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PubMed2003

Analysis of floral morphology of a cotton homeotic variant (CHV1).

Physiological and genetic variations exist frequently in the cotton plants regenerated from somatic embryos. A stable homeotic variant (CHV1) was identified from these regenerated plants. Morphological analysis suggested that all the floral organs of the CHV1 plants convert into bract leaf-like organs, this was confirmed by close inspection of floral organs surface using scanning electron microscope. However, there are placenta and ovules bearing at the basal region of central leaf-like organs. A flower of the variant consists of three to seven bracts, nineteen to fourty one bract leaf-like organs. Arrangement of the leaf-like organs is intermediate between spiral and whorl. The mechanisms responsible for the CHV1 phenotype are analyzed. The variant (CHV1) may be useful in the research of cotton flower development and the mechanism of somaclonal variation.

Arabidopsis↗
PubMed2001

Centrosomal association of histone macroH2A1.2 in embryonic stem cells and somatic cells.

The histone 2A variant macroH2A1.2 is expressed in female and male mammals and is implicated in X-chromosome inactivation and autosomal gene silencing. In undifferentiated and early differentiating murine embryonic stem (ES) cells a cytosolic pool of macroH2A1.2 has recently been reported and found to be associated with the centrosome. Here, we show that the centrosomal association of macroH2A1.2 is a widespread phenomenon and is not restricted to undifferentiated and early differentiating ES cells. By indirect immunofluorescence we detect macroH2A1.2 protein in a juxtanuclear structure that duplicates once per cell cycle and colocalizes with centrosomal gamma-tubulin in both XX and XY ES cells prior to and throughout their differentiation. MacroH2A1.2 localization to the centrosome is also observed in female and male somatic cells, both in interphase and in mitosis. Biochemical analysis demonstrates that the association between macroH2A1.2 and the centrosome in somatic cells is stable, as macroH2A1.2 copurifies with centrosomes isolated from human lymphoblasts. Therefore, in addition to a nuclear pool of macroH2A1.2 a fraction of the histone is associated with the centrosome in various cell types and throughout ES cell differentiation.

Animals↗
PubMedDate not supplied

Transferrin types, iron-binding capacity and body iron stores.

Increased body iron stores and transferrin (TF) variants have been found to be associated with adverse health effects believed to be caused by oxygen free radicals. Previous attempts to establish a relationship between TF types, serum TF concentrations and iron-binding have been inconclusive. We have studied serum iron, total iron-binding capacity (TIBC), TF saturation and serum ferritin in relation to genetic TF types in a population sample (691 females and 639 males) from northern Sweden in an attempt to elucidate whether individuals with TF variants associated with adverse somatic and reproductive effects (TFC2 and C3) have increased body iron stores. As expected there was a highly significant sex difference, males manifesting increased body iron stores viz. increased levels of serum iron, TF saturation and serum ferritin, and a lower TIBC. There was no consistent and statistically significant association between the TFC2 variant and the parameters that indicate iron binding and storage. Thus the associations between TFC2 and somatic and reproductive damage appear to be independent of iron binding and body iron stores. TIBC (and TF levels) showed significant differences between TF types in females (p = 0.0015) but not in males. In females the TFC3 variant was associated with a significantly lower (p = 0.002) TIBC value. This decreased TIBC value was, however, not accompanied by an increased ferritin value, thus there was no unequivocal evidence for an association between TFC3 and increased body iron stores.

Alleles↗
PubMed2006

Rapid screening of 4000 individuals for germ-line variations in the BRAF gene.

BACKGROUND: The BRAF gene is frequently somatically altered in malignant melanoma. A majority of variations are at the valine 600 residue leading to a V600E substitution that constitutively activates the kinase. We screened 4000 patient and control DNAs for germ-line variations at the valine 600 residue. METHODS: We developed a novel assay by adapting single-base variation assays and software for MALDI-TOF (matrix-assisted laser desorption/ionization time-of-flight) mass spectrometry to screen for all 5 reported variants at codon 600 of the BRAF gene. We screened a case-control collection comprising samples from 1082 melanoma patients and 154 of their unaffected relatives from 1278 families and from 2744 individuals from 659 unselected twin families with no history of melanoma. A panel of 66 melanoma cell lines was used for variation-positive controls. RESULTS: All melanoma cell lines that we had found previously to carry a codon 600 variation were verified in this study. Three of the 4 possible variants (V600E n = 47, V600K n = 2, V600R n = 1) were detected, but no case of V600D was available. No germ-line variants were found in the samples from the 3980 melanoma patients or from the control individuals. CONCLUSIONS: This new assay is a high-throughput, automated alternative to standard sequencing and can be used as a rapid initial screen for somatic variants associated with melanoma. Germ-line variants at valine 600 are unlikely to exist and do not contribute to the reported role of the BRAF gene in melanoma predisposition.

