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PubMed2004

45,X/47,XXX/47,XX, del(Y)(p?)/46,XX mosaicism causing true hermaphroditism.

Sex differentiation in humans depends on the presence of the Y-linked gene SRY, which is activated in the pre-Sertoli cells of the developing gonadal primordium to trigger testicular differentiation. Occasionally testicular formation can take place in subjects lacking a Y chromosome resulting in a 46,XX sex reversal condition. True hermaphroditism (TH) is a rare form of intersexuality characterized by the presence of testicular and ovarian tissue in the same individual. Genetic heterogeneity has been proposed as a cause of dual gonadal development in some cases and recently, hidden mosaicism was reported to cause TH in some 46,XX SRY negative patients. Here we report a TH case in which hidden mosaicism for the Y and X chromosome was detected by PCR and FISH in peripheral blood and gonadal tissue, supporting the fact that mosaicism may cause TH and that molecular analysis of gonadal tissue should be performed in all 46,XX cases.

Child↗
PubMed2005

Recurrence of Fabry disease as a result of paternal germline mosaicism for alpha-galactosidase a gene mutation.

We present two sisters with a severe form of Fabry disease, who both carry the same mutation in the alpha-galactosidase A (alpha-gal A) gene (Q330X). Each of the sisters developed renal failure in the third decade of life; the older sibling underwent renal transplantation at 40 years of age. The severe phenotype of the siblings correlates with results of the X-inactivation study: examination of methylation status in human androgene receptor (HUMARA) gene suggests preferential inactivation of the wild-type allele in both patients. Patients' parents had no symptoms of Fabry disease and were tested negative for the mutation Q330X in DNA isolated from peripheral leukocytes, mouth wash cells, and urinary sediment cells. Genotype analysis using DXS7424 marker showed paternal origin of the mutation. The father's sperm was then tested for presence of the mutation to examine the possibility of the germline mosaicism. Both mutant and wild-type alleles were found in DNA isolated from father's sperm. The apparent explanation of these findings is germline mosaicism due to mutation event during the embryonic development of sperm producing cells (spermatogonia). This is the first case of germline mosaicism in Fabry disease reported in the literature.

Adult↗
PubMed2005

Monozygotic twins concordant for blood karyotype, but phenotypically discordant: a case of "mosaic chimerism".

We report on 23 years old discordant monozygotic (MZ) twins, one with minor anomalies and mental delay, the other one being normal. Both had 46,XX,dup(11)(p12p15)/46,XX mosaicism in blood, with a similar proportion of abnormal cells (respectively, 16% and 17%). However, interphase fluorescence in situ hybridization (FISH) analysis performed on buccal smear and urinary sediment using specific probes located at the duplicated region showed that mosaicism was only present in the abnormal twin, with 68% abnormal cells. We hypothesize that the postzygotic chromosomal rearrangement may have occurred early in one embryo after the twinning event, and the blood mosaicism observed in both twins would have resulted from blood exchanges via placental anastomoses. This hypothesis of chimerism is strongly supported by twin-to-twin transfusion syndrome observed during fetal life of our twins. This case and those previously reported lead us to suggest that blood is particularly unsuitable for cytogenetic investigations of twins.

Adult↗
PubMed2005

Identification of high frequency of Y chromosome deletions in patients with sex chromosome mosaicism and correlation with the clinical phenotype and Y-chromosome instability.

A mosaic karyotype consisting of a 45,X cell line and a second cell line containing a normal or an abnormal Y chromosome is relatively common and is associated with a wide spectrum of clinical phenotypes. The aim of this study was to investigate patients with such a mosaic karyotype for Y chromosome material loss and then study the possible association of the absence of these regions with the phenotype, diagnosis, and Y-chromosome instability. We studied 17 clinically well-characterized mosaic patients whose karyotype consisted of a 45,X cell line and a second cell line containing a normal or an abnormal Y chromosome. The presence of the Y chromosome centromere was verified by fluorescence in situ hybridization (FISH) and was then characterized by 44 Y-chromosome specific-sequence tagged site (STS) markers. This study identifies a high frequency of Yq chromosome deletions (47%). The deletions extend from interval 5 to 7 sharing a common deleted interval (6F), which overlaps with the azoospermia factor region (AZF) region. This study finds no association between Y-chromosome loci hosting genes other than SRY, and the phenotypic sex, the diagnosis, and the phenotype of the patients. Furthermore, this study shows a possible association of these deletions with Y-chromosome instability.

