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PubMed1987

Cervical mosaic and an integrated pathophysiological approach to early cervical neoplasia.

The increasing concern for the early detection and treatment of cervical intraepithelial neoplasia (CIN) set up the basis for this study, which also considers some epidemiological factors which seem to be related to the genesis of an abnormal uterine cervical colposcopic pattern, the mosaic pattern. We have observed that women with a mosaic pattern show an increasing frequency of premalignant and/or malignant histologic changes up to 40 years of age which then falls abruptly. Sterility and hirsutism were frequent associations, these features suggesting an abnormal hormonal status. An association with infection by Gardnerella vaginalis (15.3%) was noted, and dysplasia increased in frequency to 53% when G. vaginalis was associated with mosaic. Also, 67.25% of women with mosaic showed other concomitant diseases of allergic, immunologic, or infectious type. Based upon these observations, and in an attempt to explain further interrelationships among several factors in the pathogenesis of CIN, an integrated hypothesis which may lead to new therapeutic avenues, both in the prevention and treatment of early cervical cancer, is advanced.

Adolescent↗

PubMed1993

The mosaic of midget ganglion cells in the human retina.

To study their detailed morphology, ganglion cells of the human retina were stained by intracellular tracer injection, in an in vitro, whole-mount preparation. This report focuses on the dendritic morphology and mosaic organization of the major, presumed color-opponent, ganglion cell class, the midget cells. Midget cells in the central retina were recognized by their extremely small dendritic trees, approximately 5-10 microns in diameter. Between 2 and 6 mm eccentricity, midget cells showed a steep, 10-fold increase in dendritic field size, followed by a more shallow, three- to fourfold increase in the retinal periphery, attaining a maximum diameter of approximately 225 microns. Despite large local variation in dendritic field size, midget cells formed one morphologically distinctive class at all retinal eccentricities. Two midget cell types were distinguished by their dendritic stratification in either the inner or outer portion of the inner plexiform layer (IPL), and presumably correspond to ON- and OFF-center cells respectively. The mosaic organization of the midget cells was examined by intracellularly filling neighboring cells in small patches of retina. For both the inner and outer midget populations, adjacent dendritic trees apposed one another but did not overlap, establishing a coverage of no greater than 1. The two mosaics differed in spatial scale, however: the outer midget cells showed smaller dendritic fields and higher cell density than the inner midget cells. An outer:inner cell density ratio of 1.7:1 was found in the retinal periphery. An estimate of total midget cell density suggested that the proportion of midget cells increases from about 45% of total ganglion cell density in the retinal periphery to about 95% in the central retina. Nyquist frequencies calculated from midget cell spacing closely match a recent measure of human achromatic spatial acuity (Anderson et al., 1991), from approximately 6 degrees to 55 degrees eccentricity. Outside the central retina, midget cell dendrites arborized in clusters within the overall dendritic field. With increasing eccentricity, the dendritic clusters increased in number and remained small (approximately 10-20 microns diameter) relative to the size of the dendritic field. Because neighboring midget cell dendritic trees do not overlap, the mosaic as a whole showed a pattern of clusters and holes. We hypothesize that midget cell dendritic trees may contact individual axon terminals of some midget bipolar cells and avoid contacting others, providing a basis for the formation of cone-specific connections in the IPL.

Color Perception↗

PubMed1996

Development of photoreceptor mosaics in the primate retina.

The mosaic of rods and cones in the primate retina is the neuronal array where the visual world is first mapped onto the central nervous system. Rods, which mediate scotopic vision, and cones, which mediate photopic and color vision, are found in all vertebrate species. However, regional differences in the topographic arrangement and ratio of rods to cones vary dramatically among species, including different primates. Furthermore, the proportion and distribution of the wavelength-sensitive cone subtypes vary considerably between primates that occupy different visual habitats. What genetic or environmentally regulated mechanisms specify the position, phenotype, and ratios of photoreceptor subtypes? Available data suggest that the transient appearance of early-differentiating cones may serve to delineate basic species-specific retinal coordinates and determine the opsin phenotype of local assemblies of cones in the fetal photoreceptor mosaic. This article will summarize presently available data and our ideas of how the photoreceptor mosaic is organized in the adult primate retina, the features of these mosaics, which vary between primate species, and the developmental mechanisms, which may account for the emergence of photoreceptor position and specification of their phenotypes in the primate retina.

Animals↗

PubMed1993

Tobamovirus helper specificity of satellite tobacco mosaic virus involves a domain near the 5' end of the satellite genome.