Case-Control Studies↗
PubMed1981

Expression of the albumin gene in rat hepatoma cells and their dedifferentiated variants.

Rat hepatoma clones whose cells do and do not produce albumin, as well as somatic hybrid between the two types of cells, have been examined for albumin mRNA. A direct proportionality between the rate of albumin production and the concentration of albumin mRNA sequences was found for all albumin-producing hepatoma and hybrid clones, indicating that rate of synthesis of the protein is determined by the concentration of its mRNA. Albumin-negative dedifferentiated variant and somatic hybrid cells contain fewer than one to five molecules of albumin mRNA per cell; the block in expression of the gene appears to be at the same (probably transcriptional) level in variants and their somatic hybrids.

Albumins↗
PubMed2024

A germline PDGFRB splice site variant associated with infantile myofibromatosis and resistance to imatinib.

PURPOSE: Infantile myofibromatosis is characterized by the development of myofibroblastic tumors in young children. In most cases, the disease is caused by somatic gain-of-function variants in platelet-derived growth factor (PDGF) receptor beta (PDGFRB). Here, we reported a novel germline intronic PDGFRB variant, c.2905-8G>A, in 6 unrelated infants with multifocal myofibromatosis and their relatives. METHODS: We performed constitutional and tumor DNA and RNA sequencing to identify novel variants, which were subsequently characterized in cellular assays. RESULTS: All patients had multiple skin nodules, 4 had bone lesions, and 2 had aggressive disease with bowel obstruction. The c.2905-8G>A substitution creates an alternative acceptor splice site in intron 21, inserting 2 codons in the PDGFRB transcript. Functional studies revealed that the splice change induced a partial loss of function, contrasting with previously described variants. In 4 tumor samples, we identified a second somatic hit at position Asp850 in PDGFRB exon 18, triggering constitutive receptor activation and resistance to imatinib. In addition to vinblastine and methotrexate, 2 patients received imatinib without objective response. One of them switched to dasatinib with concomitant improvement. CONCLUSION: This splice-site PDGFRB variant favors the development of myofibroma, featuring an acquired oncogenic variant in the same gene and resistance to targeted therapy.

Humans↗
PubMed2026

Somatic mutations: recent advances in brain aging and neurodegeneration.

Somatic mutations are genetic variants that occur after the single-cell phase of development and have been implicated in disease pathogenesis. While most DNA lesions are detected and repaired, examination of healthy tissue has revealed that some lesions escape repair, leading to somatic mutations that accumulate at a consistent rate, including in human brain tissue and postmitotic neurons. Emerging methodological and analytical advances have revealed the presence of persistent mutagenic mechanisms during healthy brain aging as well as mutational pattern shifts in the context of neurodegenerative diseases. Here, we highlight recent methodological advances, summarize our current understanding of somatic mutagenesis in neurotypical brain aging, and examine the role of somatic mutations in neurodegenerative diseases.

Humans↗
PubMed1983

Isolation and characterization of an embryonal carcinoma cell line lacking SSEA-1 antigen.

Stage-specific embryonic antigen 1 (SSEA-1) is a glycoconjugate that is expressed on embryonal carcinoma cells but not on their differentiated derivatives. To determine if SSEA-1 is required for the expression of the EC cell phenotype, a variant cell line lacking this antigen was isolated by exposing mutagenized OTF9-63 (an F9 subclone) cells to anti-SSEA-1 antiserum plus complement. Indirect cytotoxicity tests demonstrated that the variant cell line exhibits at least a 500-fold reduction in SSEA-1 expression. Somatic cell hybrids constructed between variant and wild-type cells expressed SSEA-1, suggesting that the lack of SSEA-1 expression in the mutant is probably due to loss, rather than masking, of the antigenic site. The variant cell line was tumorigenic in syngeneic mice, forming teratocarcinomas composed exclusively of embryonal carcinoma cells. Monolayer cultures of the variant cell line formed parietal endodermal (laminin-positive) cells following exposure to retinoic acid whereas aggregates grown in suspension culture formed visceral endoderm. Also, like their parental cells, the variant cells sorted out to form simple embryoid bodies when mixed in suspension with parietal-like endodermal cells. Thus, the expression of a number of aspects of the embryonal carcinoma phenotype is not dependent on the presence of SSEA-1.

