scholarly journals A novel nonsense PTH1R variant shows incomplete penetrance of primary failure of eruption: a case report

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Cristina Grippaudo ◽  
Concetta Cafiero ◽  
Isabella D’Apolito ◽  
Agnese Re ◽  
Maurizio Genuardi ◽  
...  
Keyword(s):  
Stop Codon ◽  
Clinical Manifestations ◽  
Premature Stop Codon ◽  
Diagnostic Value ◽  
Open Bite ◽  
Incomplete Penetrance ◽  
Functional Protein ◽  
Case Presentation ◽  
Primary Failure Of Eruption ◽  
Buccal Swabs

Abstract Background Aim of this work was to describe a rare inheritance pattern of Primary Failure of Eruption (PFE) in a small family with incomplete penetrance of PFE and a novel nonsense PTH1R variant. Case presentation The proband, a 26 year-old man with a significant bilateral open-bite, was diagnosed with PFE using clinical and radiographic characteristics. DNA was extracted from the proband and his immediate family using buccal swabs and the entire PTH1R coding sequence was analyzed, revealing a novel heterozygous nonsense variant in exon 7 of PTH1R (c.505G > T). This variant introduces a premature stop codon in position 169, predicted to result in the production of a truncated and non-functional protein. This variant has never been reported in association with PFE and is not present in the Genome Aggregation Database (gnomAD). Interestingly, the c.505G > T variant has also been identified in the unaffected mother of our proband, suggesting incomplete penetrance of PFE. Conclusions In this study, we report a new PTH1R variant that segregates in an autosomal dominant pattern and causes PFE with incomplete penetrance. This underlines the diagnostic value of a thorough clinical and genetic analysis of all family members in order to estimate accurate recurrence risks, identify subtle clinical manifestations and provide proper management of PFE patients.

scholarly journals Mutation in the RPE65 gene causing hereditary retinal dystrophy in the Briard dogs: application of a new detection method

2008 ◽  
Vol 53 (No. 4) ◽  
pp. 176-179
Author(s):  
R. Bechyňová ◽  
J. Dostál ◽  
A. Stratil ◽  
F. Jílek ◽  
P. Horák
Keyword(s):  
Autosomal Recessive ◽  
Clinical Symptoms ◽  
Stop Codon ◽  
Retinal Dystrophy ◽  
Premature Stop Codon ◽  
Causative Mutation ◽  
Functional Protein ◽  
Hereditary Retinal Dystrophy ◽  
Briard Dogs ◽  
Autosomal Recessive Manner

Inherited eye diseases are widespread in most of the pure dog breeds and they show a severe impact on canine health, welfare and working ability. Congenital stationary night blindness (CSNB) was originally described in Briards. CSNB is slow progressive retinal degeneration with very early onset of clinical symptoms and is inherited in an autosomal recessive manner. The causative mutation (Y16567.1:c.487_490delAAGA) for CSNB was identified in exon 5 of the <I>RPE6</I>5 gene. This deletion results in a frameshift and leads to a premature stop codon and expression of a non-functional protein. To date, only expensive, laborious or unpractical methods have been used for detection of the mutation in the canine <I>RPE65</I> gene. The main goals of this study were to develop a new method for routine genotyping of the causative mutation and to assess its occurrence in the Czech population of Briards. The method of electrophoresis in the gel Spraedex EL600 can be widely used for genotyping of the <I>RPE65</I> gene as a basis of proper genetic counselling and an improvement of genetic health in the Briard populations. In the studied population, the following frequencies of alleles + (wild) and – (mutant) were observed – 0.939 and 0.061, respectively.

scholarly journals A sleep modulated Channelopathy: a novel CACNA1A pathogenic variant identified in episodic Ataxia type 2 and a potential link to sleep alleviated migraine

BMC Neurology ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Abhimanyu S. Ahuja ◽  
Todd D. Rozen ◽  
Paldeep S. Atwal
Keyword(s):  
Genetic Testing ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Pathogenic Variant ◽  
Episodic Ataxia ◽  
Case Presentation ◽  
Episodic Ataxia Type 2 ◽  
Potential Link ◽  
Episodic Ataxia Type

