scholarly journals De novo mutation and somatic mosaicism of gene mutation in type 2A, 2B and 2M VWD

2016 ◽  
Vol 14 (S1) ◽  
Author(s):  
Ming-Ching Shen ◽  
Ming Chen ◽  
Gwo-Chin Ma ◽  
Shun-Ping Chang ◽  
Ching-Yeh Lin ◽  
...  
Keyword(s):  
Gene Mutation ◽  
De Novo ◽  
Somatic Mosaicism ◽  
De Novo Mutation

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.

scholarly journals De novo mutation in MEN1 is not associated with parental somatic mosaicism

2017 ◽  
Vol 24 (1) ◽  
pp. L1-L3 ◽  
Author(s):  
Yael Laitman ◽  
Anat Jaffe ◽  
Hagit Schayek ◽  
Eitan Friedman
Keyword(s):  
De Novo ◽  
Somatic Mosaicism ◽  
De Novo Mutation

scholarly journals Case Report of a de Novo Mutation of PCDH19 in Saudi Family Limited to Females

2021 ◽  
Vol 6 (12) ◽  
pp. 940-943
Author(s):  
Rawan Alsheikh, MD ◽  
Amal Al-Qassmi, MD
Keyword(s):  
De Novo ◽  
Somatic Mosaicism ◽  
Febrile Illness ◽  
Autistic Traits ◽  
De Novo Mutation ◽  
Epilepsy Syndrome ◽  
Childhood Onset ◽  
Behavioral Abnormalities ◽  
Nucleotide Mutation ◽  
Saudi Family

Up to date more than 60 different mutations in PCDH19 have been identified. Most of PCDH19 gene is located in Xq22 and produces nonclustered delta protocadherin. This disorder primarily manifests in heterozygote females due to random X chromosome inactivation leading to somatic mosaicism and abnormal cellular interference between cells with and without delta-protocadherin., but we a heterozygous nucleotide mutation causing amino acid 561 to change from Pro to Ser (p.Pro561Ser). This mutation was de novo, and this alteration was not found in her parents. PCDH19-related epilepsy is a distinct childhood-onset epilepsy syndrome characterized by brief clusters of febrile and afebrile seizures with onset primarily before the age of three years, cognitive impairment, autistic traits, and behavioral abnormalities. We describe the features of a de novo mutation in 3 sibling, presented with early onset of seizure, two of them were controlled and wean off medication was at age of six year and her sister at age of 10 year .The youngest sister still partially controlled on medication, she had seizure only during febrile illness.

scholarly journals Case report of a de novo mutation of PCDH19 in Saudi family limited to females

2022 ◽  
Vol 5 (1) ◽  
pp. 01-04
Author(s):  
Rawan Alsheikh ◽  
Amal Al-Qassmi
Keyword(s):  
De Novo ◽  
Somatic Mosaicism ◽  
Febrile Illness ◽  
Autistic Traits ◽  
De Novo Mutation ◽  
Epilepsy Syndrome ◽  
Childhood Onset ◽  
Behavioral Abnormalities ◽  
Nucleotide Mutation ◽  
Saudi Family

Up to date more than 60 different mutations in PCDH19 have been identified. Most of PCDH19 gene is located in Xq22 and produces nonclustered delta protocadherin. This disorder primarily manifests in heterozygote females due to random X chromosome inactivation leading to somatic mosaicism and abnormal cellular interference between cells with and without delta-protocadherin., but we a heterozygous nucleotide mutation causing amino acid 561 to change from Pro to Ser (p.Pro561Ser). This mutation was de novo, and this alteration was not found in her parents. PCDH19-related epilepsy is a distinct childhood-onset epilepsy syndrome characterized by brief clusters of febrile and afebrile seizures with onset primarily before the age of three years, cognitive impairment, autistic traits, and behavioral abnormalities. We describe the features of a de novo mutation in 3 sibling, presented with early onset of seizure, two of them were controlled and wean off medication was at age of six year and her sister at age of 10 year .The youngest sister still partially controlled on medication, she had seizure only during febrile illness.

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

Abstract 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.

scholarly journals Androgen Insensitivity Syndrome: Somatic Mosaicism of the Androgen Receptor in Seven Families and Consequences for Sex Assignment and Genetic Counseling

2005 ◽  
Vol 90 (1) ◽  
pp. 106-111 ◽  
Author(s):  
Birgit Köhler ◽  
Serge Lumbroso ◽  
Juliane Leger ◽  
Francoise Audran ◽  
Enric Sarret Grau ◽  
...  
Keyword(s):  
Genetic Counseling ◽  
Androgen Receptor ◽  
De Novo ◽  
Somatic Mosaicism ◽  
Androgen Insensitivity Syndrome ◽  
De Novo Mutation ◽  
Wild Type ◽  
De Novo Mutations ◽  
Androgen Insensitivity ◽  
Sex Assignment

Abstract Androgen insensitivity syndrome (AIS) is caused by numerous mutations of the androgen receptor (AR) gene. The phenotype may range from partial AIS (PAIS) with ambiguous genitalia to complete AIS (CAIS) with female genitalia. In 70% of the cases, AR mutations are transmitted in an X-linked recessive manner through the carrier mothers, but in 30%, the mutations arise de novo. When de novo mutations occur after the zygotic stage, they result in somatic mosaicisms, which are an important consideration for both virilization in later life—because both mutant and wild-type receptors are expressed—and genetic counseling. We report here six patients with AIS due to somatic mutations of the AR and one mother with somatic mosaicism who transmitted the mutation twice. Of the four patients with PAIS, three presented spontaneous or induced virilization at birth or puberty. These cases underline the crucial role of the remnant wild-type AR for virilization because the same mutations, when they are inherited, lead to CAIS. We also report two novel mutations of the AR, with somatic mosaicism, detected in patients with CAIS. Thus, the remnant wild-type receptor does not always lead to virilization. In one of these patients, a high ratio of wild-type to mutant AR expression was found in the gonads and genital skin fibroblasts. Although no prenatal virilization occurred, the possibility of virilization at puberty could not be excluded, and early gonadectomy was performed. A seventh patient had a CAIS with a novel germline AR mutation. The mutation was inherited from the mother, in whom mosaicism was detected in blood and who transmitted the mutation to a second, XX, offspring. The detection of somatic AR mutations is particularly important for the clinical management and genetic counseling of patients with AIS. Before definite sex assignment, a testosterone treatment trial should be performed in all patients with PAIS, but it becomes crucial when an AR mosaicism has been detected. In patients with CAIS or severe PAIS raised as female, there is no consensus about when (early childhood or puberty) gonadectomy should be performed. When somatic AR mutations are detected, however, gonadectomy should be performed earlier because of the risk of virilization during puberty. When a germline de novo mutation is identified in the index case, the risk of transmission to a second child due to a possible germ cell mosaicism in the mother cannot be excluded. However, given the high number of AR de novo mutations and the rarity of such reports, this risk appears to be very low.

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.

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.

Sign in / Sign up

Export Citation Format

Share Document