Animals↗
PubMed2006

Characterization of LEAFY COTYLEDON1-LIKE gene in Helianthus annuus and its relationship with zygotic and somatic embryogenesis.

The Helianthus annuus LEAFY COTYLEDON1-LIKE (HaL1L) gene encodes a heme-activated protein 3 subunit of the CCAAT box-binding factor. The phylogenetic analysis indicates that HaL1L is closely related to LEAFY COTYLEDON1 (LEC1)-type of Arabidopsis thaliana. In particular, the peptide results homologous to the LEC1-LIKE gene of A. thaliana, with which it shares a high amino acid sequence identity (56%). HaL1L transcripts are accumulated primarily at an early stage of sunflower embryogenesis. High levels of HaL1L messenger RNA (mRNA) have been detected in the developing embryo proper, suspensor, endosperm, integument, and integumentary tapetum cells, while in unfertilized ovules, HaL1L mRNA was present at rather low levels. In an attempt to examine the involvement of HaL1L on somatic embryogenesis, a somaclonal variant of H. annuus x H. tuberosus (EMB-2) that produces ectopic embryo- and shoot-like structures, arranged in clusters along leaf veins, was used. We found that the epiphyllous proliferation of ectopic embryos on EMB-2 leaves was associated to HaL1L mRNA accumulation. The detection of HaL1L transcripts was evident in somatic embryos at the heart- and early cotyledon-stage. On the contrary, no signal related to HaL1L transcript accumulation was observed in EMB-2 leaves characterized by the presence of shoot-like structures. Together, these results support the conclusion that the transcription of the HaL1L gene is maintained both in zygotic and in somatic embryogenesis. In addition, the ectopic accumulation of HaL1L mRNA in parenchymal cells around the vascular bundles of epiphyllous leaves opens the possibility that HaL1L could also be involved in switching somatic cell fate towards embryogenic competence.

Amino Acid Motifs↗
PubMed1999

XRCC1 polymorphisms: effects on aflatoxin B1-DNA adducts and glycophorin A variant frequency.

Hereditary genetic defects in DNA repair lead to increased risk of cancer. Polymorphisms in several DNA repair genes have been identified; however, the impact on repair phenotype has not been elucidated. We explored the relationship between polymorphisms in the DNA repair enzyme, XRCC1 (codons 194, 280, and 399), and genotoxic end points measured in two populations: (a) placental aflatoxin B1 DNA (AFB1-DNA) adducts in a group of Taiwanese maternity subjects (n = 120); and (b) somatic glycophorin A (GPA) variants in erythrocytes from a group of North Carolina smokers and nonsmokers (n = 59). AFB1-DNA adducts were measured by ELISA, and erythrocyte GPA variant frequency (NN and NO) was assessed in MN heterozygotes with a flow cytometric assay. XRCC1 genotypes were identified by PCR-RFLPs. The XRCC1 399Gln allele was significantly associated with higher levels of both AFB1-DNA adducts and GPA NN mutations. Individuals with the 399Gln allele were at risk for detectable adducts (odds ratio, 2.4; 95% confidence interval, 1.1-5.4; P = 0.03). GPA NN variant frequency was significantly higher in 399Gln homozygotes (19.6 x 10(-6)) than in Gln/Arg heterozygotes (11.4 x 10(-6); P < 0.05) or Arg/Arg homozygotes (10.1 x 10(-6); P = 0.01). No significant effects were observed for other XRCC1 polymorphisms. These results suggest that the Arg399Gln amino acid change may alter the phenotype of the XRCC1 protein, resulting in deficient DNA repair.

Aflatoxin B1↗
PubMed2025

Novel Insights into the Clinical Features, Genetic Spectrum and Clonal Evolution of Patients Carrying NLRP3 Mosaicism.

NLRP3 mosaicism is a well-established mechanism causing the monogenic autoinflammatory disease named cryopyrin-associated periodic syndromes (CAPS). The number of reported patients with NLRP3 mosaicism is small, and the knowledge about the long-term disease behavior is limited. Herein we assembled the largest cohort of individuals with NLRP3 mosaicism reported to date to obtain additional evidence that strengthens the understanding of this disease. The novel genetic data were obtained by using Sanger and next-generation sequencing methods, whereas in vitro analyses determined the functional consequences of detected variants. A total of seventeen individuals with NLRP3 mosaicism were enrolled, with 16/17 experiencing different CAPS phenotypes. An overrepresentation of late-onset forms was detected (37.5%). Overall, clinical manifestations, analytical results, and outcomes of treatments were markedly similar to those detected in patients with germline variants. A large mutational diversity was identified, with 16 different variants among 17 individuals. Two main patterns of mosaicism (extended vs. myeloid-restricted) were detected, with the last one overrepresented in the late-onset group. The evaluation of mosaicism over time identified three different patterns, being the group with stable mosaicism the largest one. Collected evidence supports the marked similarities among patients carrying somatic or germline NLRP3 variants. The overrepresentation of NLRP3 mosaicism in late-onset forms should be considered in patients with inflammatory manifestations starting in adulthood. Analysis of mosaicism at the biological level confirms the two known patterns of corporal distribution and reveals that mosaicism remains stable over time in most patients, but it may also vary during the course of the disease.