Cell Line↗
PubMed2005

Trisomy 10 mosaicism and maternal uniparental disomy 10 in a liveborn infant with severe congenital malformations.

We report on a liveborn infant with trisomy 10 mosaicism combined with maternal uniparental heterodisomy for chromosome 10. The mosaicism 47,XY,+10/46,XY was found in five different tissues, including one blood sample, while cultured lymphocytes from two other blood samples showed a normal karyotype, 46,XY. DNA analysis with six PCR-based microsatellite markers demonstrated the trisomic cell line to be a result of maternal meiotic nondisjunction, and revealed maternal uniparental heterodisomy in the diploid cell line, suggesting that the formation of the diploid cell line was due to trisomy rescue. The boy had severe growth retardation, major dysmorphism, and malformations, and died at 37 days. We reviewed the previous nine reports of infants and fetuses with trisomy 10 mosaicism reported in the literature. We suggest that a common clinical syndrome can be defined comprising skull, jaw and ear abnormalities, cleft lip/palate, malformations of eyes, heart and kidneys, deformity of hands and feet, and most often death neonatally or in early infancy. The cytogenetic findings in the present patient demonstrate the importance of karyotyping more than one tissue, and not only lymphocytes, when a chromosomal aberration is strongly suspected.

Abnormalities, Multiple↗
PubMed2007

A girl with neurofibromatosis type 1, atypical autism and mosaic ring chromosome 17.

We describe a girl with neurofibromatosis type 1 (NF1), mild dysmorphic features, growth and mental retardation, autism, and mosaicism of ring chromosome 17 and chromosome 17 monosomy. The extent of genetic material deleted from the ring chromosome was determined using a combination of classical cytogenetics, fluorescence in situ hybridization (FISH) and multiplex ligation-dependent probe amplification (MLPA) to be 0.6-2.5 Mb on 17p, and up to about 10 Mb on 17q. Based on our observations and on a review of the literature we argue that in addition to a universal "ring syndrome" which is based on ring instability and is less specific for the chromosome involved, various ring chromosomes underlie their own characteristic phenotypes. We propose that the symptoms leading to the diagnosis of NF1 in our patient could be attributed to mosaic hemizygosity for the NF1 gene in some of her somatic cells. A similar mechanism or a direct involvement of respective disease genes in the aberration could possibly influence also the development of autism and other symptoms. We raise a question if the loss of one copy of chromosome 17 from a substantial fraction of somatic cells can have specific consequences also for future risks of the patient, for example, due to the mosaic hemizygosity for the BRCA1 and TP53 genes.

Autistic Disorder↗
PubMed2001

Mutation of the doublecortin gene in male patients with double cortex syndrome: somatic mosaicism detected by hair root analysis.

The molecular basis of double cortex syndrome was investigated in 2 male patients. Magnetic resonance imaging of the patients' heads showed diffuse subcortical band heterotopia, as is seen in female patients. We found a heterozygous mutation for Asp50Lys or Arg39Stop in both patients. Microsatellite polymorphism analysis revealed that both patients had inherited a single X chromosome from their mothers. Restriction enzyme analysis using DNA extracted from the hair roots of each patient showed four different patterns in the combination of cells carrying wild and mutant alleles, which strongly suggest somatic mosaicism. We conclude that somatic mosaic mutations in the doublecortin gene in male patients can cause subcortical band heterotopia, and that molecular analysis using hair roots is a useful method for detecting somatic mosaicism.

Cerebral Cortex↗
PubMed1996

Somatic mosaicism in the central nervous system in spinocerebellar ataxia type 1 and Machado-Joseph disease.

