scholarly journals Biallelic mutations in the gene encoding eEF1A2 cause seizures and sudden death in F0 mice

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Faith C. J. Davies ◽  
Jilly E. Hope ◽  
Fiona McLachlan ◽  
Francis Nunez ◽  
Jennifer Doig ◽  
...  
Keyword(s):  
Sudden Death ◽  
Gene Encoding ◽  
Biallelic Mutations

scholarly journals Characterization of an N-terminal Nav1.5 channel variant – a potential risk factor for arrhythmias and sudden death?

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Stefanie Scheiper-Welling ◽  
Paolo Zuccolini ◽  
Oliver Rauh ◽  
Britt-Maria Beckmann ◽  
Christof Geisen ◽  
...  
Keyword(s):  
Sudden Death ◽  
Functional Characterization ◽  
Missense Variant ◽  
Hek293 Cells ◽  
Patch Clamp Technique ◽  
Gene Encoding ◽  
Heterozygous Variant ◽  
Cardiac Sodium Channel ◽  
Electrophysiological Measurements

Abstract Background Alterations in the SCN5A gene encoding the cardiac sodium channel Nav1.5 have been linked to a number of arrhythmia syndromes and diseases including long-QT syndrome (LQTS), Brugada syndrome (BrS) and dilative cardiomyopathy (DCM), which may predispose to fatal arrhythmias and sudden death. We identified the heterozygous variant c.316A > G, p.(Ser106Gly) in a 35-year-old patient with survived cardiac arrest. In the present study, we aimed to investigate the functional impact of the variant to clarify the medical relevance. Methods Mutant as well as wild type GFP tagged Nav1.5 channels were expressed in HEK293 cells. We performed functional characterization experiments using patch-clamp technique. Results Electrophysiological measurements indicated, that the detected missense variant alters Nav1.5 channel functionality leading to a gain-of-function effect. Cells expressing S106G channels show an increase in Nav1.5 current over the entire voltage window. Conclusion The results support the assumption that the detected sequence aberration alters Nav1.5 channel function and may predispose to cardiac arrhythmias and sudden cardiac death.

scholarly journals The identification of novel mutations in PLCZ1 responsible for human fertilization failure and a therapeutic intervention by artificial oocyte activation

2020 ◽  
Vol 26 (2) ◽  
pp. 80-87 ◽  
Author(s):  
Jian Mu ◽  
Zhihua Zhang ◽  
Ling Wu ◽  
Jing Fu ◽  
Biaobang Chen ◽  
...  
Keyword(s):  
Human Reproduction ◽  
Missense Mutations ◽  
Oocyte Activation ◽  
Fertilization Failure ◽  
Gene Encoding ◽  
Human Fertilization ◽  
Molecular Events ◽  
Whole Exome ◽  
Artificial Oocyte Activation ◽  
Biallelic Mutations

Abstract Fertilization involves a series of molecular events immediately following egg–sperm fusion; Ca2+ oscillations are the earliest signaling event, and they initiate the downstream reactions including pronucleus formation. Successful human reproduction requires normal fertilization. In clinical IVF or ICSI attempts, some infertile couples suffer from recurrent fertilization failure. However, the genetic reasons for fertilization failure are largely unknown. Here, we recruited several couples diagnosed with fertilization failure even though their gametes are morphologically normal. Through whole-exome sequencing and Sanger sequencing, we identified biallelic mutations in gene-encoding phospholipase C zeta 1 (PLCZ1) in four independent males in couples diagnosed with fertilization failure. Western blotting showed that missense mutations decreased the level of PLCZ1 and that nonsense or frameshift mutations resulted in undetectable or truncated proteins. Expression of these mutations in mice significantly reduced the levels of oocyte activation. Artificial oocyte activation in patient oocytes could rescue the phenotype of fertilization failure and help establish pregnancy and lead to live birth. Our findings expand the spectrum of PLCZ1 mutations that are responsible for human fertilization failure and provide a potentially feasible therapeutic treatment for these patients.

scholarly journals Ectodermal Dysplasia-Syndactyly Syndrome with Toe-Only Minimal Syndactyly Due to a Novel Mutation in NECTIN4: A Case Report and Literature Review

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 748
Author(s):  
Roberta Rotunno ◽  
Andrea Diociaiuti ◽  
Maria Lisa Dentici ◽  
Martina Rinelli ◽  
Michele Callea ◽  
...  
Keyword(s):  
Frameshift Mutation ◽  
Ectodermal Dysplasia ◽  
Scalp Hair ◽  
Novel Mutation ◽  
Adherens Junction ◽  
Female Child ◽  
The Novel ◽  
Nail Dystrophy ◽  
Gene Encoding ◽  
Biallelic Mutations