Abstract Background To describe a patient with sleep alleviated episodic ataxia type 2 with a novel CACNA1A pathogenic variant and provide a possible link to sleep responsive migraine. Case presentation A 26-year-old woman with recurrent attacks of dizziness, nausea, vomiting, ataxia and dysarthria presented for a possible diagnosis of vestibular migraine. Unique to her attacks was if she could fall asleep for as little as 15 min the spells would subside. If however she remained awake the attacks would continue unabated. A presumed diagnosis of episodic ataxia type 2 was made and she became attack free on acetazolamide without recurrence. Genetic testing demonstrated a novel pathogenic variant in CACNA1A on chromosome 19. This pathogenic variant has not been previously reported in the literature and is suggested to truncate the CACNA1A polypeptide by introducing a premature stop codon. Conclusion A case of episodic ataxia type 2 with a novel pathogenic variant in CACNA1A is described. Interestingly, the patient’s symptoms would completely alleviate with sleep which suggests a sleep modulated channelopathy. The mechanisms by which sleep could potentially alter this pathogenic variant are hypothesized. A potential link to sleep alleviated migraine is suggested. Further study of this novel pathogenic variant may help us understand not only how sleep can modulate episodic ataxia type 2, but also migraine.

Hereditary vitamin D-resistant rickets: a report of four cases with two novel variants in the VDR gene and successful use of intermittent intravenous calcium via a peripheral route

2020 ◽  
Vol 33 (4) ◽  
pp. 557-562 ◽  
Author(s):  
Saygın Abalı ◽  
Mayuko Tamura ◽  
Serap Turan ◽  
Zeynep Atay ◽  
Pınar Isguven ◽  
...  
Keyword(s):  
Vitamin D ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Splice Acceptor Site ◽  
Acceptor Site ◽  
Vdr Gene ◽  
Case Presentation ◽  
Novel Variants ◽  
Vitamin D Resistant Rickets ◽  
Resistant Rickets

AbstractBackgroundHereditary vitamin D-resistant rickets (HVDRR) is caused by vitamin D receptor (VDR) defects. Patients with HVDRR do not respond to standard doses of calcitriol and oral calcium (Ca) treatment and need to be treated with intravenous Ca (IV-Ca) via a central route. However, central catheter-related complications can cause significant morbidity.Case presentationFour unrelated patients with HVDRR presenting with rickets and alopecia totalis were administered intermittent IV-Ca treatment (2–5 times/week) through a peripheral route. No complications such as infection, extravasation or arrhythmias were detected upon peripheral infusion. Peripheral 1–22 months’ duration of IV-Ca normalized parathyroid hormone (PTH) and alkaline phosphatase (ALP) in all patients, after which, oral Ca of 200–400 mg/kg/day and calcitriol of 0.5 μg/kg/day were sufficient to maintain normal PTH levels. Molecular studies on the VDR gene showed a previously reported homozygous c.454C > T (p.Q152*) pathogenic variant in two patients. Two novel homozygous variants in the other two patients were detected: (1) c.756-2A > G, which affects the splice acceptor site, and (2) c.66dupG (p.I23Dfs*20) variant leading to a frameshift that results in a premature stop codon.ConclusionsPeripheral IV-Ca treatment is an effective and practical alternative treatment mode that provides dramatic clinical benefit in patients with HVDRR.

scholarly journals A Single Base Insertion in F9 Causing Hemophilia B in a Family of Newfoundland–Parti Standard Poodle Hybrid Dogs

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1491
Author(s):  
Henrike Kuder ◽  
Liubov Sandzhieva-Vuzzo ◽  
Alexandra Kehl ◽  
Jonathan M. Rappaport ◽  
Elisabeth Müller ◽  
...  
Keyword(s):  
Stop Codon ◽  
Molecular Genetic ◽  
Genetic Defect ◽  
Clinical Manifestations ◽  
Premature Stop Codon ◽  
Factor Ix ◽  
Hemophilia B ◽  
Surgical Removal ◽  
Standard Poodle ◽  
Plasma Factor