Spinocerebellar ataxia type 1 and Machado-Joseph disease are two autosomal dominant cerebellar ataxias caused by expansions of unstable CAG repeats in the coding region of the causative genes. The selectivity of cell death and the resulting characteristic neuropathological features in each of these diseases are not explained by the gene expression patterns. Since the repeat size correlates with age at onset and severity of these diseases, somatic mosaicism, the result of mitotic instability of the CAG repeat, could be the basis for specificity of neurodegeneration; brain structures with larger expanded repeats would be more severely affected. To study the association between neuropathological changes and somatic mosaicism of the CAG repeat size in the central nervous system of patients with these two ataxias, we determined the size of the (CAG)n expansion in 20 different regions of the brain, brainstem, cerebellum, and spinal cord from 3 patients with spinocerebellar ataxia type 1 and 3 with Machado-Joseph disease; these regions were selected for their differential neuropathological involvement in the two disorders. We observed a considerable homogeneity of repeat size ranges in all but 1 of the 20 regions examined: The cerebellar cortex showed slightly smaller (CAG)n tracts in all specimens from both groups of patients. Our results suggest that the pattern of repeat size mosaicism, similar in spinocerebellar ataxia type 1 and Machado-Joseph disease, reflects the developmental pathways and cell composition of different central nervous system regions and is not the cause of selective cell death in these disorders.

Age of Onset↗
PubMed1988

Androgen receptor-deficient Tfm cells in the mosaic epididymis of sex-reversed mice heterozygous for Tfm: an autoradiographic study with [3H]-dihydrotestosterone and [3H]-estradiol.

Testicular feminization (Tfm) in the mouse is characterized by androgen insensitivity of the target cells. We describe the presence of androgen-insensitive Tfm cells in the epididymis of mosaic mice produced by converting female carriers of the Tfm mutation (XTfm/X+) to males via the sex reversal factor (Sxr). The mosaic arises by random X-inactivation. In the epididymal duct, flat undifferentiated Tfm cells are interspersed between high columnar wild-type cells. By thaw-mount autoradiography we show that after injection of [3H]dihydrotestosterone, radioactivity is concentrated in the nuclei of high columnar wild-type cells, whereas the nuclei of the low cuboid Tfm cells remain free of nuclear radioactivity. After injection of [3H]estradiol, both Tfm and wild-type cells show nuclear labeling. Our observations demonstrate that Tfm cells in the mosaic epididymis selectively lack nuclear dihydrotestosterone-binding sites, whereas estradiol-binding sites are intact.

Androgen-Insensitivity Syndrome↗
PubMed2005

Somatic mosaicism of CIAS1 in a patient with chronic infantile neurologic, cutaneous, articular syndrome.

Chronic infantile neurologic, cutaneous, articular syndrome (CINCA syndrome) is a severe inflammatory disease that was recently found to be associated with mutations in CIAS1. However, CIAS1 mutations have been detected in only half of CINCA syndrome patients, and it remains unclear which genes are responsible for the syndrome in the remaining patients. We describe here a patient with CINCA syndrome who exhibited CIAS1 somatic mosaicism. We genetically analyzed the CIAS1 gene in various blood cells and the buccal mucosa of the patient. The production of interleukin-1beta (IL-1beta) by peripheral blood mononuclear cells (PBMCs) was measured by enzyme-linked immunosorbent assay, and the ability of the mutant CIAS1 gene to enhance ASC-dependent NF-kappaB activation was assessed to confirm that the mutations of CIAS1 found were responsible for the patient's clinical manifestations of the CINCA syndrome. The patient had 1 heterologous single-nucleotide polymorphism, 587G>A (S196N), and 1 heterologous mutation, 1709A>G (Y570C), in exon 3 of CIAS1. The latter mutation was found to occur as somatic mosaicism. The patient's PBMCs produced a large amount of IL-1beta in the absence of stimulation, unlike those from controls or from his mother, who also bore the S196N polymorphism. In addition, the Y570C mutation (with or without the S196N polymorphism) increased the ability of CIAS1 to induce ASC-dependent NF-kappaB activation, unlike the wild-type gene or the gene bearing the S196N polymorphism alone. The findings in this patient indicate that somatic mosaicism is one reason CIAS1 mutations have not been detected in some patients with CINCA syndrome.

