or losses nor recurring regions of UPD, one patient showed a deletion spanning a 1.3 Mb region on the long arm of chromosome 4 (start: 105,497,200 bp from pter; end: 106,825,780 bp from pter). The deleted region contained TET2, a gene recently found to be altered in many subtypes of myeloid malignancies. To further clarify the 4q24 deletion detected by SNP-A analysis we performed fluorescence in situ hybridization (FISH). 20 out of 100 analyzed interphase nuclei and three metaphases showed only one signal for the probe spanning the TET2 gene in this patient. Interphase FISH with the TET2 probe was performed in nine additional cases not analyzed by SNP arrays due to a lack of material, but no additional case showing a deletion was detected. In addition to FISH, we performed TET2 sequencing in 19/23 RARS-T patients. TET2 mutations were detected in 5/19 patients (26%), of which 3/5 also presented the JAK2V617F mutation, whereas the remaining 2/5 did neither show JAK2V617F nor MPL nor CBL mutations. The five patients showed 6 individually different TET2 mutations. Three were nonsense and two missense mutations. One patient displayed a frameshift mutation leading to a premature stop codon. In summary, RARS-T patients demonstrated a high frequency of both JAK2 and TET2 mutations. Together with the less common MPL mutations described by others RARS-T presents a variety of mutations that overlap with the spectrum of mutations seen in MPN and other myeloid malignancies. Thus, a combination of molecular markers including JAK2 and TET2 should be investigated to more precisely describe RARS-T as an independent disease entity. Disclosures Flach: MLL Munich Leukemia Laboratory: Employment. Schindela:MLL Munich Leukemia Laboratory: Employment. Dicker:MLL Munich Leukemia Laboratory: Employment. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Weiss:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership.

scholarly journals Murine cytomegalovirus open reading frame m29.1 augments virus replication both in vitro and in vivo

2007 ◽  
Vol 88 (11) ◽  
pp. 2941-2951 ◽  
Author(s):  
Mohammad M. Ahasan ◽  
Clive Sweet
Keyword(s):  
Virus Replication ◽  
Post Infection ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Open Reading Frame ◽  
Murine Cytomegalovirus ◽  
Reading Frame ◽  
Codon Mutation

Murine cytomegalovirus mutant Rc29, with a premature stop codon mutation in the m29 open reading frame (ORF), produced no apparent phenotype in cell culture or following infection of BALB/c mice. In contrast, a similar mutant virus, Rc29.1, with a premature stop codon mutation in its m29.1 ORF, showed reduced virus yields (2–3 log10 p.f.u. ml−1) in tissue culture. Mutant virus yields in BALB/c mice were delayed, reduced (∼1 log10 p.f.u. per tissue) and persisted less well in salivary glands compared with wild-type (wt) and revertant (Rv29.1) virus. In severe combined immunodeficiency mice, Rc29.1 virus showed delayed and reduced replication initially in all tissues (liver, spleen, kidneys, heart, lung and salivary glands). This delayed death until 31 days post-infection (p.i.) compared with wt (23 days p.i.) but at death virus yields were similar to wt. m29 gene transcription was initiated at early times post-infection, while production of a transcript from ORF m29.1 in the presence of cycloheximide indicated that it was an immediate-early gene. ORFs m29.1 and M28 are expressed from a bicistronic message, which is spliced infrequently. However, it is likely that each ORF expresses its own protein, as antiserum derived in rabbits to the m29.1 protein expressed in bacteria from the m29.1 ORF detected only one protein in Western blot analysis of the size predicted for the m29.1 protein. Our results suggest that neither ORF is essential for virus replication but m29.1 is important for optimal viral growth in vitro and in vivo.

scholarly journals Hereditary Multiple Exostoses: Clinical, Molecular and Radiologic Survey in 9 Families

2017 ◽  
Vol 118 (2-3) ◽  
pp. 87-94
Author(s):  
Karel Medek ◽  
Jiří Zeman ◽  
Tomáš Honzík ◽  
Hana Hansíková ◽  
Štěpánka Švecová ◽  
...  
Keyword(s):  
Malignant Transformation ◽  
De Novo ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Gene Mutations ◽  
Nonsense Mutations ◽  
Hereditary Multiple Exostoses ◽  
Multiple Exostoses ◽  
The Mean

