scholarly journals A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy

2014 ◽  
Vol 47 (1) ◽  
pp. 39-46 ◽  
Author(s):  
Mikko Muona ◽  
Samuel F Berkovic ◽  
Leanne M Dibbens ◽  
Karen L Oliver ◽  
Snezana Maljevic ◽  
...  
Keyword(s):  
De Novo ◽  
De Novo Mutation ◽  
Progressive Myoclonus Epilepsy ◽  
Myoclonus Epilepsy

scholarly journals Biallelic and de novo variants in ATP6V0A1 cause progressive myoclonus epilepsy and developmental and epileptic encephalopathy

2021 ◽  
Author(s):  
Laura C Bott ◽  
Mitra Forouhan ◽  
Maria Lieto ◽  
Ambre Sala ◽  
Ruth Ellerington ◽  
...  
Keyword(s):  
Protein Trafficking ◽  
Atp Hydrolysis ◽  
De Novo ◽  
Proton Translocation ◽  
Critical Role ◽  
Epileptic Encephalopathy ◽  
Developmental Defect ◽  
Lysosomal Disease ◽  
Progressive Myoclonus Epilepsy ◽  
Myoclonus Epilepsy

The vacuolar H+-ATPase is a large multi-subunit proton pump, composed of an integral membrane V0 domain, involved in proton translocation, and a peripheral V1 domain, catalysing ATP hydrolysis. This complex is widely distributed on the membrane of various subcellular organelles, such as endosomes and lysosomes, and plays a critical role in cellular processes ranging from autophagy to protein trafficking and endocytosis. Here we identified 17 individuals from 14 unrelated families with variants in ATP6V0A1, the brain-enriched isoform in the V0 domain. Five affected subjects carried biallelic variants in this gene and presented with a phenotype of early-onset progressive myoclonus epilepsy with ataxia, while 12 individuals were found as de novo cases (missense variants) and showed severe developmental and epileptic encephalopathy. We describe that the disease-associated variants lead to failure of lysosomal hydrolysis by directly impairing acidification of the endolysosomal compartment. The R740Q mutation, which alone accounts for almost 50% of the variants identified in this cohort, causes autophagic dysfunction and a severe developmental defect in C. elegans. Altogether, our findings establish a novel cause of lysosomal disease and provide a direct link with endolysosomal acidification in the pathophysiology of these conditions.

A KCNC1 mutation in Epilepsy of Infancy with Focal Migrating Seizures produces functional channels that fail to be regulated by phosphorylation

2021 ◽  
Author(s):  
Yalan Zhang ◽  
Syed R Ali ◽  
Rima Nabbout ◽  
Giulia Barcia ◽  
Leonard K. Kaczmarek
Keyword(s):  
De Novo ◽  
Channel Modulation ◽  
Progressive Myoclonus Epilepsy ◽  
C Terminus ◽  
Myoclonus Epilepsy ◽  
Voltage Dependent ◽  
Genes Encoding ◽  
Clear Change

Channelopathies caused by mutations in genes encoding ion channels generally produce a clear change in channel function. Accordingly, mutations in KCNC1, which encodes the voltage-dependent Kv3.1 potassium channel, result in Progressive Myoclonus Epilepsy as well as other Developmental and Epileptic Encephalopathies, and these have been shown to reduce or fully abolish current amplitude. One exception to this is the mutation A513V Kv3.1b, located in the cytoplasmic C-terminal domain of the channel protein. This de novo variant was detected in a patient with Epilepsy of Infancy with Focal Migrating Seizures (EIFMS) but no difference could be detected between A513V Kv3.1 current and that of wild type Kv3.1. Using both biochemical and electrophysiological approaches, we have now confirmed that this variant produces functional channels but find that the A513V mutation renders the channel completely insensitive to regulation by phosphorylation at S503, a nearby regulatory site in the C-terminus. In this respect, the mutation resembles those in another channel, KCNT1, which are the major cause of EIFMS. Because the amplitude of Kv3.1 current is constantly adjusted by phosphorylation in vivo, our findings suggest that loss of such regulation contributes to EIFMS phenotype and emphasize the role of channel modulation for normal neuronal function.

scholarly journals Intranasal oxytocin administration ameliorates social behavioral deficits in a POGZWT/Q1038R mouse model of autism spectrum disorder

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Kohei Kitagawa ◽  
Kensuke Matsumura ◽  
Masayuki Baba ◽  
Momoka Kondo ◽  
Tomoya Takemoto ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Social Behavior ◽  
Mouse Model ◽  
Mouse Models ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
De Novo Mutation ◽  
Behavioral Deficits

