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.

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 A Novel de Novo sp6 Mutation Causes Severe Hypoplastic Ame-Logenesis Imperfecta

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 346
Author(s):  
Youn Jung Kim ◽  
Yejin Lee ◽  
Hong Zhang ◽  
Ji-Soo Song ◽  
Jan C-C. Hu ◽  
...  
Keyword(s):  
Western Blot ◽  
Missense Mutation ◽  
Autosomal Dominant ◽  
De Novo ◽  
Clinical Phenotype ◽  
Tooth Enamel ◽  
Genetic Disorders ◽  
Mrna Level ◽  
Amelogenesis Imperfecta ◽  
Wild Type

Amelogenesis imperfecta (AI) is a heterogeneous group of rare genetic disorders affecting tooth enamel formation. Here we report an identification of a novel de novo missense mutation [c.817_818delinsAT, p.(Ala273Met)] in the SP6 gene, causing non-syndromic autosomal dominant AI. This is the second paper on amelogenesis imperfecta caused by SP6 mutation. Interestingly the identified mutation in this study is a 2-bp variant at the same nucleotide positions as the first report, but with AT instead of AA insertion. Clinical phenotype was much more severe compared to the previous report, and western blot showed an extremely decreased level of mutant protein compared to the wild-type, even though the mRNA level was similar.

scholarly journals A CACNA1A variant associated with trigeminal neuralgia alters the gating of Cav2.1 channels

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Eder Gambeta ◽  
Maria A. Gandini ◽  
Ivana A. Souza ◽  
Laurent Ferron ◽  
Gerald W. Zamponi
Keyword(s):  
Trigeminal Neuralgia ◽  
Missense Mutation ◽  
Neurotransmitter Release ◽  
Trigeminal System ◽  
Wild Type ◽  
Calcium Dependent ◽  
Whole Cell Patch Clamp ◽  
C Terminus ◽  
Dependent Inactivation

AbstractA novel missense mutation in the CACNA1A gene that encodes the pore forming α1 subunit of the CaV2.1 voltage-gated calcium channel was identified in a patient with trigeminal neuralgia. This mutation leads to a substitution of proline 2455 by histidine (P2455H) in the distal C-terminus region of the channel. Due to the well characterized role of this channel in neurotransmitter release, our aim was to characterize the biophysical properties of the P2455H variant in heterologously expressed CaV2.1 channels. Whole-cell patch clamp recordings of wild type and mutant CaV2.1 channels expressed in tsA-201 cells reveal that the mutation mediates a depolarizing shift in the voltage-dependence of activation and inactivation. Moreover, the P2455H mutant strongly reduced calcium-dependent inactivation of the channel that is consistent with an overall gain of function. Hence, the P2455H CaV2.1 missense mutation alters the gating properties of the channel, suggesting that associated changes in CaV2.1-dependent synaptic communication in the trigeminal system may contribute to the development of trigeminal neuralgia.

Multiple Congenital Ocular Anomalies in a silver coat Missouri Fox Trotter stallion

2021 ◽  
Vol 49 (05) ◽  
pp. 350-354
Author(s):  
Verena Maria Herb ◽  
Verena Zehetner ◽  
Klaas-Ole Blohm
Keyword(s):  
Missense Mutation ◽  
Coat Color ◽  
Incidental Finding ◽  
Unknown Origin ◽  
Allelic Frequency ◽  
Cystic Lesions ◽  
Wild Type Allele ◽  
Wild Type ◽  
Type Allele ◽  
Phenotype Characterization

AbstractThis is the first description of Multiple Congenital Ocular Anomalies (MCOA) in a silver coat Missouri Fox Trotter determined to be heterozygous for the Silver PMEL17 missense mutation associated with MCOA and a silver coat in other breeds. The stallion was treated for meningoencephalitis and bilateral uveitis of unknown origin. A complete ophthalmic examination and ocular ultrasonography were performed. As an incidental finding, the patient exhibited bilateral cystic lesions restricted to the temporal anterior uvea consistent with the Cyst phenotype and was genotyped heterozygous for the Silver mutation. Additionally, 4 other non-silver colored Missouri Fox Trotters were genotyped homozygous for the wild-type allele. Screening for PMEL17 mutation in Missouri Fox Trotters accompanied by ophthalmic phenotype characterization is recommended to determine the allelic frequency and facilitate informed breeding decisions since the silver coat color is particularly popular.

PS02.024: PRIMA-1 INDUCES P53-MEDIATED APOPTOSIS BY UPREGULATING NOXA IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA WITH TP53 MISSENSE MUTATION

2018 ◽  
Vol 31 (Supplement_1) ◽  
pp. 126-127
Author(s):  
Haruna Furukawa ◽  
Tomoki Makino ◽  
Makoto Yamasaki ◽  
Koji Tanaka ◽  
Yasuhiro Miyazaki ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Missense Mutation ◽  
Cell Lines ◽  
Squamous Cell ◽  
Antitumor Effect ◽  
Xenograft Model ◽  
Wild Type ◽  
Massive Apoptosis