Hemophilia B is an x-linked recessive hereditary coagulopathy that has been reported in various species. We describe a male Newfoundland–Parti Standard Poodle hybrid puppy and its family with hemophilia B from clinical manifestations to the molecular genetic defect. The index case presented for dyspnea was found to have a mediastinal hematoma, while surgical removal and transfusion support brought some relief, progressive hematoma formations led to humane euthanasia. Sequencing the F9 exons revealed a single nucleotide insertion resulting in a frameshift in the last exon (NM_001003323.2:c.821_822insA), predicted to result in a premature stop codon (NP_001003323.1:p.Asn274LysfsTer23) with a loss of 178 of 459 amino acids. The unexpected high residual plasma factor IX activity (3% to 11% of control) was likely erroneous, but no further studies were performed. Both the purebred Newfoundland dam and her sister were heterozygous for the insertion. Five additional male offspring developed severe hemorrhage and were hemizygous for the F9 variant and/or had a prolonged aPTT. In contrast, other male littermates had normal aPTTs and no evidence of bleeding. While they are related to a common Newfoundland granddam, the prevalence of the pathogenic variant in the Newfoundland breed is currently unknown. These clinical to molecular genetic studies illustrate that precision medicine is achievable in clinical companion animal practice.

scholarly journals Biallelic splicing variants in the nucleolar 60S assembly factor RBM28 cause the ribosomopathy ANE syndrome

2021 ◽  
Vol 118 (19) ◽  
pp. e2017777118
Author(s):  
Carson J. Bryant ◽  
Cláudia F. Lorea ◽  
Hiram Larangeira de Almeida ◽  
Letícia Weinert ◽  
Leonardo Vedolin ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Stop Codon ◽  
Large Subunit ◽  
Ribosomal Subunit ◽  
Premature Stop Codon ◽  
Syndrome Patient ◽  
Human Genetic Disease ◽  
Functional Protein ◽  
Splicing Variants ◽  
Assembly Factor

Alopecia, neurologic defects, and endocrinopathy (ANE) syndrome is a rare ribosomopathy known to be caused by a p.(Leu351Pro) variant in the essential, conserved, nucleolar large ribosomal subunit (60S) assembly factor RBM28. We report the second family of ANE syndrome to date and a female pediatric ANE syndrome patient. The patient presented with alopecia, craniofacial malformations, hypoplastic pituitary, and hair and skin abnormalities. Unlike the previously reported patients with the p.(Leu351Pro) RBM28 variant, this ANE syndrome patient possesses biallelic precursor messenger RNA (pre-mRNA) splicing variants at the 5′ splice sites of exon 5 (ΔE5) and exon 8 (ΔE8) of RBM28 (NM_018077.2:c.[541+1_541+2delinsA]; [946G > T]). In silico analyses and minigene splicing experiments in cells indicate that each splice variant specifically causes skipping of its respective mutant exon. Because the ΔE5 variant results in an in-frame 31 amino acid deletion (p.(Asp150_Lys180del)) in RBM28 while the ΔE8 variant leads to a premature stop codon in exon 9, we predicted that the ΔE5 variant would produce partially functional RBM28 but the ΔE8 variant would not produce functional protein. Using a yeast model, we demonstrate that the ΔE5 variant does indeed lead to reduced overall growth and large subunit ribosomal RNA (rRNA) production and pre-rRNA processing. In contrast, the ΔE8 variant is comparably null, implying that the partially functional ΔE5 RBM28 protein enables survival but precludes correct development. This discovery further defines the underlying molecular pathology of ANE syndrome to include genetic variants that cause aberrant splicing in RBM28 pre-mRNA and highlights the centrality of nucleolar processes in human genetic disease.

scholarly journals Staphylococcal Enterotoxin Type R Pseudogene Presence in Staphylococcus aureus Reference and Outbreak Strains

2018 ◽  
Vol 101 (1) ◽  
pp. 216-220 ◽  
Author(s):  
Jennifer M Hait ◽  
Reginald W Bennett ◽  
Steven R Monday
Keyword(s):  
Staphylococcus Aureus ◽  
Expression Vector ◽  
Frameshift Mutation ◽  
Stop Codon ◽  
Protein A ◽  
Premature Stop Codon ◽  
Functional Protein ◽  
Reading Frame ◽  
Enterotoxin Genes ◽  
Limited Effectiveness