The molecular basis of the interactions between plant virus satellites and their helper viruses is not understood. The features of the satellite tobacco mosaic virus (STMV) genome that determine tobamovirus helper specificity were investigated using two independent strategies. The first tested the possible significance of regions of nearly identical sequence within the 3'-terminal 150 bases of the genomes of STMV and its natural helper virus, tobacco mild green mosaic virus (TMGMV). A chimeric STMV clone containing the 3' terminus of tobacco mosaic virus (TMV-U1) RNA was infectious in coinfections with TMGMV, but it did not replicate with TMV-U1. In the second strategy, populations of STMV adapted to replication with four alternative helper tobamoviruses were generated by serial passage in tobacco. RNase protection analyses of these RNA populations showed that in all cases there had been a genetic change 50 to 60 bases from the 5' terminus of the STMV genome. Similar changes were detected in several progenies of STMV clones replicated with TMV-U1, indicating that change at this site was essential for replication with a helper virus other than TMGMV. Sequence analyses of the changes at this 'helper adaptation domain' showed consistently the deletion of a single G from five consecutive Gs at bases 61 to 65. Infectivity experiments with STMV clones containing this G deletion showed that this change alone was not sufficient to modify helper specificity, so additional factors which remain to be identified must also be involved. Nevertheless, these experiments show the ability of STMV populations to undergo rapid, reproducible evolution by both selection of pre-existing variants and de novo mutation, and constitute the first molecular demonstration that the helper virus acts as a selection pressure on the evolution of satellite populations.

Amino Acid Sequence↗

PubMed1964

TOBACCO MOSAIC VIRUS: CYTOLOGICAL EVIDENCE OF THE SYNTHESIS IN THE NUCLEUS.

Living tomato hair cells were directly injected with tobacco mosaic virus or tobacco mosaic virus RNA with a fine glass needle. Use of a fluorescent tobacco mosaic virus antibody showed the presence of the virus protein in the nucleus 6 to 18 hours after the injection. As time of infection progressed, staining of the cytoplasm became more prominent.

Cell Nucleus↗

PubMed2024

A healthy live birth after mosaic blastocyst transfer in preimplantation genetic testing for GATA1-related cytopenia combined with HLA matching.

BACKGROUND: GATA1-related cytopenia (GRC) is characterized by thrombocytopaenia and/or anaemia ranging from mild to severe. Haematopoietic stem cell transplantation (HSCT) is a healing therapeutic choice for GRC patients. We identified a novel pathogenic variant (GATA1: c.1019delG) in a boy with GATA1-related cytopenia. Then we performed preimplantation genetic testing (PGT) in this GRC family. After a mosaic embryo transfered, a healthy and HLA-compatible with the proband baby was delivered. CASE PRESENTATION: The proband is a 6-year-old boy who was diagnosed to have transfusion-dependent anaemia since 3 year old. Whole-exome sequencing (WES) showed that the proband has a hemizygous variant c.1019delG in GATA1, which is inherited from his mother. His parents decided to undergo PGT to have a health and HLA-compatible offspring. After whole genome amplification (WGA) of biopsied trophectoderm (TE) cells, next generation sequencing (NGS)-based PGT was preformed to analyse embryos on chromosomal aneuploidy, target mutation and HLA typing. There were 3 embryos HLA-matched to the proband. The genotypes of the 3 embryos were heterozygous variant, hemizygous variant, normal respectively. After a heterozygous, mosaic partial trisomy (chr)16, and HLA-matched embryo transfer, a healthy baby was delivered and whose HSCT is compatible with the proband. CONCLUSIONS: NGS-based PGT-HLA is a valuable procedure for the treatment of GATA1-related cytopenia caused by GATA1 variants, or other haematological disorders, oncological and immunological diseases. Furthermore, our study reconfirms that mosaic embryos transfer would bring healthy offspring.

Child↗

PubMed2001

Phenotypic heterogeneity in bullous congenital ichthyosiform erythroderma: possible somatic mosaicism for keratin gene mutation in the mildly affected mother of the proband.

