Somatic mosaicism in a case of apparently sporadic Creutzfeldt-Jakob disease carrying a de novo D178N mutation in the PRNP gene

2010 ◽  
Vol 153B (7) ◽  
pp. 1283-1291 ◽  
Author(s):  
A. Alzualde ◽  
F. Moreno ◽  
P. Martínez-Lage ◽  
I. Ferrer ◽  
A. Gorostidi ◽  
...  
Keyword(s):  
De Novo ◽  
Somatic Mosaicism ◽  
Prnp Gene ◽  
Jakob Disease ◽  
D178n Mutation

scholarly journals De novo TRPV4 Leu619Pro variant causes a new channelopathy characterised by giant cell lesions of the jaws and skull, skeletal abnormalities and polyneuropathy

2021 ◽  
pp. jmedgenet-2020-107427
Author(s):  
Aviel Ragamin ◽  
Carolina C Gomes ◽  
Karen Bindels-de Heus ◽  
Renata Sandoval ◽  
Angelia V Bassenden ◽  
...  
Keyword(s):  
Giant Cell ◽  
De Novo ◽  
Neuromuscular Disorders ◽  
Somatic Mosaicism ◽  
Ion Leakage ◽  
Gain Of Function ◽  
Therapeutic Modalities ◽  
Organ Systems ◽  
Heterozygous Variant ◽  
Systemic Disorder

BackgroundPathogenic germline variants in Transient Receptor Potential Vanilloid 4 Cation Channel (TRPV4) lead to channelopathies, which are phenotypically diverse and heterogeneous disorders grossly divided in neuromuscular disorders and skeletal dysplasia. We recently reported in sporadic giant cell lesions of the jaws (GCLJs) novel, somatic, heterozygous, gain-of-function mutations in TRPV4, at Met713.MethodsHere we report two unrelated women with a de novo germline p.Leu619Pro TRPV4 variant and an overlapping systemic disorder affecting all organs individually described in TRPV4 channelopathies.ResultsFrom an early age, both patients had several lesions of the nervous system including progressive polyneuropathy, and multiple aggressive giant cell-rich lesions of the jaws and craniofacial/skull bones, and other skeletal lesions. One patient had a relatively milder disease phenotype possibly due to postzygotic somatic mosaicism. Indeed, the TRPV4 p.Leu619Pro variant was present at a lower frequency (variant allele frequency (VAF)=21.6%) than expected for a heterozygous variant as seen in the other proband, and showed variable regional frequency in the GCLJ (VAF ranging from 42% to 10%). In silico structural analysis suggests that the gain-of-function p.Leu619Pro alters the ion channel activity leading to constitutive ion leakage.ConclusionOur findings define a novel polysystemic syndrome due to germline TRPV4 p.Leu619Pro and further extend the spectrum of TRPV4 channelopathies. They further highlight the convergence of TRPV4 mutations on different organ systems leading to complex phenotypes which are further mitigated by possible post-zygotic mosaicism. Treatment of this disorder is challenging, and surgical intervention of the GCLJ worsens the lesions, suggesting the future use of MEK inhibitors and TRPV4 antagonists as therapeutic modalities for unmet clinical needs.

Cellular factors important for the de novo formation of yeast prions

2008 ◽  
Vol 36 (5) ◽  
pp. 1083-1087 ◽  
Author(s):  
Mick Tuite ◽  
Klement Stojanovski ◽  
Frederique Ness ◽  
Gloria Merritt ◽  
Nadejda Koloteva-Levine
Keyword(s):  
De Novo ◽  
Prion Diseases ◽  
Underlying Mechanism ◽  
Structural Form ◽  
Yeast Saccharomyces Cerevisiae ◽  
Yeast Prions ◽  
Cellular Factors ◽  
Jakob Disease ◽  
Protein Rich ◽  
Cis And Trans

Prions represent an unusual structural form of a protein that is ‘infectious’. In mammals, prions are associated with fatal neurodegenerative diseases such as CJD (Creutzfeldt–Jakob disease), while in fungi they act as novel epigenetic regulators of phenotype. Even though most of the human prion diseases arise spontaneously, we still know remarkably little about how infectious prions form de novo. The [PSI+] prion of the yeast Saccharomyces cerevisiae provides a highly tractable model in which to explore the underlying mechanism of de novo prion formation, in particular identifying key cis- and trans-acting factors. Most significantly, the de novo formation of [PSI+] requires the presence of a second prion called [PIN+], which is typically the prion form of Rnq1p, a protein rich in glutamine and aspartic acid residues. The molecular mechanism by which the [PIN+] prion facilitates de novo [PSI+] formation is not fully established, but most probably involves some form of cross-seeding. A number of other cellular factors, in particular chaperones of the Hsp70 (heat-shock protein 70) family, are known to modify the frequency of de novo prion formation in yeast.