Abstract Novel staphylococcal enterotoxins (SEs) expressed by Staphylococcus aureus strains have been described throughout the years, among these being the SE protein SER. To further characterize this toxin, this research used 13 S. aureus strains previously determined to contain the SE type R (ser) gene. These S. aureus isolates were evaluated using serological assays for identification of SEA–SEE and PCR for the detection of newly described SE and SE-like enterotoxin genes seg–seu. PCR-based cloning was performed such that the ser gene could be ligated into the pTrc99A plasmid expression vector. Ligation products were used to transform Escherichia coli (DH10Br) strains so that the ser open reading frame (ORF) could be sequenced and expressed for further characterization. Four of the 13 S. aureus strains tested harbored a ser ORF that yielded a PCR-positive result, but contained a frameshift mutation that subsequently introduced a premature stop codon abrogating expression of a full-sized functional protein. In this study, 30% of the PCR-positive ser strains tested were found to carry genes that coded for a nonfunctional SER protein, a finding that clearly illustrates the limited effectiveness of PCR for reliably evaluating enterotoxin potential for ser and, perhaps, other enterotoxin types.

scholarly journals Case Report: A Novel Variant c.2262+3A>T of the SCN5A Gene Results in Intron Retention Associated With Incessant Ventricular Tachycardias

2021 ◽  
Vol 8 ◽  
Author(s):  
Jie Yin ◽  
Jia Zhou ◽  
Jinlong Chen ◽  
Ting Xu ◽  
Zhongman Zhang ◽  
...  
Keyword(s):  
Cardiac Electrophysiology ◽  
Splice Variants ◽  
Stop Codon ◽  
Clinical Manifestations ◽  
Premature Stop Codon ◽  
Splice Donor Site ◽  
Molecular Defect ◽  
Truncated Protein ◽  
Mutant Transcript ◽  
Ventricular Tachycardias

Objective: Voltage-gated sodium channel Nav1.5 encoded by the SCN5A gene plays crucial roles in cardiac electrophysiology. Previous genetic studies have shown that mutations in SCN5A are associated with multiple inherited cardiac arrhythmias. Here, we investigated the molecular defect in a Chinese boy with clinical manifestations of arrhythmias.Methods: Gene variations were screened using whole-exome sequencing and validated by direct Sanger sequencing. A minigene assay and reverse transcription PCR (RT-PCR) were performed to confirm the effects of splice variants in vitro. Western blot analysis was carried out to determine whether the c.2262+3A&gt;T variant produced a truncated protein.Results: By genetic analysis, we identified a novel splice variant c.2262+3A&gt;T in SCN5A gene in a Chinese boy with incessant ventricular tachycardias (VT). This variant was predicted to activate a new cryptic splice donor site and was identified by in silico analysis. The variant retained 79 bp at the 5′ end of intron 14 in the mature mRNA. Furthermore, the mutant transcript that created a premature stop codon at 818 amino acids [p.(R818*)] could be produced as a truncated protein.Conclusion: We verified the pathogenic effect of splicing variant c.2262+3A&gt;T, which disturbed the normal mRNA splicing and caused a truncated protein, suggesting that splice variants play an important role in the molecular basis of early onset incessant ventricular tachycardias, and careful molecular profiling of these patients will be essential for future effective personalized treatment options.

Ectopic Transcript Analysis Indicates that Allelic Exclusion is an Important Cause of Type I Protein C Deficiency in Patients with Nonsense and Frameshift Mutations in the PROC Gene

1996 ◽  
Vol 75 (06) ◽  
pp. 870-876 ◽  
Author(s):  
José Manuel Soria ◽  
Lutz-Peter Berg ◽  
Jordi Fontcuberta ◽  
Vijay V Kakkar ◽  
Xavier Estivill ◽  
...  
Keyword(s):  
Splice Site ◽  
Protein C ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Allelic Exclusion ◽  
Polymorphism Analysis ◽  
Type I ◽  
Protein C Deficiency ◽  
Nonsense Mutations ◽  
Stop Codons