Adolescent↗
PubMed2003

Determinants of the exclusion zone in dopaminergic amacrine cell mosaics.

A fundamental organizing feature of the retina is the presence of regularly spaced distributions of neurons, yet we have little knowledge of how this patterning emerges during development. Among these retinal mosaics, the spatial organization of the dopaminergic amacrine cells is unique: using nearest-neighbor and Vornoi domain analysis, we found that the dopaminergic amacrine cells were neither randomly distributed, nor did they achieve the regularity documented for other retinal cell types. Autocorrelation analysis revealed the presence of an exclusion zone surrounding individual dopaminergic amacrine cells and modeling studies confirmed this organization, as the mosaic could be simulated by a minimal distance spacing rule defined by a broad set of parameters. Experimental studies determined the relative contributions of tangential dispersion, fate determination, and cell death in the establishment of this exclusion zone. Clonal boundary analysis and simulations of proximity-driven movement discount tangential dispersion, while data from bcl-2 overexpressing mice rule out feedback-inhibitory fate-deterministic accounts. Cell death, by contrast, appears to eliminate dopaminergic amacrine cells that are within close proximity, thereby establishing the exclusion zone surrounding individual cells and in turn creating their mosaic regularity.

Amacrine Cells↗
PubMed1988

Glycoconjugate boundaries during early postnatal development of the neostriatal mosaic.

The dispositions of galactosyl-containing glycoconjugates were studied during postnatal development of the caudate putamen in mice. The binding of the lectin peanut agglutinin, which has an affinity for galactosyl B-1,3 N-acetylgalactosamine residues, was compared to acetylcholinesterase staining and tyrosine hydroxylase immunoreactivity in the immature and adult neostriatum. The binding of peanut agglutinin conjugated to horseradish peroxidase, in sections that were processed for peroxidase histochemistry, was extremely pronounced in the neostriatum through the first postnatal week and constituted ringlike or polygonally shaped structures, which, overall, produced a variegated mosaic. These structures consist of outer rims of dense lectin-associated reaction product surrounding lightly labeled centers. Lectin delineations of the neostriatal mosaic are no longer visible in the second postnatal week. When adjacent sections were processed for lectin binding or acetylcholinesterase histochemistry, the dense lectin binding sites represented borders of acetylcholinesterase-rich and -poor zones. The distribution of dense patches of tyrosine hydroxylase immunoreactive fibers and terminals also coincides with the acetylcholinesterase-rich zones during the same times, and thus the glycoconjugate-delineated boundaries can also be directly compared with the distribution of nigrostriatal dopaminergic projections. The findings presented here represent the first demonstration of a probe that recognizes apparent borders of neostriatal compartments during a limited period of development. They are consistent with previous observations made on transient glycoconjugate "hidden boundaries" during development of other central nervous system structures, including the somatosensory cortical barrel field, and thalamic and brainstem nuclei (Cooper and Steindler, '86a,b; Steindler and Cooper, in press). In those studies, glia were shown to be the major source of glycoconjugate-associated patterns, and thus, glia and glycoconjugates that they synthesize during pattern formation events may be involved in the formation and stabilization of neurochemically distinct components of the neostriatal mosaic.

Acetylcholinesterase↗
PubMed1995

Genetic mosaic analysis of the equatorial-less mutation in Drosophila melanogaster.

