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.

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.

Complex recombination with deletion in the F8 and duplication in the TMLHE mediated by int22h copies during early embryogenesis

2017 ◽  
Vol 117 (08) ◽  
pp. 1478-1485 ◽  
Author(s):  
Changming Chen ◽  
Xiaoling Xie ◽  
Xi Wu ◽  
Yeling Lu ◽  
Xuefeng Wang ◽  
...  
Keyword(s):  
Germ Cells ◽  
Genetic Variant ◽  
Early Embryogenesis ◽  
Female Carrier ◽  
Haemophilia A ◽  
Intron 22 Inversion ◽  
Intron 1 ◽  
Supplementary Material ◽  
Novel Complex ◽  
Break Induced Replication

SummaryHaemophilia A (HA) is a common X-linked recessive bleeding disorder and almost one half of patients with severe HA are caused by intron 22 inversion (Inv22) in the F8. Inv22 is considered to be almost exclusively of meiotic origin in germ cells during spermatogenesis and only one mosaic Inv22 female carrier with the mutation possibly occurring during mitosis of the embryo has been reported so far. Previously we have identified a novel complex recombination mediated by int22h copies in a sporadic severe HA pedigree and herein we have localised the sequences flanking the breakpoint region using genome walking technique, AccuCopy technique, gene chip and real-time PCR. The disease causing genetic variant registered an 18.1 kb deletion including part of int22h-1 through the intron 23 of F8 and a 113.3 kb duplication of part of int22h-2 through the intron 1 of TMLHE inserted in the religated region of the F8. Two intrinsically linked mechanisms of recombination-dependent DNA replication: microhomology-mediated break-induced replication (MMBIR) followed by break-induced replication (BIR) might be responsible for the incident of the complex recombination during early embryogenesis of the proband’s mother.Supplementary Material to this article is available online at www.thrombosis-online.com.

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

The Drosophila cdc25 homolog twine is required for meiosis

Development ◽  
1992 ◽  
Vol 116 (2) ◽  
pp. 405-416 ◽  
Author(s):  
C. Courtot ◽  
C. Fankhauser ◽  
V. Simanis ◽  
C.F. Lehner
Keyword(s):  
Cell Cycle ◽  
Missense Mutation ◽  
Germ Cells ◽  
Mitotic Cell ◽  
Genomic Region ◽  
Mitotic Cell Cycle ◽  
Phenotypic Analysis ◽  
Male And Female ◽  
Cell Divisions ◽  
Drosophila Mutant

We have identified a second cdc25 homolog in Drosophila. In contrast to string (the first homolog identified in Drosophila) this second homolog, twine, does not function in the mitotic cell cycle, but is specialized for meiosis. Expression of twine was observed exclusively in male and female gonads. twine transcripts are present in germ cells during meiosis, and appear only late during gametogenesis, well after the end of the mitotic germ cell divisions. The sterile Drosophila mutant, mat(2)synHB5, which had previously been isolated and mapped to the same genomic region as twine (35F), was found to carry a missense mutation in the twine gene. This missense mutation in twine abolished its ability to complement a mutation in Schizosaccharomyces pombe cdc25. Phenotypic analysis of mat(2)synHB5 mutant flies revealed a complete block of meiosis in males and severe meiotic defects in females.

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 Functions of cyclins and CDKs in mammalian gametogenesis†

2019 ◽  
Vol 101 (3) ◽  
pp. 591-601 ◽  
Author(s):  
Jessica Y Chotiner ◽  
Debra J Wolgemuth ◽  
P Jeremy Wang
Keyword(s):  
Germ Cells ◽  
Cultured Cells ◽  
Early Embryogenesis ◽  
Meiotic Cell ◽  
Cell Cycles ◽  
Genetic Ablation ◽  
Cyclin Dependent Kinases ◽  
Long Period ◽  
Cell Divisions ◽  
Prophase I