SummaryNonsense mutations, deletions and splice site mutations are a common cause of type I protein C deficiency. Either directly or indirectly by altering the reading frame, these' lesions generate or may generate premature stop codons and could therefore be expected to result in premature termination of translation. In this study, the possibility that such mutations could instead exert their pathological effects at an earlier stage in the expression pathway, through “allelic exclusion” at the RNA level, was investigated. Protein C (PROC) mRNA was analysed in seven Spanish type I protein C deficient patients heterozygous for two nonsense mutations, a 7bp deletion, a 2bp insertion and three splice site mutations. Ectopic RNA transcripts from patient and control lymphocytes were analysed by RT-PCR and direct sequencing of amplified PROC cDNA fragments. The nonsense mutations and the deletion were absent from the cDNAs indicating that only mRNA derived from the normal allele had been expressed. Similarly for the splice site mutations, only normal PROC cDNAs were obtained. In one case, exclusion of the mutated allele could be confirmed by polymorphism analysis. In contrast to these six mutations, the 2 bp insertion was not associated with loss of mRNA from the mutated allele. In this case, cDNA analysis revealed the absence of 19 bases from the PROC mRNA consistent with the generation and utilization of a cryptic splice site 3’ to the site of mutation, which would result in a frameshift and a premature stop codon. It is concluded that allelic exclusion is a common causative mechanism in those cases of type I protein C deficiency which result from mutations that introduce premature stop codons

DIAGNOSTIC VALUE OF SPECIFIC ANTIBODY SYNTHESIS IN BRAIN OF PATIENTS WITH NEUROINFECTIONS

2019 ◽  
Vol 72 (8) ◽  
pp. 1437-1441
Author(s):  
Pavel Dyachenko ◽  
Igor Filchakov ◽  
Anatoly Dyachenko ◽  
Victoria Kurhanskaya
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Clinical Manifestations ◽  
Diagnostic Value ◽  
Diagnostic Challenge ◽  
Specific Antibodies ◽  
Intrathecal Synthesis ◽  
Varicella Zoster ◽  
Mrz Reaction ◽  
Wide Range

Introduction: Viral encephalitis accounts for 40-70% of all cases worldwide, central nervous system infections pose a diagnostic challenge because clinical manifestations are not typically pathognomonic for specific pathogens, and a wide range of agents can be causative. The aim: To assess the diagnostic value of intrathecal synthesis of specific antibodies in patients with inflammatory lesions of the central nervous system. Materials and methods: Within the framework of the study, two groups of 90 people in each were formed from the patients with neuroinfections admitted to our Center. Intrathecal synthesis (ITS) of total (unspecific) IgG in members of one of group (group of compare) was determined. Brain synthesis of specific antibodies (Ab) to some neurotropic pathogens (herpes simplex virus 1/2, cytomegalovirus, Epstein-Barr virus, varicella zoster virus, rubella virus, Borrelies) was studied in the second group of patients (group of interest). There were no statistically significant differences between groups by gender and age. Encephalitis and encephalomyelitis prevailed among patients of both groups Results: ITS of total IgG was established in 30 (33.3 ± 6.1 %) patients of the first group with IgG index more than 0.6 indicating on inflammatory process in CNS and no marked changes of CSF. ITS of specific Ab was determined in 23 of 90 (25.6 ± 4.6 %) patients included into group of interest. In more than half of cases Ab to several infectious agents were detected simultaneously. ITS of various specificity, in particular, to measles and rubella viruses, and VZV, known as MRZ-reaction, is characteristic of some autoimmune lesions of CNS, multiple sclerosis first of all. In fact, further research of 5 patients with MRZ-reaction confirmed their autoimmune failure of CNS. Detection of ITS in the CSF samples didn’t depend on concentration of specific Ab in serum and CSF and wasn’t followed by HEB dysfunctions which were observed with the same frequency in patients with or without ITS (13.0 % and 13.6 % respectively). Conclusion: Specific Ab synthesis to several neurotropic pathogens in the CSF of significant part of examined patients was established. Thus, diagnostic value of ITS of specific immunoglobulins seems to be limited to cases in which autoimmune damage of the CNS is suspected.

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