Humans↗
PubMed2006

Mitochondrial DNA involvement in human longevity.

The main message of this review can be summarized as follows: aging and longevity, as complex traits having a significant genetic component, likely depend on a number of nuclear gene variants interacting with mtDNA variability both inherited and somatic. We reviewed the data available in the literature with particular attention to human longevity, and argued that what we hypothesize for aging and longevity could have a more general relevance and be extended to other age-related complex traits such as Alzheimer's and Parkinson's diseases. The genetics which emerges for complex traits, including aging and longevity, is thus even more complicated than previously thought, as epistatic interactions between nuclear gene polymorphisms and mtDNA variability (both somatic and inherited) as well as between mtDNA somatic mutations (tissue specific) and mtDNA inherited variants (haplogroups and sub-haplogroups) must be considered as additional players capable of explaining a part of the aging and longevity phenotype. To test this hypothesis is one of the main challenge in the genetics of aging and longevity in the next future.

Cell Nucleus↗
PubMed1992

The assessment of in vivo somatic mutations in survivors of childhood malignancy.

The assessment of chromosomal mutations in children may provide information about aetiology and risk of second malignancies. A somatic cell mutation assay which determines variant erythrocytes lacking expression of an allelic form of the sialoglycoprotein, glycophorin A, was applied to samples from children before and after receiving potentially genotoxic therapy. Fifty-six children who had received treatment for their malignancy, 15 with malignancy but prior to treatment and 43 control children were assessed for the presence of Nø and NN mutant variant red cells. Control children had mean (s.d.) Nø and NN variant frequencies (Vf) of 9.5 (7.0) and 5.8 (3.3) x 10(6) erythrocytes respectively. Comparison between pre-treatment and control groups demonstrated that prior to chemotherapy, patients with paediatric malignancy do not have mutant frequencies significantly different from the normal population. Children who had received chemotherapy, with or without radiotherapy, showed a significant elevation of both Nø and NN variants over 10 years from the end of treatment. Exposure of children to radiotherapy or known chemical mutagens leads to an increased frequency of variant erythrocytes which is probably the result of in vivo somatic cell mutations. The long term implications have yet to be determined.

Adolescent↗
PubMed1988

Correlation between reversion of a dedifferentiated rat hepatoma line and the recovery of tumorigenicity.

The injection into athymic nude mice of well-differentiated cells of the H4IIEC3 rat hepatoma line leads to tumor take and growth. Animals given injections of cells of a "dedifferentiated" variant subclone, however, do not develop tumors, whereas revertant clones are malignant. Nevertheless, tumors are obtained by increasing the number of injected dedifferentiated cells, and the cells from these tumors do express liver-specific messenger RNAs. Finally, the differentiated state of these tumor cells is stable in vitro. This correlation between the differentiated state of the cells and tumorigenicity is also observed in somatic hybrids between the variant cells and the differentiated ancestors. These hybrids express the hepatic functions and give rise to tumors. The only in vitro character of transformation which distinguishes the two types of cells is anchorage independence of growth. Since two other independent variants develop tumors, it is established that the nonmalignant state is not simply due to the lack of expression of liver-specific traits. There is strong evidence that different mechanisms are responsible for the dedifferentiated state of the two classes of variants, and this supports the hypothesis that the correlation between the dedifferentiated state of the nonmalignant variant and its nontumorigenic phenotype relies on the level of regulation specifically affected in this clone.

Animals↗
PubMed2026

Somatic mutations and genome mosaicism in aging and disease.

