scholarly journals A.4 A Novel Recessive TNNT1 Congenital Core-Rod Myopathy in French Canadians

2021 ◽  
Vol 48 (s3) ◽  
pp. S14-S15
Author(s):  
D Pellerin ◽  
A Aykanat ◽  
B Ellezam ◽  
EC Troiano ◽  
J Karamchandani ◽  
...  
Keyword(s):  
Lower Extremity ◽  
Troponin T ◽  
Novel Mutation ◽  
Nemaline Myopathy ◽  
Homozygous Mutation ◽  
Wild Type ◽  
French Canadians ◽  
Restrictive Lung Disease ◽  
Core Rod ◽  
Myopathic Changes

Background: Mutations in the slow skeletal muscle troponin T (TNNT1) gene cause a congenital nemaline myopathy resulting in death from respiratory insufficiency in early infancy. We report on four French Canadians with a novel congenital TNNT1 myopathy. Methods: Patients underwent lower extremity and paraspinal MRI, quadriceps biopsy and genetic testing. TNNT1 expression in muscle was assessed by quantitative PCR and immunoblotting. Wild type or mutated TNNT1 mRNAs were co-injected with morpholinos in a zebrafish knockdown model to assess for rescue of the morphant phenotype. Results: Four patients shared a novel missense homozygous mutation in TNNT1. They developed from childhood slowly progressive limb-girdle weakness with spinal rigidity and contractures. They suffered from restrictive lung disease and recurrent episodes of rhabdomyolysis. Older patients remained ambulatory into their sixties. Lower extremity MRI showed symmetrical myopathic changes. Paraspinal MRI showed diffuse fibro-fatty involution. Biopsies showed multi-minicores. Nemaline rods were seen in half the patients. TNNT1 mRNA expression was similar in controls and patients, while levels of TNNT1 protein were reduced in patients. Wild type TNNT1 mRNA rescued the zebrafish morphants but mutant transcripts failed to do so. Conclusions: This study expands the spectrum of TNNT1-related myopathy to include a milder clinical phenotype caused by a functionally-confirmed novel mutation.

scholarly journals P.028 A milder congenital myopathy in the french canadians caused by a novel TNNT1 homozygous missense mutation

2019 ◽  
Vol 46 (s1) ◽  
pp. S21
Author(s):  
D Pellerin ◽  
A Aykanat ◽  
B Ellezam ◽  
J Karamchandani ◽  
J Mathieu ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Clinical Phenotype ◽  
Fatty Infiltration ◽  
Nemaline Myopathy ◽  
Wild Type ◽  
French Canadians ◽  
Restrictive Lung Disease ◽  
Leg Muscles ◽  
Slow Skeletal Muscle ◽  
Nemaline Rods

Background: Mutations of the slow skeletal muscle troponin-T1 (TNNT1) gene are a rare cause of nemaline myopathy. The phenotype is characterized by severe amyotrophy and contractures. Death from respiratory insufficiency occurs in infancy. We report on four French Canadians with a novel congenital TNNT1-related myopathy. Methods: Patients underwent MRI of leg muscles, quadriceps biopsy and genetic testing. Wild type or mutated human TNNT1 mRNAs were co-injected with morpholinos in a zebrafish knockdown model to assess their relative abilities to rescue the morphant phenotype. Results: Three adults and one child shared a novel missense homozygous pathogenic variant in the TNNT1 gene. They developed from childhood slowly progressive limb-girdle weakness with spinal rigidity and contractures. They suffered from restrictive lung disease and recurrent episodes of infection-triggered rhabdomyolysis, which were relieved by dantrolene in one patient. Older patients remained ambulatory into their sixties. MRI of leg muscles showed symmetrical atrophy and fatty infiltration in a proximal-to-distal gradient. Biopsies showed multi-minicores, while nemaline rods were seen in half the patients. Wild type TNNT1 mRNA rescued the zebrafish morphants but mutant transcripts failed to rescue the morphants. Conclusions: This study expands the spectrum of TNNT1-related myopathy to include a milder clinical phenotype caused by a functionally-confirmed novel missense mutation.