WDR45 Gene and Its Role in Pediatric Epilepsies

2021 ◽  
Author(s):  
Federica Filosco ◽  
Sebastiano Billone ◽  
Ausilia Collotta ◽  
Tiziana Timpanaro ◽  
Monica Tosto ◽  
...  
Keyword(s):  
Language Impairment ◽  
Pediatric Patients ◽  
De Novo ◽  
Somatic Mosaicism ◽  
Brain Magnetic Resonance Imaging ◽  
Iron Accumulation ◽  
Psychomotor Development ◽  
Specific Gene ◽  
Brain Iron ◽  
De Novo Mutations

AbstractWD repeat domain 45 (WDR45) gene has been increasingly found in patients with developmental delay (DD) and epilepsy. Previously, WDR45 de novo mutations were reported in sporadic adult and pediatric patients presenting iron accumulation, while heterozygous mutations were associated with β-propeller protein-associated neurodegeneration (BPAN), a subtype of neurodegeneration with brain iron accumulation disorders, characterized by extrapyramidal movement disorders and abnormal accumulation of iron in the basal ganglia. Overall, people harboring WDR45 mutations have moderate to severe DD and different types of seizures. The phenotype of adult patients is characterized by extrapyramidal movement, dystonia, parkinsonism, language impairment, and involvement of the substantia nigra and in the globus pallidus at brain magnetic resonance imaging. Importantly, there are no findings of brain iron accumulation in brain in BPAN patients in the first decade of life, thus suggesting a progressive course of the disease. Comparatively, the main phenotype of pediatric patients is epilepsy with early onset, most of which present infantile spasms and arrest or regression of psychomotor development. The phenotype of patients with WDR45 mutations is variable, being different if caused by somatic mosaicism or germline mutations, and presenting with a different spectrum of manifestations in males and females. The treatment of affected individuals is symptomatic. Regarding the seizures, specific, gene-based approaches with specific antiepileptic drugs are not currently available. The early diagnosis of BPAN could be useful in some aspects, such as providing families a supportive treatment to their affected children.

scholarly journals The First Meta-Analysis of the M129V Single-Nucleotide Polymorphism (SNP) of the Prion Protein Gene (PRNP) with Sporadic Creutzfeldt–Jakob Disease

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3132
Author(s):  
Yong-Chan Kim ◽  
Byung-Hoon Jeong
Keyword(s):  
Prion Protein ◽  
Protein Gene ◽  
Meta Analysis ◽  
Prnp Gene ◽  
Case Control ◽  
Prion Protein Gene ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Jakob Disease ◽  
Sporadic Cjd

Prion diseases are fatal, chronic, and incurable neurodegenerative diseases caused by pathogenic forms of prion protein (PrPSc) derived from endogenous forms of prion protein (PrPC). Several case–control and genome-wide association studies have reported that the M129V polymorphism of the human prion protein gene (PRNP) is significantly associated with susceptibility to sporadic Creutzfeldt–Jakob disease (CJD). However, since some case–control studies have not shown these associations, the results remain controversial. We collected data that contain the genotype and allele frequencies of the M129V single-nucleotide polymorphism (SNP) of the PRNP gene and information on ethnic backgrounds from sporadic CJD patients. We performed a meta-analysis by collecting data from eligible studies to evaluate the association between the M129V SNP of the PRNP gene and susceptibility to sporadic CJD. We found a very strong association between the M129V SNP of the PRNP gene and susceptibility to sporadic CJD using a meta-analysis for the first time. We validated the eligibility of existing reports and found severe heterogeneity in some previous studies. We also found that the MM homozygote is a potent risk factor for sporadic CJD compared to the MV heterozygote in the heterozygote comparison model (MM vs. MV, odds ratio = 4.9611, 95% confidence interval: 3.4785; 7.0758, p < 1 × 10−10). To the best of our knowledge, this was the first meta-analysis assessment of the relationship between the M129V SNP of the PRNP gene and susceptibility to sporadic CJD.

scholarly journals A Corticobasal Syndrome Variant of Familial Creutzfeldt-Jakob Disease with Stroke-Like Onset