BACKGROUND: Bullous congenital ichthyosiform erythroderma (BCIE) shows phenotypic variability. An epidermal nevus may represent somatic mosaicism for keratin gene mutation, which produces generalized BCIE in the next generation. This fact provides evidence that a postzygotic mutation can be passed on to the next generation in BCIE. We hypothesized that the same phenomenon occurred in a family with BCIE whose phenotypes were extremely different. OBSERVATIONS: We studied a 19-year-old boy with severe ichthyosiform erythroderma and prominent palmoplantar hyperkeratosis with digital contracture. In contrast, the proband's mother exhibited only mild ichthyosiform skin, granular verrucous lesions, and less severe streaky palmoplantar hyperkeratosis. Mutation analysis in the proband showed a keratin K1 mutation (N187S, ie, an A-to-G transition at the second position of codon 187, resulting in an asparagine-to-serine substitution). In the mother, the same keratin gene mutation was recognized, but only faintly in the leukocyte DNA, indicating that the amount of the mutated allele in leukocyte DNA was very low compared with that from the proband. CONCLUSIONS: We speculate that the mildly affected mother showed keratin 1 gene mosaicism, and that the BCIE phenotype had been transmitted in a severe form through a mechanism that passes the keratin gene mutation to the next generation. These results suggest that mild forms of BCIE may actually represent extensive epidermal nevi/keratin gene mosaicism.

Adolescent↗

PubMed2006

The role of X inactivation and cellular mosaicism in women's health and sex-specific diseases.

Sex-specific manifestations of disease are most often attributed to differences in the reproductive apparatus or in life experiences. However, a good deal of sex differences in health issues have their origins in the genes on the sex chromosomes themselves and in X inactivation-the developmental program that equalizes their expression in males and females. Most females are mosaics, having a mixture of cells expressing either their mother's or father's X-linked genes. Often, cell mosaicism is advantageous, ameliorating the deleterious effects of X-linked mutations and contributing to physiological diversity. As a consequence, most X-linked mutations produce male-only diseases. Yet, in some cases the dynamic interactions between cells in mosaic females lead to female-specific disease manifestations.

Autoimmune Diseases↗

PubMed1996

Trisomy 15 mosaicism and uniparental disomy (UPD) in a liveborn infant.

We describe a liveborn infant with uniparental disomy (UPD) with trisomy 15 mosaicism. Third trimester amniocentesis yielded a 46,XX/47,XX,+15 karyotype. Symmetrical growth retardation, distinct craniofacies, congenital heart disease, severe hypotonia and minor skeletal anomalies were noted. The infant died at 6 weeks of life. Peripheral lymphocyte chromosomes were "normal" 46,XX in 100 cells. Parental lymphocyte chromosomes were normal. Skin biopsy showed 47,XX,+15 in 80% of fibroblasts and results were equivalent in fibroblasts from autopsy lung tissue. Molecular analysis revealed maternal uniparental heterodisomy for chromosome 15 in the 46,XX cell line. We describe an emerging phenotype of trisomy 15 mosaicism, confirm that more than one tissue should be studied in all cases of suspected mosaicism, and suggest that UPD be considered in all such cases.

Abnormalities, Multiple↗

PubMed1996

Mosaic vs. nonmosaic trisomy 9: report of a liveborn infant evaluated by fluorescence in situ hybridization and review of the literature.

We report on a newborn infant with multiple congenital anomalies and apparent nonmosaic trisomy 9 in the blood (by conventional cytogenetic studies) who died shortly after birth. Clinical observations at birth and autopsy are compared with phenotypes of mosaic and nonmosaic trisomy 9 cases reported previously. Unlike the initial cytogenetic analysis, fluorescence in situ hybridization (FISH) studies of metaphase and interphase blood cells and skin fibroblasts detected the presence of euploid and trisomy 9 cells. These results suggest that earlier reports of trisomy 9, which relied on conventional chromosome analysis of a few metaphase cells and/or only one tissue type, may not have excluded mosaicism, and that trisomy 9 may be viable only in the mosaic state.

Abnormalities, Multiple↗

PubMed1996

The fragile X phenotype in a mosaic male with a deletion showing expression of the FMR1 protein in 28% of the cells.

The instability of the CGG repeat region of FMR1 is not restricted to the CGG repeat but expands to flanking sequences as well. A mosaic fragile X male is reported with a deletion of part of the CGG repeat and 30 bp immediately 3' of the repeat, thus confirming the presence of a hotspot for deletions in the CGG region of FMR1. The deletion, detected in 28% of his lymphocytes, did not impair the transcription and translation of FMR1, suggesting that regulatory elements are not present in the deleted region. The patient has the characteristic fragile X phenotype and assuming that the mosaic pattern detected in the lymphocytes reflects the mosaic pattern in brain, 28% expression of FMRP may not be sufficient for normal cognitive functioning.