eql (equatorial-less) is a recessive lethal mutation on the second chromosome of Drosophila melanogaster. J. Campos-Ortega found that eql clones in somatic mosaic flies have reduced numbers of photoreceptor cells, and he suggested that only the R1, R6, and R7 photoreceptor cells were missing in this mutant. These photoreceptor cells help to define the inverted orientation of ommatidial facets along the equatorial midline of the fly eye, hence the mutation was named "equatorial-less." We have conducted a detailed analysis of the eql mutation, by serial section reconstruction of eql clones marked with bw- or w- in somatic mosaic flies. We found that all photoreceptor cell types (R1-R8) could be deleted by the eql mutation, and in rare cases the number of photoreceptor cells was increased. The apparent lack of photoreceptor cell type specificity was confirmed by our analysis of genetically mosaic facets, which indicated that no single photoreceptor cell, or subset of photoreceptor cells, was uniquely required to express eql+. Rather, eql appears to function in all photoreceptor cells, and possibly in all eye precursor cells. The distribution of photoreceptor cell numbers in w eql facets was consistent with the hypothesis that each photoreceptor cell was deleted independently of the others. The eql gene is located on the right arm of chromosome 2 at map location 2-104.5 +/- 0.7 and lies between the polytene chromosome bands 59D8 and 60A7.

Animals↗
PubMed1998

Mosaic genes and their role in penicillin-resistant Streptococcus pneumoniae.

Penicillin resistance in clinical isolates of Streptococcus pneumoniae is mediated by mosaic genes encoding altered penicillin binding proteins. Mosaic sequence blocks are the result of a genetic exchange between related streptococcal species. It is likely that resistance has emerged in commensal streptococci before being transferred into the pneumococcus. Closely related mosaic genes are found in different pneumococcal clones and in different streptococcal species isolated worldwide since the first reports on such strains in the late 70s, demonstrating the importance of commensal streptococci for the spread of selectable markers in naturally transforming pathogens.

Bacterial Proteins↗
PubMed2001

A novel MSP/DHPLC method for the investigation of the methylation status of imprinted genes enables the molecular detection of low cell mosaicisms.

We describe a new procedure for the analysis of the methlyation status of imprinted genes based on methylation-specific PCR followed by denaturing high performance liquid chromatography (MSP/DHPLC). The method offers a rapid and very reliable alternative to conventional methods used for such purposes such as Southern blots and methylation specific PCR (allele-specific MSP). The efficient resolution of the differentially methylated alleles is demonstrated for two human imprinted genes, namely the SNRPN gene and the LIT1 gene (KCNQ1OT1). Abnormal imprinting of the two genes is associated with the Angelman/Prader-Willi syndromes and the Beckwith-Wiedemann syndrome, respectively. The MSP/DHPLC method is based on PCR amplification of gene segments which show parent-of-origin specific methylation. Genomic DNA is subjected to an in vitro bisulfite treatment prior to PCR amplifications using primers specific for modified DNA. Both alleles are theoretically amplified with equal efficiency and are represented by identically sized PCR products; they differ, however, at a number of positions within the amplified DNA segment. The DHPLC analysis allows a very efficient resolution of the two populations of PCR products. The high sensitivity and quantitative properties of the MSP/DHPLC method are illustrated based on its ability to reveal a low cell mosaicism in an infant with a maternal uniparental disomy 15 (i.e., Prader-Willi syndrome patient). The minor cell line (approximately 8% in blood) was not detectable with conventional molecular analysis. While the detection of low cell mosaicisms of structurally abnormal chromosomes usually relies on cytogenetic studies, the MSP/DHPLC method described here not only offers an alternative at the molecular level, but may also reveal mosaicisms concerning structurally intact chromosomes.

Adult↗
PubMed1993

Development and maintenance of a simple reflex circuit in small-patch mosaics of Drosophila: effects of altered neuronal function and developmental arrest.