Hereditary multiple exostoses (HME) represents a heterogeneous group of diseases often associated with progressive skeletal deformities. Most frequently, mutations inEXT1andEXT2genes with autosomal dominant inheritance are responsible for HME. In our group of 9 families with HME we evaluated the clinical course of the disease and analysed molecular background using Sanger sequencing and MLPA inEXT1andEXT2genes. The mean age in our group of patients, when the first exostosis was recognised was 4.5 years (range 2–10 years) and the number of exostoses per one patient documented on X-ray ranged from 2 to 54. Most of the exostoses developed before the growth was completed and they were dominantly localised in the distal femurs, proximal tibia, proximal humerus and distal radius. In all patients, at least one to 8 surgeries were necessary due to complaints and local complications, but neither patient developed malignant transformation. In half of the patients, the disease resulted in short stature. DNA analyses were positive in 7 families. In five probands, differentEXT1gene mutations resulting in premature stop-codon (p.Gly124Argfs*65, p.Leu191*, p.Trp364Lysfs*11, p.Val371Glyfs*10, p.Leu490Profs*31) were found. In two probands, nonsense mutations were found inEXT2gene (p.Val187Profs*115, p.Cys319fs*46). Five mutations have been novel and two mutations have occurredde novoin probands. Although the risk for malignant transformation is usually low, especially in patients with low number of exostoses, early diagnostics and longitudinal follow up of patients is of a big importance, because early surgery can prevent progression of secondary bone deformities.

scholarly journals Novel Mutations Segregating with Complete Androgen Insensitivity Syndrome and their Molecular Characteristics

2019 ◽  
Vol 20 (21) ◽  
pp. 5418
Author(s):  
Malcher ◽  
Jedrzejczak ◽  
Stokowy ◽  
Monem ◽  
Nowicka-Bauer ◽  
...  
Keyword(s):  
Stop Codon ◽  
Premature Stop Codon ◽  
Androgen Insensitivity Syndrome ◽  
Molecular Characteristics ◽  
Heterozygous Mutation ◽  
Transactivation Domain ◽  
Rna Seq ◽  
Nonsynonymous Mutation ◽  
Complete Androgen Insensitivity Syndrome ◽  
Androgen Insensitivity

We analyzed three cases of Complete Androgen Insensitivity Syndrome (CAIS) and report three hitherto undisclosed causes of the disease. RNA-Seq, Real-timePCR, Western immunoblotting, and immunohistochemistry were performed with the aim of characterizing the disease-causing variants. In case No.1, we have identified a novel androgen receptor (AR) mutation (c.840delT) within the first exon in the N-terminal transactivation domain. This thymine deletion resulted in a frameshift and thus introduced a premature stop codon at amino acid 282. In case No.2, we observed a nonsynonymous mutation in the ligand-binding domain (c.2491C>T). Case No.3 did not reveal AR mutation; however, we have found a heterozygous mutation in CYP11A1 gene, which has a role in steroid hormone biosynthesis. Comparative RNA-Seq analysis of CAIS and control revealed 4293 significantly deregulated genes. In patients with CAIS, we observed a significant increase in the expression levels of PLCXD3, TM4SF18, CFI, GPX8, and SFRP4, and a significant decrease in the expression of SPATA16, TSACC, TCP10L, and DPY19L2 genes (more than 10-fold, p < 0.05). Our findings will be helpful in molecular diagnostics of patients with CAIS, as well as the identified genes could be also potential biomarkers for the germ cells differentiation process.

scholarly journals New Insights Into Pheochromocytoma Surveillance of Young Patients With VHL Missense Mutations

2019 ◽  
Vol 3 (9) ◽  
pp. 1682-1692 ◽  
Author(s):  
Gustavo F C Fagundes ◽  
Janaina Petenuci ◽  
Delmar M Lourenco ◽  
Ericka B Trarbach ◽  
Maria Adelaide A Pereira ◽  
...  
Keyword(s):  
Stop Codon ◽  
Young Patients ◽  
Renal Cysts ◽  
Pancreatic Cysts ◽  
Missense Mutations ◽  
Biochemical Screening ◽  
Von Hippel Lindau ◽  
Large Gene ◽  
Vhl Disease ◽  
Splicing Site

Abstract Context Von Hippel-Lindau (VHL) disease is an autosomal dominant syndrome caused by germline mutations in the VHL gene. Guidelines recommend pheochromocytoma (PHEO) biochemical screening should start at age 5 years. Objective Genotype–phenotype correlations in VHL, focusing on PHEO penetrance in children, were studied. Design We retrospectively evaluated 31 individuals (median age at diagnosis was 26 years) with diagnosed VHL disease. Results PHEO was diagnosed in six children with VHL. A large PHEO (5 cm) was detected in a 4-year-old boy with p.Gly114Ser mutation. PHEO penetrance was 55% starting at age 4 years. VHL missense mutations were identified in 11 of 22 families (50%), frameshift mutations in four (18.2%), stop codon in three (13.6%), splicing site in two (9.1%), and large gene deletion in two (9.1%). The codon 167 (n = 10) was a hotspot for VHL mutations and was significantly associated with PHEO (90% vs. 38%; P = 0.007). PHEOs and pancreatic neuroendocrine tumors (PNETs) were strongly associated with VHL missense mutations compared with other mutations (89.5% vs. 0% and 73.7% vs. 16.7%; P = 0.0001 and 0.002, respectively). In contrast, pancreatic cysts (91.7% vs. 26.3%; P = 0.0001), renal cysts (66.7% vs. 26.3%; P = 0.027), and central nervous system hemangioblastomas (91.7% vs. 47.3%; P = 0.012) were more frequent in VHL with nonmissense mutations. Conclusion VHL missense mutations were highly associated with PHEO and PNETs. Our data support that in children with VHL harboring missense mutations, biochemical screening for PHEO should be initiated at diagnosis.