Abstract 34: Acetylation of GATA 4 Enhanced Direct Cardiac Reprogramming of Induced Cardiomyocytes

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Vivek P Singh ◽  
Megumi Mathison ◽  
Jaya P Pinnamaneni ◽  
Deepthi Sanagasetti ◽  
Narasimhaswamy S Belaguli ◽  
...  
Keyword(s):  
Ventricular Function ◽  
Troponin T ◽  
Novel Mutation ◽  
Cardiac Regeneration ◽  
Negative Control ◽  
Direct Reprogramming ◽  
Wild Type ◽  
Reprogramming Efficiency

Objective: Direct reprogramming of fibroblasts into induced cardiomyocytes (iCMs) by forced expression of cardiomyogenic factors, GMT (GATA4, Mef2c and Tbx5), has recently been demonstrated, suggesting a promising statregy for cardiac regeneration. However, the efficiency of direct reprogramming is usually relatively low and requires extensive epigenetic redesigning, although the underlying mechanism are largely unknown. Methods: In a recent study, we created a novel mutation in rat GATA 4 by replacing lysine residue with glutamine at position 299 i.e. (K299Q), to mimic constitutive acetylation and examined whether constitutive acetylation of GATA4, when compared with wild type GATA4, further enhance GMT-mediated direct reprogramming efficiency of induced cardiomyocytes in vitro and accordingly ventricular function after myocardial infarction in rat, in vivo . Results: We found that acetylated GATA 4 (K299Q), in the presence of Mef2c and Tbx5 upregulated cardiac-specific markers, suppressed fibroblast genes, in rat cardiac fibroblasts (RCFs) more efficiently when compared with Mef2c, Tbx5 plus wild type GATA4. FACS analyses revealed that G(K299Q) MT induced significantly more cardiomyocyte marker cardiac troponin T (cTnT) expression compared with GMT alone. Mechanistic studies demonstrated that the K299Q substitution, resulting in enriched p300 occupancy at the GATA 4 promoter, induced acetylation of Histine 3, decreased HDAC expression. In addition, substitution augmented the increase in an acetylated form of GATA-4 and its DNA binding and transcriptional activity, compared with wildtype GATA 4. In agreement with upregulated cTNT gene expression in vitro , echocardiographic analysis demonstrate that the acetylated G(K299Q) MT vectors have improved effect in enhancing ventricular function than GMT vectors from postinfarct baselines as compared to negative control [G(K299Q) MT, 15.6% ± 2.7%; G(WT)MT, 12.8% ± 1.7%; GFP, -2.3% ± 1.1%]. Conclusions: Collectivily, these data indicate that acetylated GATA4 (K299Q) significantly increases reprogramming efficiency of induced cardiomyocytes (iCMs), in vitro and in vivo, and provide new insight into the molecular mechanism underlying cardiac regeneration.

A Novel Mutation Glyl672→Arg in Type 2A and a Homozygous Mutation in Type 2B von Willebrand Disease

1996 ◽  
Vol 76 (02) ◽  
pp. 253-257 ◽  
Author(s):  
Takeshi Hagiwara ◽  
Hiroshi Inaba ◽  
Shinichi Yoshida ◽  
Keiko Nagaizumi ◽  
Morio Arai ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Novel Mutation ◽  
Point Mutations ◽  
Japanese Patients ◽  
Von Willebrand Disease ◽  
Homozygous Mutation ◽  
Missense Mutations ◽  
Reaction Products ◽  
Type 3 ◽  
Von Willebrand

SummaryGenetic materials from 16 unrelated Japanese patients with von Willebrand disease (vWD) were analyzed for mutations. Exon 28 of the von Willebrand factor (vWF) gene, where point mutations have been found most frequent, was screened by various restriction-enzyme analyses. Six patients were observed to have abnormal restriction patterns. By sequence analyses of the polymerase chain-reaction products, we identified a homozygous R1308C missense mutation in a patient with type 2B vWD; R1597W, R1597Q, G1609R and G1672R missense mutations in five patients with type 2A; and a G1659ter nonsense mutation in a patient with type 3 vWD. The G1672R was a novel missense mutation of the carboxyl-terminal end of the A2 domain. In addition, we detected an A/C polymorphism at nucleotide 4915 with HaeIII. There was no particular linkage disequilibrium of the A/C polymorphism, either with the G/A polymorphism at nucleotide 4391 detected with Hphl or with the C/T at 4891 detected with BstEll.

scholarly journals A BAFF-R mutation associated with non-Hodgkin lymphoma alters TRAF recruitment and reveals new insights into BAFF-R signaling

2010 ◽  
Vol 207 (12) ◽  
pp. 2569-2579 ◽  
Author(s):  
Joanne M. Hildebrand ◽  
Zhenghua Luo ◽  
Michelle K. Manske ◽  
Tammy Price-Troska ◽  
Steven C. Ziesmer ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
Novel Mutation ◽  
B Cell Development ◽  
Signaling Cascades ◽  
Binding Motif ◽  
Wild Type ◽  
Immunoglobulin Production ◽  
Gene Encoding ◽  
Non Hodgkin Lymphoma