AbstractAutism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Recent studies have suggested that the oxytocin system, which regulates social behavior in mammals, is potentially involved in ASD. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. However, limited studies have shown the involvement of the oxytocin system in the behavioral phenotypes in mouse models of ASD. We have previously demonstrated that a mouse model that carries the ASD patient-derived de novo mutation in the pogo transposable element derived with zinc finger domain (POGZWT/Q1038R mice), showed ASD-like social behavioral deficits. Here, we have explored whether oxytocin (OXT) administration improves impaired social behavior in POGZWT/Q1038R mice and found that intranasal oxytocin administration effectively restored the impaired social behavior in POGZWT/Q1038R mice. We also found that the expression level of the oxytocin receptor gene (OXTR) was low in POGZWT/Q1038R mice. However, we did not detect significant changes in the number of OXT-expressing neurons between the paraventricular nucleus of POGZWT/Q1038R mice and that of WT mice. A chromatin immunoprecipitation assay revealed that POGZ binds to the promoter region of OXTR and is involved in the transcriptional regulation of OXTR. In summary, our study demonstrate that the pathogenic mutation in the POGZ, a high-confidence ASD gene, impairs the oxytocin system and social behavior in mice, providing insights into the development of oxytocin-based therapeutics for ASD.

scholarly journals The L1-dependant and Pol III transcribed Alu retrotransposon, from its discovery to innate immunity

2021 ◽  
Vol 48 (3) ◽  
pp. 2775-2789
Author(s):  
Ludwig Stenz
Keyword(s):  
Human Genome ◽  
Viral Infections ◽  
De Novo ◽  
Current Knowledge ◽  
Innate Immune ◽  
De Novo Mutation ◽  
Neuronal Diversity ◽  
Alu Sequences ◽  
Pol Iii ◽  
The Brain

AbstractThe 300 bp dimeric repeats digestible by AluI were discovered in 1979. Since then, Alu were involved in the most fundamental epigenetic mechanisms, namely reprogramming, pluripotency, imprinting and mosaicism. These Alu encode a family of retrotransposons transcribed by the RNA Pol III machinery, notably when the cytosines that constitute their sequences are de-methylated. Then, Alu hijack the functions of ORF2 encoded by another transposons named L1 during reverse transcription and integration into new sites. That mechanism functions as a complex genetic parasite able to copy-paste Alu sequences. Doing that, Alu have modified even the size of the human genome, as well as of other primate genomes, during 65 million years of co-evolution. Actually, one germline retro-transposition still occurs each 20 births. Thus, Alu continue to modify our human genome nowadays and were implicated in de novo mutation causing diseases including deletions, duplications and rearrangements. Most recently, retrotransposons were found to trigger neuronal diversity by inducing mosaicism in the brain. Finally, boosted during viral infections, Alu clearly interact with the innate immune system. The purpose of that review is to give a condensed overview of all these major findings that concern the fascinating physiology of Alu from their discovery up to the current knowledge.

scholarly journals Publisher Correction: Germline de novo mutation clusters arise during oocyte aging in genomic regions with high double-strand-break incidence

2021 ◽  
Author(s):  
Jakob M. Goldmann ◽  
Vladimir B. Seplyarskiy ◽  
Wendy S. W. Wong ◽  
Thierry Vilboux ◽  
Pieter B. Neerincx ◽  
...  
Keyword(s):  
De Novo ◽  
Strand Break ◽  
Double Strand Break ◽  
De Novo Mutation ◽  
Oocyte Aging ◽  
Genomic Regions

Sleep Exacerbations and Facial Twitching: Diagnostic Clues for ADCY5-Related Dyskinesias

2020 ◽  
Author(s):  
Margherita Nosadini ◽  
Gianluca D'Onofrio ◽  
Maria Federica Pelizza ◽  
Concetta Luisi ◽  
Davide Padrin ◽  
...  
Keyword(s):  
Movement Disorder ◽  
Developmental Delay ◽  
De Novo ◽  
Brain Magnetic Resonance Imaging ◽  
Neurological Impairment ◽  
De Novo Mutation ◽  
Oligoclonal Bands ◽  
Emotional Stimuli ◽  
Childhood Onset ◽  
Ataxic Gait

Abstract Background Mutations in the adenylate cyclase 5 (ADCY5) gene are associated with childhood-onset paroxysmal dyskinesia. Methods We report a new video-documented case of pediatric ADCY5-related dyskinesia with de novo ADCY5 mutation. Results A boy born to nonconsanguineous parents after an uneventful pregnancy had developmental delay and hypotonia. At the age of 7 months, he presented with paroxysmal jerky–choreic–dystonic involuntary movements in wakefulness involving limbs, trunk, and face, exacerbated by emotional stimuli. These episodes gradually worsened in duration and frequency: at the age of 2.5 years, they occurred up to six times per day, and appeared also during sleep in prolonged bouts; the boy also had basal choreoathetoid–dystonic movements, hyperactivity, paraparetic–ataxic gait, generalized hypotonia with brisk tendon reflexes, drooling, and language delay with intellectual disability. Brain magnetic resonance imaging, electroencephalogram, electromyogram, eye review, metabolic investigations, oligoclonal bands, and autoantibodies were normal. Extensive genetic testing had not let to a diagnosis, until a heterozygous de novo mutation c.1252C > T (p.Arg418Trp) was identified in the ADCY5 gene. Clonazepam had partial effectiveness. The boy walked at the age of 3.5 years. At the age of 5 years, the paroxysmal movement disorder has slightly improved. Conclusion ADCY5 mutations should be considered among the differential diagnoses of early-onset paroxysmal choreic–athetosic–myoclonic–dystonic movement disorder involving limbs, trunk, and face, in patients with global neurological impairment with hypotonia and developmental delay. Facial dyskinesias and exacerbation by drowsiness/sleep and emotional stimuli are important clues that may allow a timely recognition of the disorder and avoidance of unnecessary diagnostic investigations.