Aged↗

PubMed1996

A fragile X mosaic male with a cryptic full mutation detected in epithelium but not in blood.

Individuals with developmental delay who are found to have only fragile X premutations present an interpretive dilemma. The presence of the premutation could be an unrelated coincidence, or it could be a sign of mosaicism involving a full mutation in other tissues. To investigate three cases of this type, buccal epithelium was collected on cytology brushes for Southern blot analysis. In one notable case, the blood specimen of a boy with developmental delay was found to have a premutation of 0.1 extra kb, which was shown by PCR to be an allele of 60 +/- 3 repeats. There was no trace of a full mutation. Mosaicism was investigated as an explanation for his developmental delay, although the condition was confounded by prematurity and other factors. The cheek epithelium DNA was found to contain the premutation, plus a methylated full mutation with expansions of 0.9 and 1.5 extra kb. The three populations were nearly equal in frequency but the 1.5 kb expansion was the most prominent. Regardless of whether this patient has clinical signs of fragile X syndrome, he illustrates that there can be gross tissue-specific differences in molecular sub-populations in mosaic individuals. Because brain and epithelium are more closely related embryonically than are brain and blood, cryptic full mutations in affected individuals may be evident in epithelial cells while being absent or difficult to detect in blood. This phenomenon may explain some atypical cases of the fragile X phenotype associated with premutations or near-normal DNA findings.

Adult↗

PubMed1996

Trisomy 7 CVS mosaicism: pregnancy outcome, placental and DNA analysis in 14 cases.

Prenatal diagnosis by chorionic villus sampling (CVS) documents placental chromosomal mosaicism in approximately 2% of viable pregnancies at 9-12 weeks of gestation and can involve various chromosomes and placental cell lineages. Confined placental mosaicism (CPM) is the result of postzygotic mitotic errors occurring in either diploid or trisomic zygotes. With trisomic zygote rescue, depending on the parental origin of the chromosome which is lost, uniparental disomy (UPD) or biparental disomy (BPD) may arise [Kalousek et al., Am J Hum Genet 52: 8-16, 1993]. In this paper, we present 14 pregnancies which were diagnosed by CVS as mosaic trisomy 7. All follow-up amniocenteses showed a normal diploid karyotype. Using both classical cytogenetics and interphase analysis, studies of term placentae showed variable levels of trisomy 7. DNA analysis was performed in nine cases to determine whether the diploid fetus had BPD 7 or UPD 7. Fetal UPD 7 was present only in one case; in eight other cases biparental inheritance was demonstrated. DNA analysis to establish the origin of trisomy 7 in the placenta was fully informative in six cases. One trisomy resulted from a meiotic error and was associated with fetal UPD 7, while the rest were somatic in origin. It is difficult to compare the effect of CPM for trisomy 7 to other trisomies confined to the placenta, as for most chromosomes there are few available cases. It appears that intrauterine fetal growth is not greatly affected by the presence of a trisomy 7 cell line in the placenta. This finding is in contrast to the serious effect of high levels of trisomy 16 within the placenta on fetal intrauterine growth in a series of well-documented cases of CPM 16 [Kalousek et al. 1993].

Chorionic Villi Sampling↗

PubMed1996

Familial ring (19) chromosome mosaicism: case report and review.

Ring (19) chromosomal mosaicism has been identified in a 14-month-old girl referred for cytogenetic evaluation due to microcephaly and developmental delay with autistic-like mannerisms. An analysis of her peripheral blood lymphocytes showed a 46,XX,r(19) cell line in 119/121 of cells examined. Of the two remaining cells, one had a normal female chromosome complement and the other showed loss of one of the chromosome 19 homologs. Further analysis by fluorescence in situ hybridization using an all human telomere probe showed the presence of a single hybridization signal on the r(19) chromosome. Subsequent cytogenetic characterization of cells derived from the patient's phenotypically normal mother also demonstrated the presence of a ring 19 chromosome in 4/100 cells. The remaining cells had a normal female chromosome complement. These findings represent the first reported case of familial ring 19 mosaicism. The cytogenetic and clinical findings in these two individuals are discussed in relation to six previously reported cases of de novo ring chromosome 19 mosaicism.

Adult↗

PubMed1997

Mosaicism for deletion 1p36.33 in a patient with obesity and hyperphagia.