2016 ◽  
Vol 2016 ◽  
pp. 1-3 ◽  
Author(s):  
Ján Necpál ◽  
Martin Stelzer ◽  
Silvia Koščová ◽  
Michal Patarák
Keyword(s):  
Corticobasal Degeneration ◽  
Early Death ◽  
Prnp Gene ◽  
Corticobasal Syndrome ◽  
Progressive Dementia ◽  
Rare Presentation ◽  
Alien Hand ◽  
Jakob Disease ◽  
Neurological Features ◽  
Characteristic Features

Creutzfeldt-Jakob disease (CJD) is an untreatable rare human prion disease characterized by rapidly progressive dementia along with various neurological features, including myoclonus and sometimes other movement disorders. The clinical course is typically insidious and rapid, leading to an early death. In general, the most common form is sporadic CJD; however, Slovakia is typical for a high percentage of genetic cases. We present an unusual case report of a 65-year-old man with a sudden, stroke-like onset of motor aphasia with right-sided levodopa unresponsive parkinsonism, alien hand, and other characteristic features of corticobasal syndrome (CBS), with rapid deterioration and death on the 32nd day of the disease. Various neurodegenerative disorders are manifested with CBS as a clinical phenotype, including corticobasal degeneration (CBD), progressive supranuclear palsy, Alzheimer’s disease, and CJD. In our patient, mutation E200K and M129M polymorphism of the PRNP gene and typical immunohistochemical findings pointed to a diagnosis of CJD. The patient’s mother died of CJD many years ago. Several CBS-CJD cases were described, but the atypical stroke-like onset of CBS-CJD, an extremely rare presentation of CJD, makes our case unique worldwide.

De novo factor VIII gene intron 22 inversion in a female carrier presents as a somatic mosaicism

Blood ◽  
2000 ◽  
Vol 96 (8) ◽  
pp. 2905-2906 ◽  
Author(s):  
Johannes Oldenburg ◽  
Simone Rost ◽  
Osman El-Maarri ◽  
Marco Leuer ◽  
Klaus Olek ◽  
...  
Keyword(s):  
Germ Cells ◽  
De Novo ◽  
Somatic Mosaicism ◽  
Mitotic Cell ◽  
De Novo Mutation ◽  
Female Carrier ◽  
Meiotic Cell ◽  
Cell Divisions ◽  
Intron 22 Inversion ◽  
Bivalent Formation

The intron 22 inversion represents the most prevalentfactor VIII gene defect in severe hemophilia A, accounting for about 40% of all mutations. It is hypothesized that the inversion mutations occur almost exclusively in germ cells during meiotic cell division by intrachromosomal recombination between 1 of 2 telomeric copies of the Int22h region and its intragenic homologue. The majority of inversion mutations originate in male germ cells, where the lack of bivalent formation may facilitate flipping of the telomeric end of the single X chromosome. This is the first intron 22 inversion that presents as a somatic mosaicism in a female, affecting only about 50% of lymphocyte and fibroblast cells of the proposita. Supposing a post-zygotic de novo mutation as the usual cause of somatic mosaicism, the finding would imply that the intron 22 inversion mutation is not restricted to meiotic cell divisions but can also occur during mitotic cell divisions, either in germ cell precursors or in somatic cells.

The risk of developing Creutzfeldt-Jakob disease in subjects with the PRNP gene codon 200 point mutation

Neurology ◽  
1994 ◽  
Vol 44 (9) ◽  
pp. 1683-1683 ◽  
Author(s):  
J. Chapman ◽  
J. Ben-Israel ◽  
Y. Goldhammer ◽  
A. D. Korczyn
Keyword(s):  
Point Mutation ◽  
Prnp Gene ◽  
Jakob Disease

Double mutations at codon 180 and codon 232 of the PRNP gene in an apparently sporadic case of Creutzfeldt-Jakob disease

1993 ◽  
Vol 120 (2) ◽  
pp. 208-212 ◽  
Author(s):  
Seiji Hitoshi ◽  
Hiroshi Nagura ◽  
Hiroshi Yamanouchi ◽  
Tetsuyuki Kitamoto
Keyword(s):  
Prnp Gene ◽  
Sporadic Case ◽  
Jakob Disease

Genetic basis of Creutzfeldt-Jakob disease in the United Kingdom: a systematic analysis of predisposing mutations and allelic variation in the PRNP gene

1996 ◽  
Vol 98 (3) ◽  
pp. 259-264 ◽  
Author(s):  
O. Windl ◽  
Maureen Dempster ◽  
J. Peter Estibeiro ◽  
Richard Lathe ◽  
Rajith de Silva ◽  
...  
Keyword(s):  
United Kingdom ◽  
Genetic Basis ◽  
Allelic Variation ◽  
Prnp Gene ◽  
Systematic Analysis ◽  
The United Kingdom ◽  
Jakob Disease
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