Age-related genome mosaicism is an inherent feature of multicellularity and genomic instability. It occurs because of DNA mutations, the accumulation of which leads to diverse genomic landscapes across different tissues. DNA mutations in the genome are consequences of DNA damage, changes in the chemical structure of DNA, such as strand breaks or loss of bases. DNA damage is very frequent and normally repaired quickly. However, errors intrinsic to DNA repair or replication can give rise to permanent changes in genome sequence information. Such DNA mutations are diverse and include single-nucleotide variants, small insertions and deletions, and larger genome structural variants. Since the 1950s, somatic mutations have been proposed to be a major cause of aging. Indeed, somatic mutations are the cause of cancer, the risk of which increases exponentially with age, and possibly other age-related diseases, such as neurodegenerative diseases and cardiomyopathies. Somatic mutations vary from cell to cell owing to the innate stochasticity of their occurrence, from error-prone processing of randomly inflicted DNA damage. With the emergence of single-cell and single-molecule sequencing, it has become possible to quantitatively analyze somatic mutations in human cells and tissues. Here, we discuss a possible causal relationship between mutation-driven mosaicism of the somatic genome and aging-related functional decline and disease by exploring several predictions of the somatic mutation theory of aging.

Humans↗
PubMed2002

[Osteogenesis in healthy children and in children with growth retardation depending on body constitution].

Somatometric and radiographic study of bones of the hand and of the distal forearm was performed in 258 healthy children and adolescents (148 boys and 110 girls) aged 11-17 years and in 115 children (84 boys and 31 girl) aged 13-16 years which were under the observation due to growth retardation. It was shown that within the groups of the same age children with various somatometric characteristics possessed different levels of skeletal (and therefore, biological) maturity. In the group of healthy children, different variants of skeletal maturation were established, which corresponded to the constitutionally stipulated rates of somatic development including accelerated, average and retarded. In children with growth retardation, the third (retarded) variant of somatic development rate was prevalent, which was also found in the group of healthy children and was accompanied with its peculiar osteogenesis characteristics. In the other cases, when such abnormalities of skeletal maturation as asymmetry in the appearance of ossification centers and synostoses as well as the presence of pseudoepiphyses, were observed, growth retardation could be caused by some endocrine pathology. Thus, the radiographic study enables the differentiated approach to the evaluation of the morphological status of children and adolescents and permits to avoid the unjustified administration of hormonal treatment.

Adolescent↗
PubMed2003

Cribriform-morular variant of papillary thyroid carcinoma: a pathological and molecular genetic study with evidence of frequent somatic mutations in exon 3 of the beta-catenin gene.

The cribriform-morular variant (C-MV), an unusual and peculiar subtype of papillary thyroid carcinoma (PTC), has been observed frequently in familial adenomatous polyposis (FAP)-associated thyroid carcinoma and also in sporadic thyroid carcinoma. In this paper, five young women with the C-MV of PTC, aged 22-34 years at cancer diagnosis, are reported; two of them had attenuated FAP. Grossly, one FAP-associated tumour and one sporadic tumour were multicentric and the others were solitary. Histologically, the tumours were encapsulated and exhibited a combination of cribriform, follicular, trabecular, solid, and papillary patterns of growth, with morular areas. Immunohistochemically, the tumour cells showed cytoplasmic expression of thyroglobulin, neuron-specific enolase, epithelial membrane antigen, high- and low-molecular-weight cytokeratins, vimentin, and bcl-2 protein; nuclear expression of oestrogen and progesterone receptors, and retinoblastoma protein; and cytoplasmic and nuclear accumulation of beta-catenin. Germline mutations of the adenomatous polyposis coli (APC) gene were investigated using the protein truncation test in four subjects, including two FAP individuals. Germline APC mutation was identified in only one FAP patient with the multicentric C-MV of PTC, who had a thymidine deletion at codon 512, resulting in a frameshift leading to a premature stop codon. No loss of heterozygosity of loci close to the APC gene was detected in tumour tissues from these four patients. Somatic mutation analysis of exon 3 of the beta-catenin gene (CTNNB1) revealed alterations in seven tumours from all five individuals: one at a serine residue (codon 29), three at amino acids adjacent to serine or threonine residues (codons 22, 39, and 44), and three at other amino acids (codons 49, 54, and 56). Moreover, each of two different tumours examined from two patients with the multicentric C-MV of PTC, had different somatic mutations of the CTNNB1 gene. Taken together, these data suggest that accumulation of mutant beta-catenin contributes to the development of the C-MV of PTC.

Adenocarcinoma, Papillary↗
PubMed1990

Morphologic variants in parents of children with malformation syndromes: are they indicators of somatic mosaicism?

The ostensibly normal parents of 27 probands with recessive or sporadic multiple malformation syndromes were reexamined. By means of careful investigations and anthropometric measurements in nine of them, morphologic variants were found that were compatible with the syndromes and were also observed in the proband. Although other factors should also be considered, the findings may be explained by germline and somatic mosaicism in the parents.

Abnormalities, Multiple↗