A combined genetic, anatomical, and behavioral approach has been undertaken to study the developmental and functional plasticity of identified bristle mechanosensory neurons in Drosophila. A stereotyped grooming reflex in decapitated flies enabled simple but reliable assessments of the functional output of individual bristle sensory cells to correlate with their axonal projections and terminal arbors revealed by the cobalt backfill technique. Construction of small-patch mosaics that contain only a single mutant bristle allowed functional perturbation of individual neurons within an otherwise normal environment. Mutations that affect nerve excitability and membrane recycling have been used to examine their effects on neuronal pathfinding, arborization, and the initiation and maintenance of functional connections. Previous studies (Burg and Wu, 1986, J. Neurosci. 6:2968-2976; 1989, Dev. Biol. 131:505-514) have demonstrated that para(ts)nap(ts) double-mutant sensory neurons, in which action potentials are unconditionally blocked by defects in sodium currents, and eag Sh double-mutant sensory cells, in which membrane excitability is increased by alterations in potassium currents, can establish and maintain central projections that are indistinguishable from their functionally normal counterparts. Mutations of the shi(ts) gene cause a temperature-sensitive, reversible block of the membrane recycling process, resulting in arrest of neuronal growth in culture (Kim and Wu, 1987, J. Neurosci. 7:3245-3255) and depletion of synaptic vesicles that leads to transmission blockade at established synapses (Ikeda, Ozawa, and Hagiwara, 1976, Nature 259:489-491; Koenig and Ikeda, 1983, J. Neurobiol. 14:411-419; 1989, J. Neurosci. 9:3844-3860). Prolonged heat treatments (up to 16% of total development time) of small-patch shi(ts) mosaics at different pupal stages did not prevent the establishment of central projections characteristic of the various sensory cell types. However, none of the shi(ts) sensory neurons heat-pulsed during the initial or the final 16% of pupal development were able to initiate the reflex behavior, although a proportion of those treated in other periods apparently established functional contacts with appropriate targets to support the characteristic cleaning reflex. The possibility exists that the membrane recycling process blocked in shi(ts) cells provides a crucial mechanism for cell-cell interactions taking place during initial differentiation and final synaptic stabilization, and possibly competition, in the developing sensory neuron. Heat treatments of adult shi(ts) mosaics blocked the reflex initiated by the mutant (but not the surrounding normal) bristles, as expected from the effect of synaptic block.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed2005

Prenatal diagnosis of trisomy 6 mosaicism.

We report on a fetus with multiple congenital anomalies detected at the prenatal ultrasound examination and a trisomy 6 mosaicism in the amniocytes. The pregnancy was interrupted in the 18th gestational week and the autopsy revealed malformations including cleft right hand, arthrogryposis and hypoplasia of the 4th digit of the left hand, syndactylies and overlapping toes, facial dysmorphism with hypertelorism and low-set ears, ventricular septum defect (VSD), intestinal malrotation and scoliosis. Trisomy 6 mosaicism was detected in cultured amniocytes (13.3%), confirmed in umbilical cord fibroblasts (40%) and by fluorescence in situ hybridization on other fetal tissues. Trisomy 6 mosaicism is a very rare finding with only eight cases previously reported to our best knowledge.

Abnormalities, Multiple↗
PubMed2006

Postnatal follow-up of prenatally diagnosed trisomy 16 mosaicism.

OBJECTIVE: To determine the long-term outcome of pregnancies prenatally diagnosed with trisomy 16 and identify variables associated with the outcome. METHODS: We reviewed all published and our unpublished data from trisomy 16 pregnancies for which outcomes were available for children of greater than 1 year of age. RESULTS: Nineteen cases were diagnosed with trisomy 16 on chorionic villus sampling (CVS) and 17 cases at amniocentesis. Age at last follow-up ranges from 1 to 13 years. Among the CVS group, four out of five patients, with a birth weight and/or length below -2 SD and postnatal growth information, showed catch-up growth (80%). Among the amniotic fluid (AF) group, the birth weight was available in 13 cases. Eleven of the 13 cases had a birth weight less than -2 SD. In eight cases, the length was also below -2 SD (length data unavailable in one case). Nine out of ten cases (90%) and seven out of eight (87.5%) showed catch-up growth for weight and length, respectively. In terms of development, no cases of CVS mosaicism had global developmental delay. One child had a history of delay in speech development. Among the AF-detected cases, 4/17 cases had global developmental delay. All four children with global developmental delay had more than one major malformation compared to 6 out of 32 children in the group with normal development (p = 0.004). The finding of uniparental disomy (UPD) was not associated with developmental delay. CONCLUSIONS: The majority of prenatally diagnosed trisomy 16 mosaic cases have a good postnatal outcome. However, the finding of mosaicism on AF and the presence of major congenital anomalies are associated with an increased risk of developmental delay.

Amniocentesis↗