Abstract Background TP53 is associated with the resistance of cytotoxic treatment and patient prognosis, and the mutation rate of TP53 in esophageal squamous cell carcinoma (ESCC) is extraordinarily high, at over 90%. PRIMA-1 (p53 re-activation and induction of massive apoptosis) has recently been reported to restore wild type activity to mutant p53 and induce massive p53-dependent apoptosis. APR-246 (methylated PRIMA-1) has been tested in a phase I/II clinical trial with promising results; however, the effects and mechanism in ESCC remain unknown. This study was designed to assess the antitumor effect of PRIMA-1 treatment in both ESCC cell lines with different TP53 status and an ESCC xenograft model and uncover the molecular mechanism of PRIMA-1. Methods After evaluating the TP53 mutation status of a panel of eleven ESCC cell lines by Sanger sequencing, we assessed the in vitro effect of PRIMA-1 administration on cells with different p53 status by conducting cell viability and apoptosis assays. The expression levels of proteins in TP53-related pathways were examined by Western blotting, while knockdown studies were conducted to investigate the mechanism underlying PRIMA-1’s function. An ESCC xenograft model was further used to evaluate the therapeutic effect of PRIMA-1 in vivo. Results PRIMA-1 markedly inhibited cell growth and induced apoptosis by upregulating Noxa expression in ESCC cell lines with a TP53 missense mutation, whereas no apoptosis was induced in ESCC with wild type TP53 and with TP53 frameshift and nonsense mutations. Importantly, the knockdown of Noxa cancelled the apoptosis induced by PRIMA treatment in ESCC cell lines with a TP53 missense mutation. PRIMA-1 administration, compared with placebo, showed a significant antitumor effect by inducing Noxa in the xenograft model of an ESCC cell line with a TP53 missense mutation. Conclusion PRIMA-1 exhibits a significant antitumor effect, inducing massive apoptosis through the upregulation of Noxa in ESCC with a TP53 missense mutation. Disclosure All authors have declared no conflicts of interest.

scholarly journals Integrated K+ channel and K+-Cl− cotransporter functions regulate fin proportionality in zebrafish

2019 ◽  
Author(s):  
Jennifer S. Lanni ◽  
David Peal ◽  
Laura Ekstrom ◽  
Haining Chen ◽  
Caroline Stanclift ◽  
...  
Keyword(s):  
Potassium Channel ◽  
Missense Mutation ◽  
Signaling Pathway ◽  
Normal Development ◽  
Growth Restriction ◽  
K Channel ◽  
Loss Of Function ◽  
Wild Type ◽  
Original Size ◽  
Dose Dependent

SummaryThe coordination of growth during development establishes proportionality within and among the different anatomic structures of organisms. Innate memory of this proportionality is preserved, as shown in the ability of regenerating structures to return to their original size. Although the regulation of this coordination is incompletely understood, mutant analyses of zebrafish with long-finned phenotypes have uncovered important roles for bioelectric signaling in modulating growth and size of the fins and barbs. To date, long-finned mutants identified are caused by hypermorphic mutations, leaving unresolved whether such signaling is required for normal development. We isolated a new zebrafish mutant, schleier, with proportional overgrowth phenotypes caused by a missense mutation and loss of function in the K+-Cl− cotransporter Kcc4a. Genetic depletion of Kcc4a in wild-type fish leads to a dose-dependent loss of growth restriction in fins and barbs, supporting a requirement for Kcc4a in regulation of proportion. Epistasis experiments suggest that Kcc4a and the two-pore potassium channel Kcnk5b both contribute to a common bioelectrical signaling response in the fin. These data suggest that an integrated bioelectric signaling pathway is required for the coordination of size and proportion during development.Graphical Abstract

scholarly journals Clinical and molecular characterisation of the R751L-CFTR mutation

2020 ◽  
Author(s):  
Iram J Haq ◽  
Mike Althaus ◽  
Aaron Ions Gardner ◽  
Hui Ying Yeoh ◽  
Urjita Joshi ◽  
...  
Keyword(s):  
Xenopus Oocytes ◽  
Clinical Phenotype ◽  
Chloride Secretion ◽  
Biological Properties ◽  
Sodium Absorption ◽  
Wild Type ◽  
Sweat Chloride ◽  
Epithelial Cultures ◽  
Molecular Phenotypes ◽  
Cf Transmembrane Conductance Regulator

Cystic fibrosis (CF) arises from mutations in the CF transmembrane conductance regulator (CFTR) gene, resulting in progressive and life-limiting respiratory disease. R751L is a rare CFTR mutation that is poorly characterised. Our aims were to describe the clinical and molecular phenotypes associated with R751L. Relevant clinical data were collected from three heterozygote individuals harbouring R751L (2 patients with G551D/R751L and 1 with F508del/R751L). Assessment of R751L-CFTR function was made in primary human bronchial epithelial cultures (HBEs) and Xenopus oocytes. Molecular properties of R751L-CFTR were investigated in the presence of known CFTR modulators. Although sweat chloride was elevated in all three patients, the clinical phenotype associated with R751L was mild. Chloride secretion in F508del/R751L HBEs was reduced compared to non-CF HBEs and associated with a reduction in sodium absorption by the epithelial sodium channel (ENaC). However, R751L-CFTR function in Xenopus oocytes together with folding and cell surface transport of R751L-CFTR were not different to wild-type CFTR. Overall, R751L-CFTR was associated with reduced sodium chloride absorption but had similar functional properties to wild-type CFTR. This is the first report of R751L-CFTR that combines clinical phenotype with characterisation of functional and biological properties of the mutant channel. Our work will build upon existing knowledge of mutations within this region of CFTR and importantly inform approaches for clinical management. Elevated sweat chloride and reduced chloride secretion in HBEs may be due to alternative non-CFTR factors, which require further investigation.

Prevalence and clinical phenotype of the p.Val226Met glucokinase gene mutation in French Canadians in Quebec, Canada

2007 ◽  
Vol 90 (1) ◽  
pp. 87-92 ◽  
Author(s):  
Mélanie Henderson ◽  
Emile Levy ◽  
Edgard Delvin ◽  
Monique Losekoot ◽  
Marie Lambert
Keyword(s):  
Gene Mutation ◽  
Clinical Phenotype ◽  
French Canadians ◽  
Glucokinase Gene
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