The cytokine B cell activating factor (BAFF) and its receptor, BAFF receptor (BAFF-R), modulate signaling cascades critical for B cell development and survival. We identified a novel mutation in TNFRSF13C, the gene encoding human BAFF-R, that is present in both tumor and germline tissue from a subset of patients with non-Hodgkin lymphoma. This mutation encodes a His159Tyr substitution in the cytoplasmic tail of BAFF-R adjacent to the TRAF3 binding motif. Signaling through this mutant BAFF-R results in increased NF-κB1 and NF-κB2 activity and increased immunoglobulin production compared with the wild-type (WT) BAFF-R. This correlates with increased TRAF2, TRAF3, and TRAF6 recruitment to His159Tyr BAFF-R. In addition, we document a requirement for TRAF6 in WT BAFF-R signaling. Together, these data identify a novel lymphoma-associated mutation in human BAFF-R that results in NF-κB activation and reveals TRAF6 as a necessary component of normal BAFF-R signaling.

scholarly journals Goα Regulates Volatile Anesthetic Action in Caenorhabditis elegans

Genetics ◽  
2001 ◽  
Vol 158 (2) ◽  
pp. 643-655 ◽  
Author(s):  
Bruno van Swinderen ◽  
Laura B Metz ◽  
Laynie D Shebester ◽  
Jane E Mendel ◽  
Paul W Sternberg ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Novel Mutation ◽  
Volatile Anesthetic ◽  
Loss Of Function ◽  
Wild Type ◽  
Α Subunit ◽  
C Elegans ◽  
Missense Mutant ◽  
Anesthetic Action ◽  
Mutant Phenotypes

Abstract To identify genes controlling volatile anesthetic (VA) action, we have screened through existing Caenorhabditis elegans mutants and found that strains with a reduction in Go signaling are VA resistant. Loss-of-function mutants of the gene goa-1, which codes for the α-subunit of Go, have EC50s for the VA isoflurane of 1.7- to 2.4-fold that of wild type. Strains overexpressing egl-10, which codes for an RGS protein negatively regulating goa-1, are also isoflurane resistant. However, sensitivity to halothane, a structurally distinct VA, is differentially affected by Go pathway mutants. The RGS overexpressing strains, a goa-1 missense mutant found to carry a novel mutation near the GTP-binding domain, and eat-16(rf) mutants, which suppress goa-1(gf) mutations, are all halothane resistant; goa-1(null) mutants have wild-type sensitivities. Double mutant strains carrying mutations in both goa-1 and unc-64, which codes for a neuronal syntaxin previously found to regulate VA sensitivity, show that the syntaxin mutant phenotypes depend in part on goa-1 expression. Pharmacological assays using the cholinesterase inhibitor aldicarb suggest that VAs and GOA-1 similarly downregulate cholinergic neurotransmitter release in C. elegans. Thus, the mechanism of action of VAs in C. elegans is regulated by Goα, and presynaptic Goα-effectors are candidate VA molecular targets.

Sucrose Transporter Gene AtSUC4 Responds to Drought Stress by Regulating the Sucrose Distribution and Metabolism in Arabidopsis thaliana

2013 ◽  
Vol 765-767 ◽  
pp. 2971-2975 ◽  
Author(s):  
Xue Gong ◽  
Ming Li Liu ◽  
Li Jun Zhang ◽  
Wei Liu ◽  
Che Wang
Keyword(s):  
Arabidopsis Thaliana ◽  
Drought Stress ◽  
Plant Stress ◽  
Homozygous Mutation ◽  
Transporter Gene ◽  
Wild Type ◽  
Sucrose Transporters ◽  
Whole Plant ◽  
Plant Stress Tolerance ◽  
Plant Level

Sucrose transporters (SUCs or SUTs) are considered as the important carriers and responsible for the loading, unloading and distribution of sucrose, but at present there is no report that SUCs are involved in sucrose distribution and metabolism under drought stress at the whole-plant level. AtSUC4, as the unique member of SUT4-clade inArabidopsis thaliana, may be important for plant stress tolerance. Here, by analyzing two homozygous mutation lines ofAtSUC4(Atsuc4-1andAtsuc4-2), we found drought stress induced higher sucrose, lower fructose and glucose contents in shoots, and lower sucrose, higher fructose and glucose contents in roots of these mutants compared with the wild-type (WT), leading to an imbalance of sucrose distribution, fructose and glucose (sucrose metabolites) accumulation changes at the whole-plant level. Thus we believe thatAtSUC4regulates sucrose distribution and metabolism in response to drought stress.