We report on a 4-year-old girl with obesity and hyperphagia whose peripheral blood cytogenetic analysis showed mosaicism for a deletion of band 1p36.33. Terminal 1p deletions are rarely reported and this patient represents the first identified case of mosaicism. Given the subtlety of the cytogenetic abnormality and the possibility of mosaicism, the incidence of such deletions has probably been underestimated. While a characteristic phenotype associated with this karyotypic abnormality was described recently, the present report highlights the additional clinical findings of obesity and hyperphagia and the overlap of manifestations with Prader-Willi syndrome.

Child, Preschool↗

PubMed1997

Cytogenetic analysis of spontaneous abortions: comparison of techniques and assessment of the incidence of confined placental mosaicism.

Cytogenetic studies on spontaneous abortions traditionally have used one of two methodologies, direct preparations or long-term culture, to determine the chromosome constitution of either the cytotrophoblast or villous stroma, respectively. Few studies have utilized both techniques simultaneously to compare the relative efficiencies of each method and to assess the contribution of confined placental mosaicism (CPM). The present report summarizes cytogenetic studies on 691 consecutive spontaneous abortions using long-term culture, direct preparations, or both. All 691 cases were analyzed by long-term culture and 177 cases were analyzed using both long-term culture and direct preparations. The results indicate that the two methods have similar success rates, 82% for long-term culture and 76% for direct preparation; however, the proportion of normal females was significantly increased in the culture method, presumably attributable to maternal contamination. In 107 cases, results were obtained from both methods with 22 discrepancies identified. However, most of these involved a 46,XX result in culture, consistent with maternal contamination in the cultured preparation. Therefore, to estimate the proportion of CPM we excluded cases with a 46,XX result in culture and found four (6.1%) of the remaining 65 cases to be consistent with CPM. These cases consisted of normal or mosaic aneuploid cytotrophoblast and non-mosaic aneuploid villous stroma. These studies suggest that each method has specific advantages in the analysis of spontaneous abortions. Direct preparations are less prone to maternal contamination, but certain chromosome abnormalities are more likely to be identified using long-term culture.

Abortion, Spontaneous↗

PubMed1997

True trisomy 2 mosaicism in amniocytes and newborn liver associated with multiple system abnormalities.

Among 58,000 amniocenteses completed, our laboratories found one case of true cytogenetic trisomy 2 mosaicism in a fetus with multiple abnormalities. In contrast, 11 fetuses phenotypically normal at birth were found to have true trisomy 2 mosaicism in their chorionic villus cells among the 10,500 fetuses tested by chorionic villus sampling (CVS). In our single abnormal case, amniocentesis performed at 19 weeks after finding an elevated maternal serum AFP found two independent cultures with trisomy 2 karyotypes in 8 of 25 and 7 of 31 amniocytes, respectively. Although oligohydramnios was noted by ultrasound, the mother elected to continue the pregnancy. At 26 weeks the fetus had intrauterine growth retardation (IUGR), hydronephrosis, and cardiac abnormalities. When delivered by Cesarean section at 30 weeks, the infant had multiple anomalies and developed necrotizing enterocolitis and severe cholestasis. At 5 months coronal magnetic resonance imaging (MRI) displayed delayed myelination and abnormal brain morphology. The patient also exhibited significant growth failure and developmental delay. Although chromosomes were normal in blood, skin fibroblasts, and ascites fluid cells, 4 of 100 hepatic biopsy fibroblasts were 47,XY,+2. Molecular analysis excluded uniparental disomy (UPD) of chromosome 2 in the 46,XY cell line. This and other reports of rare phenotypically abnormal trisomy 2 mosaic fetuses identified by karyotyping amniocytes emphasizes the substantially higher fetal risk of abnormal development than when trisomy 2 is found only in chorionic villus cells.

Abnormalities, Multiple↗

PubMed1997

Complex congenital heart malformations in mosaic tetrasomy 8p: case report and review of the literature.

We describe a 5-month-old boy with complex congenital heart defects (dTGA, DORV, VSD, ASD, and PDA), minor facial and ear anomalies, deep palmar creases, multiple vertebral anomalies, agenesis of the corpus callosum, and mosaic tetrasomy 8p (47,XY,+i(8)(p10)[88%]/46,XY[12%] in blood with normal chromosomes in cultured skin fibroblasts. This infant represents the eleventh reported case of mosaic tetrasomy 8p since its first description by Kristofferson et al. [1988: Clin Genet 34:201-203]. The pattern of heart malformations and discordance of blood and fibroblast karyotypes make our case unique. Our report and review suggest that an important distinction between mosaic tetrasomy 8p and other chromosome 8 aneuploidies involves the increased incidence and complexity of congenital heart malformations.

Aneuploidy↗