Ectodermal dysplasia-syndactyly syndrome 1 (EDSS1) is characterized by cutaneous syndactyly of the toes and fingers and abnormalities of the hair and teeth, variably associated with nail dystrophy and palmoplantar keratoderma (PPK). EDSS1 is caused by biallelic mutations in the NECTIN4 gene, encoding the adherens junction component nectin-4. Nine EDSS1 cases have been described to date. We report a 5.5-year-old female child affected with EDSS1 due to the novel homozygous frameshift mutation c.1150delC (p.Gln384ArgfsTer7) in the NECTIN4 gene. The patient presents brittle scalp hair, sparse eyebrows and eyelashes, widely spaced conical teeth and dental agenesis, as well as toenail dystrophy and mild PPK. She has minimal proximal syndactyly limited to toes 2–3, which makes the phenotype of our patient peculiar as the overt involvement of both fingers and toes is typical of EDSS1. All previously described mutations are located in the nectin-4 extracellular portion, whereas p.Gln384ArgfsTer7 occurs within the cytoplasmic domain of the protein. This mutation is predicted to affect the interaction with afadin, suggesting that impaired afadin activation is sufficient to determine EDSS1. Our case, which represents the first report of a NECTIN4 mutation with toe-only minimal syndactyly, expands the phenotypic and molecular spectrum of EDSS1.

scholarly journals The microcephaly gene Donson is essential for progenitors of cortical glutamatergic and GABAergic neurons

PLoS Genetics ◽  
2021 ◽  
Vol 17 (3) ◽  
pp. e1009441
Author(s):  
Sathish Venkataramanappa ◽  
Dagmar Schütz ◽  
Friederike Saaber ◽  
Praveen Ashok Kumar ◽  
Philipp Abe ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Replication Fork ◽  
Essential Gene ◽  
Gabaergic Neurons ◽  
Protection Factor ◽  
Gene Encoding ◽  
Glutamatergic Neurons ◽  
Proliferation And Differentiation ◽  
Biallelic Mutations ◽  
Dorsal Extension

Biallelic mutations in DONSON, an essential gene encoding for a replication fork protection factor, were linked to skeletal abnormalities and microcephaly. To better understand DONSON function in corticogenesis, we characterized Donson expression and consequences of conditional Donson deletion in the mouse telencephalon. Donson was widely expressed in the proliferation and differentiation zones of the embryonic dorsal and ventral telencephalon, which was followed by a postnatal expression decrease. Emx1-Cre-mediated Donson deletion in progenitors of cortical glutamatergic neurons caused extensive apoptosis in the early dorsomedial neuroepithelium, thus preventing formation of the neocortex and hippocampus. At the place of the missing lateral neocortex, these mutants exhibited a dorsal extension of an early-generated paleocortex. Targeting cortical neurons at the intermediate progenitor stage using Tbr2-Cre evoked no apparent malformations, whereas Nkx2.1-Cre-mediated Donson deletion in subpallial progenitors ablated 75% of Nkx2.1-derived cortical GABAergic neurons. Thus, the early telencephalic neuroepithelium depends critically on Donson function. Our findings help explain why the neocortex is most severely affected in individuals with DONSON mutations and suggest that DONSON-dependent microcephaly might be associated with so far unrecognized defects in cortical GABAergic neurons. Targeting Donson using an appropriate recombinase is proposed as a feasible strategy to ablate proliferating and nascent cells in experimental research.

Novel biallelic mutations in the PNPT1 gene encoding a mitochondrial-RNA-import protein PNPase cause delayed myelination

2017 ◽  
Vol 93 (2) ◽  
pp. 242-247 ◽  
Author(s):  
R. Sato ◽  
N. Arai-Ichinoi ◽  
A. Kikuchi ◽  
T. Matsuhashi ◽  
Y. Numata-Uematsu ◽  
...  
Keyword(s):  
Mitochondrial Rna ◽  
Gene Encoding ◽  
Biallelic Mutations ◽  
Rna Import ◽  
Delayed Myelination

Lifestyle Cuts Women's Risk of Sudden Death

2011 ◽  
Vol 44 (13) ◽  
pp. 32
Author(s):  
MARY ANN MOON
Keyword(s):  
Sudden Death
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