scholarly journals CRISPR knockouts of pmela and pmelb engineered a golden tilapia by regulating relative pigment cell abundance

2021 ◽  
Author(s):  
Chenxu Wang ◽  
Jia Xu ◽  
Thomas D. Kocher ◽  
Minghui Li ◽  
Deshou Wang
Keyword(s):  
Pigment Cell ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Homozygous Mutation ◽  
Body Color ◽  
Wild Type ◽  
Double Mutation ◽  
Vertical Bars ◽  
White Plumage ◽  
New Strategies

Premelanosome protein (pmel) is a key gene for melanogenesis in vertebrates. Mutations in this gene are responsible for white plumage in chicken, but its role in pigmentation of fish remains to be demonstrated. In this study we found that most fishes have two pmel genes arising from the teleost-specific whole genome duplication. Both pmela and pmelb were expressed at high levels in the eyes and skin of Nile tilapia. We mutated both genes in tilapia using CRISPR/Cas9 gene editing. Homozygous mutation of pmela resulted in yellowish body color with weak vertical bars and a hypo-pigmented retinal pigment epithelium (RPE) due to significantly reduced number and size of melanophores. In contrast, we observed an increased number and size of xanthophores in mutants compared to wild-type fish. Homozygous mutation of pmelb resulted in a similar, but milder phenotype than pmela -/- mutants, without effects on RPE pigmentation. Double mutation of pmela and pmelb resulted in loss of additional melanophores compared to the pmela -/- mutants, and also an increase in the number and size of xanthophores, producing a strong golden body color without bars in the trunk. The RPE pigmentation of pmela -/ - ;pmelb -/- was similar to pmela -/- mutants, with much less pigmentation than pmelb -/- mutants and wild-type fish. Taken together, our results indicate that, while both pmel genes are important for the formation of body color in tilapia, pmela plays a more important role than pmelb. To our knowledge, this is the first report on mutation of pmelb or both pmela;pmelb in fish. Studies on these mutants suggest new strategies for breeding golden tilapia, and also provide a new model for studies of pmel function in vertebrates.

scholarly journals Identification and Functional Characterization of a Novel De Novo RUNX2 Frameshift Mutation Associated With Cleidocranial Dysplasia

2021 ◽  
Author(s):  
Lei Gong ◽  
Bekzod Odilov ◽  
Feng Han ◽  
Fuqiang Liu ◽  
Yujing Sun ◽  
...  
Keyword(s):  
Frameshift Mutation ◽  
De Novo ◽  
Novel Mutation ◽  
Genetic Disorder ◽  
Functional Characterization ◽  
Sporadic Case ◽  
Luciferase Assay ◽  
Cleidocranial Dysplasia ◽  
Wild Type ◽  
Bone And Cartilage Development

Abstract BackgroundCleidocranial dysplasia (CCD) is a rare genetic disorder affecting bone and cartilage development. Clinical features of CCD comprise short stature, delayed ossification of craniofacial structures with numerous Wormian bones, underdeveloped or aplastic clavicles and multiple dental anomalies. Several studies have revealed that CCD development is strongly linked with different mutations in Runt-related Transcription Factor 2 (RUNX2) gene. In this study, we report a case with typical CCD presentations. MethodsWe performed genetic testing of participants and found a novel RUNX2 frameshift mutation: c.1550delT in a sporadic case. We also compared the functional activity of the mutant and wild-type RUNX2 through immunofluorescence microscopy and osteocalcin promoter luciferase assay. ResultsBoth mutant RUNX2 and wild‑type RUNX2 protein were similarly confined in the nuclei. The novel mutation caused abrogative transactivation activity of RUNX2 on osteocalcin promoter. ConclusionsWe explored a novel RUNX2 deletion/frameshift mutation in a sporadic CCD patient. This finding emphasizes on crucial role of VWRPY domain in RUNX2 transactivation ability.

scholarly journals the Prevalence of UGT1A1*93 and ABCC5 Polymorphisms in Cancer Patients Receiving Irinotecan-Based Chemotherapy at Al-Najaf Al-Ashraf

2019 ◽  
Vol 28 (2) ◽  
pp. 24-29
Author(s):  
Ahmed F. Al_talkani ◽  
Sarmed H. Kathem
Keyword(s):  
Cancer Patients ◽  
Topoisomerase I ◽  
Antineoplastic Agent ◽  
Limiting Factors ◽  
Cancer Center ◽  
Heterozygous Mutation ◽  
Homozygous Mutation ◽  
Wild Type ◽  
Isolation And Purification ◽  
Wide Range