Abstract Cyclins and cyclin-dependent kinases (CDKs) are key regulators of the cell cycle. Most of our understanding of their functions has been obtained from studies in single-cell organisms and mitotically proliferating cultured cells. In mammals, there are more than 20 cyclins and 20 CDKs. Although genetic ablation studies in mice have shown that most of these factors are dispensable for viability and fertility, uncovering their functional redundancy, CCNA2, CCNB1, and CDK1 are essential for embryonic development. Cyclin/CDK complexes are known to regulate both mitotic and meiotic cell cycles. While some mechanisms are common to both types of cell divisions, meiosis has unique characteristics and requirements. During meiosis, DNA replication is followed by two successive rounds of cell division. In addition, mammalian germ cells experience a prolonged prophase I in males or a long period of arrest in prophase I in females. Therefore, cyclins and CDKs may have functions in meiosis distinct from their mitotic functions and indeed, meiosis-specific cyclins, CCNA1 and CCNB3, have been identified. Here, we describe recent advances in the field of cyclins and CDKs with a focus on meiosis and early embryogenesis.

scholarly journals Overlooked roles of DNA damage and maternal age in generating human germline mutations

2019 ◽  
Vol 116 (19) ◽  
pp. 9491-9500 ◽  
Author(s):  
Ziyue Gao ◽  
Priya Moorjani ◽  
Thomas A. Sasani ◽  
Brent S. Pedersen ◽  
Aaron R. Quinlan ◽  
...  
Keyword(s):  
Dna Damage ◽  
Maternal Age ◽  
De Novo ◽  
Germline Mutations ◽  
Strand Break ◽  
De Novo Mutation ◽  
Substantial Contribution ◽  
Base Substitution ◽  
Induced Mutations ◽  
Cell Divisions

The textbook view that most germline mutations in mammals arise from replication errors is indirectly supported by the fact that there are both more mutations and more cell divisions in the male than in the female germline. When analyzing large de novo mutation datasets in humans, we find multiple lines of evidence that call that view into question. Notably, despite the drastic increase in the ratio of male to female germ cell divisions after the onset of spermatogenesis, even young fathers contribute three times more mutations than young mothers, and this ratio barely increases with parental age. This surprising finding points to a substantial contribution of damage-induced mutations. Indeed, C-to-G transversions and CpG transitions, which together constitute over one-fourth of all base substitution mutations, show genomic distributions and sex-specific age dependencies indicative of double-strand break repair and methylation-associated damage, respectively. Moreover, we find evidence that maternal age at conception influences the mutation rate both because of the accumulation of damage in oocytes and potentially through an influence on the number of postzygotic mutations in the embryo. These findings reveal underappreciated roles of DNA damage and maternal age in the genesis of human germline mutations.

scholarly journals Skewed X-inactivation in a Female Carrier with X-linked Chronic Granulomatous Disease

2019 ◽  
Author(s):  
Itzel López-Hernández ◽  
Caroline Deswarte ◽  
Miguel Ángel Alcantara-Ortigoza ◽  
María del Mar Saez-de-Ocariz ◽  
Marco Antonio Yamazaki-Nakashimada ◽  
...  
Keyword(s):  
Chronic Granulomatous Disease ◽  
De Novo ◽  
X Inactivation ◽  
De Novo Mutation ◽  
Female Carrier ◽  
Reactive Oxygen Metabolites ◽  
Granulomatous Disease ◽  
Oxygen Metabolites ◽  
Skewed X Inactivation ◽  
Skewed X Chromosome Inactivation

Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by defective phagocytic NADPH oxidase, causing a complete lack or significant decrease in the production of microbicidal reactive oxygen metabolites. It mainly affects male children; however, there are scarce reports of adult females diagnosed with X-linked-CGD attributed to an extremely skewed X-chromosome inactivation. This condition is characterized by severe and recurrent infections that usually develop after childhood. In clinical practice, physicians who usually confront these patients should suspect this entity and differentiate it from a secondary immunodeficiency. Here, we report a 38-year-old Mexican female with juvenile-onset X linked-CGD, caused by a de novo mutation and extremely skewed X-inactivation, whose clinical features were similar to those in patients with classic X-linked-CDG.

Sign in / Sign up

Export Citation Format

Share Document