scholarly journals Complete Genome Sequence of Porcine Circovirus Strain YiY-3-2-H5 with a Novel Insertion, Isolated from Hunan Province, China

2016 ◽  
Vol 4 (2) ◽  
Author(s):  
Qian Gong ◽  
Yi Hu ◽  
Yang Zhan ◽  
Dongliang Wang ◽  
Naidong Wang ◽  
...  
Keyword(s):  
Complete Genome ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Porcine Circovirus Type ◽  
Hunan Province ◽  
Porcine Circovirus ◽  
Reading Frame ◽  
Pcv2 Strain ◽  
Open Reading Frame 1

The complete genome of porcine circovirus type 2 (PCV2) strain YiY-3-2-H5 contains a cytidine insertion at position 962 in open reading frame 1. This insertion causes a reading frameshift of the rep gene, and thereafter a premature stop codon is present at the 3′ terminal end of this gene.

Three Novel ADAMTS-13 Gene Mutations in Thrombotic Thrombocytopenic Purpura (TTP).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3965-3965
Author(s):  
Nam Keun Kim ◽  
Moon Ju Jang ◽  
Sun Kim ◽  
Sun Ju Lee ◽  
Hye Won Park ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Thrombus Formation ◽  
Gene Mutations ◽  
Missense Mutations ◽  
Thrombocytopenic Purpura ◽  
Congenital Thrombotic Thrombocytopenic Purpura ◽  
Platelet Thrombus ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Splicing Site

Abstract ADAMTS-13 is an enzyme which cleave von Willebrand factor (VWF) to prevent excessive platelet thrombus formation. Mutation of ADAMTS-13 is associated with congenital thrombotic thrombocytopenic purpura (TTP). In this study, we report three novel missense mutations of ADAMTS-13 gene in TTP families. Genetic analysis of ADAMTS-13 gene was performed in 6 TTP families. Three novel ADAMTS-13 gene mutations (2708C>T [S903L], 3650T>C [I1217T] and 3941C>T [S1314L]) detected in 3 families. They were all found with heterozygous genotype in exon 21, 26 and 28, respectively. The 3650T>C mutation was found at exon 26 in the patient and his mother. A heterozygous guanine to adenine substitution was found at 5′ splicing site of intron 3(IVS+ 1) in the patient, his brother and his father. The plasma ADAMTS-13 activities of the patient, father, mother, and brother were less than 3%, 56%, 55% and 62% respectively. ADAMTS-13 inhibitors were not detected in all family members. 3941C>T was found at exon 28 in the patient and her father. The plasma ADAMTS-13 activities of the patient, father, and mother were 96%, 83%, and 83% respectively.

Long-term administration of antisense oligonucleotides into the paraspinal muscles of mdx mice reduces kyphosis

2008 ◽  
Vol 105 (2) ◽  
pp. 662-668 ◽  
Author(s):  
Nicola Laws ◽  
Renée A. Cornford-Nairn ◽  
Nicole Irwin ◽  
Russell Johnsen ◽  
Susan Fletcher ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Rna Splicing ◽  
Antisense Oligonucleotides ◽  
Latissimus Dorsi ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Paraspinal Muscles ◽  
Reading Frame

The mdx mouse model of muscular dystrophy has a premature stop codon preventing production of dystrophin. This results in a progressive phenotype causing centronucleation of skeletal muscle fibers, muscle weakness, and fibrosis and kyphosis. Antisense oligonucleotides alter RNA splicing to exclude the nonsense mutation, while still maintaining the open reading frame to produce a shorter, but partially functional dystrophin protein that should ameliorate the extent of pathology. The present study investigated the benefits of chronic treatment of mdx mice by once-monthly deep intramuscular injections of antisense oligonucleotides into paraspinal muscles. After 8 mo of treatment, mdx mice had reduced development of kyphosis relative to untreated mdx mice, a benefit that was retained until completion of the study at 18 mo of age (16 mo of treatment). This was accompanied by reduced centronucleation in the latissimus dorsi and intercostals muscles and reduced fibrosis in the diaphragm and latissimus dorsi. These benefits were accompanied by a significant increase in dystrophin production. In conclusion, chronic antisense oligonucleotide treatment provides clear and ongoing benefits to paralumbar skeletal muscle, with associated marked reduction in kyphosis.

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