Irinotecan (CPT-11) is a semisynthetic derivative of the antineoplastic agent camptothecin used in a wide range as an anti-cancer agent in many solid tumors because of its cytotoxic effect through the interaction with the topoisomerase I enzyme. The major limiting factors for irinotecan treatment are its association with potentially life-threatening toxicities including neutropenia and acute or delayed-type diarrhea, results from distinct interindividual and interethnic variability due to gene polymorphism. This is a cross sectional pharmacogentics study was conducted on 25 cancer patients to estimate the prevalence of UGT1A1*93 and ABCC5 allele single nucleotide polymorphism (SNP) in Iraqi cancer patients treated with irinotecan-based therapy at Middle Euphrates Cancer Center. Four drops of venous blood was drawn for each patient and was applied onto the FTA classic card to perform a genotyping assay for the 2 SNPs. After DNA isolation and purification, real time PCR was performed to detect the SNPs of each gene. Results of this study showed the prevalence of one allele variant (heterozygous mutation) of UGT1A1*93 was 64% compared to 36% of patients were wild type to this SNP. No patient (0%) could be detected with homozygous polymorphism of the UGT1A1*93. For the ABCC5 polymorphism, results revealed that 32% of patients have one polymorphic allele (heterozygous), while 28% of them have two polymorphic alleles (homozygous mutation). Wild type ABCC5 gene constitutes 40% of patients.   As a conclusion, high prevalence of UGT1A1*93 and ABCC5 polymorphic alleles were detected in patients at Middle Euphrates Cancer Center which may explain the high toxicity features associated with irinotecan therapy. 

Abstract 17062: Reversible Golimumab Induced Cardiomyopathy - First Reported Case Report

Circulation ◽  
2021 ◽  
Vol 144 (Suppl_2) ◽  
Author(s):  
Mian Tanveer Ud Din ◽  
Michael Nestasie ◽  
John Balacko ◽  
Craig Alpert
Keyword(s):  
Lower Extremity ◽  
Troponin T ◽  
Inflammatory Diseases ◽  
Systolic Function ◽  
Left Ventricular ◽  
Tnf Alpha ◽  
Lower Extremity Edema ◽  
Ventricular Systolic Function ◽  
Immune Mediated ◽  
Biventricular Systolic Function

Case Presentation: An 80 year old female with medical history of hypertension, diabetes mellitus, chronic atrial fibrillation presented with four weeks of lower extremity edema and dyspnea. Notably, she had also been taking Golimumab for 6 months for Rheumatoid Arthritis (RA). Vital signs on presentations were: Temp:99 F, HR: 140bpm, BP: 105/64, oxygen saturation of 88% on room air. Physical exam revealed crackles at the mid lower lung fields bilaterally and 2+ lower extremity edema. EKG showed new ST inversions in lead 1, avF and V2. Troponin T was elevated to 0.11 ng/ml and proBNP was 21,246 pg/ml. Chest X Ray showed cardiomegaly with diffuse alveolar opacities. Transthoracic echocardiogram (TTE) revealed severely reduced left ventricular systolic function with LVEF of 25-29%, left ventricular regional wall hypokinesis and mildly reduced right ventricular systolic function. All findings were new compared to her last TTE 3 months prior, which showed preserved biventricular systolic function. Coronary angiography revealed no coronary artery disease. The patient was started on intravenous furosemide, and her home beta blocker and ARB were resumed. The patient’s Golimumab was discontinued given prior reports of TNF alpha inhibitor induced cardiomyopathy. Over the ensuing days, she was aggressively diuresed with improvement in oxygenation and ultimately discharged home. Three months after discontinuation of Golimumab, repeat TTE showed normalization of biventricular systolic function. Discussion: TNF alpha inhibitors have revolutionized the treatment of chronic immune mediated inflammatory diseases. Several TNF alpha inhibitors have been associated with cardiomyopathy, however there remains a paucity of evidence regarding cardiotoxicity with Golimumab. We now present, to our knowledge, the first reported case of reversible heart failure due to Golimumab in an 80 year old woman with RA. Golimumab, like other TNF alpha inhibitors, represents a historic advancement in the treatment of immune mediated inflammatory diseases. However, our case implicates this innovative drug in cardiotoxicity similar to other TNF alpha inhibitors. Further prospective studies are needed to establish a stronger correlation between Golimumab and cardiotoxicity.

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