Neugeborenes mit Nasenagenesie: Neonatologische Herausforderungen bei der Versorgung eines Neugeborenen mit Bosma-Arhinie-Mikrophthalmie-Syndrom (BAMS)

2021 ◽  
Vol 100 (04) ◽  
pp. 294-296
Author(s):  
Helen Stromiedel ◽  
Chantal Van Quekelberghe ◽  
Gökhan Yigit ◽  
Ammar Al Naimi ◽  
Franz Bahlmann ◽  
...  
Keyword(s):  
De Novo ◽  
De Novo Mutation ◽  
Intrauterine Wachstumsrestriktion

ZusammenfassungAnhand eines weiblichen Neugeborenen soll das seltene Krankheitsbild der konnatalen Nasenagenesie vorgestellt werden. In der Schwangerschaft fielen eine intrauterine Wachstumsrestriktion mit Polyhydramnion und eine Mittelgesichtshypoplasie auf. Das Atemwegsmanagement nach primärer Sectio in der 38 + 4 SSW gelang mittels Schienung durch einen Güdel- bzw. im Verlauf Rachentubus ohne Zeichen einer respiratorischen Insuffizienz. Neben der vollständigen Nasenagenesie zeigten sich bei unauffälligen zerebralen Strukturen ein Hypertelorismus, ein gotischer Gaumen, ein beidseitiger Mikrophthalmus und Iriskolobom. Die Nahrungsaufnahme wurde mit einer orogastralen Sonde sichergestellt, durch Trinktraining und einen speziellen Schnuller konnten eine bessere Koordination und Trinkleistung erzielt werden. Der sich bei assoziierten Fehlbildungen ergebende Verdacht auf ein Bosma-Arhinie-Mikrophthalmie-Syndrom (BAMS) wurde humangenetisch durch den Nachweis einer heterozygoten de novo Mutation im SMCHD1-Gen, welches eine Schlüsselfunktion in der Embryogenese der menschlichen Nase spielt, bestätigt (c.1043A > G; pHis348Arg). Aus neonatologischer Sicht ist oftmals die initiale Kreißsaal-Versorgung eine Herausforderung: Patienten mit Nasenagenesie werden häufig postpartal intubiert und elektiv tracheotomiert. Bei fehlender respiratorischer Problematik und Nahrungsaufnahme mit perzentilengerechtem Wachstum besteht jedoch keine dringliche Indikation zur frühzeitigen plastisch-chirurgischen Versorgung, insbesondere da diese mit Gefahren wie Sepsis und Wachstumsstörungen im Mittelgesicht behaftet ist.

scholarly journals Enhanced specificity of clinical high-sensitivity tumor mutation profiling in cell-free DNA via paired normal sequencing using MSK-ACCESS

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
A. Rose Brannon ◽  
Gowtham Jayakumaran ◽  
Monica Diosdado ◽  
Juber Patel ◽  
Anna Razumova ◽  
...  
Keyword(s):  
Cancer Patients ◽  
De Novo ◽  
Low Frequency ◽  
High Sensitivity ◽  
Clinical Analysis ◽  
De Novo Mutation ◽  
Cell Free Dna ◽  
Free Dna ◽  
Somatic Alterations ◽  
Mutation Profiling

AbstractCirculating cell-free DNA from blood plasma of cancer patients can be used to non-invasively interrogate somatic tumor alterations. Here we develop MSK-ACCESS (Memorial Sloan Kettering - Analysis of Circulating cfDNA to Examine Somatic Status), an NGS assay for detection of very low frequency somatic alterations in 129 genes. Analytical validation demonstrated 92% sensitivity in de-novo mutation calling down to 0.5% allele frequency and 99% for a priori mutation profiling. To evaluate the performance of MSK-ACCESS, we report results from 681 prospective blood samples that underwent clinical analysis to guide patient management. Somatic alterations are detected in 73% of the samples, 56% of which have clinically actionable alterations. The utilization of matched normal sequencing allows retention of somatic alterations while removing over 10,000 germline and clonal hematopoiesis variants. Our experience illustrates the importance of analyzing matched normal samples when interpreting cfDNA results and highlights the importance of cfDNA as a genomic profiling source for cancer patients.

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