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PubMed2006

Somatic and germline mosaicisms in severe myoclonic epilepsy of infancy.

Severe Myoclonic Epilepsy in Infancy (SMEI) is an intractable epileptic syndrome with onset in the first year of life and is commonly caused by de novo mutations in the SCN1A gene, encoding the alpha1-subunit of the neuronal voltage-gated sodium channel. We report two unrelated families in which probands were affected by SMEI and their parents showed a single febrile seizure during early childhood or no neurological symptoms. Semiquantitative analysis of SCN1A mutations allowed the detection of a somatic and germline mosaicism in one of the parents. The study provides the first example of parental mosaicisms in SMEI and opens a new insight into the phenotypic variability and complex inheritance of this condition. The identification of germline mosaicisms has important consequences in genetic counseling of SMEI when SCN1A mutations appear to occur de novo with standard screening methods.

Alleles↗
PubMed2004

Genetic mosaic analysis in the nervous system.

Genetic mosaic techniques provide a powerful tool for dissecting gene function in the intricate genetic networks that underlie the formation and function of nervous systems. For instance, it is possible to make individual cells or groups of cells homozygous for mutations of interest at specific points during an organism's development. It is also possible to resolve lineage relationships and to characterize cellular morphology and connectivity. Current techniques for creating genetically mosaic organisms incorporate improved controls over clone induction, identification, and/or mosaic tissue characterization.

Animals↗
PubMed2004

Screening for mutations in the SRY gene in patients with mixed gonadal dysgenesis or with Turner syndrome and Y mosaicism.

OBJECTIVE: To investigate the presence of mutations in the open reading frame (ORF), as well as on the 5' and 3', flanking regions of the SRY gene in patients with mixed gonadal dysgenesis (MGD) or with Turner syndrome (TS) and Y mosaicism. STUDY DESIGN: We studied 13 patients with MGD and three patients with TS and Y mosaicism. DNA was isolated from blood leukocytes for subsequent polymerase chain reaction (PCR) and direct sequencing were performed in the ORF, as well as from the 5' and 3' flanking regions of the SRY gene. RESULTS: No mutations were present in any of the patients studied. CONCLUSION: The absence of mutations in these regions indicated that mutations were an unlikely cause of MGD or TS with Y mosaicism and suggested that there are others genes playing an important role in sex development.

Adolescent↗
PubMed2004

The chromosome of Shigella flexneri bacteriophage Sf6: complete nucleotide sequence, genetic mosaicism, and DNA packaging.

Shigella flexneri temperate bacteriophage Sf6 is of interest in part because its prophage expresses the oac gene that alters the antigenic properties of the surface O-antigen polysaccharide of its host bacterium. We have determined the complete sequence of its 39,044 bp genome. The sequence shows that Sf6 is a member of the canonical lambdoid phage group, and like other phages of this type has a highly mosaic genome. It has chromosomal regions that encode proteins >80% identical with at least 15 different previously characterized lambdoid phages and prophages, but 43% of the genome, including the virion assembly genes, is homologous to the genome of one phage, HK620. An analysis of the nucleotide differences between Sf6 and HK620 indicates that even these similar regions are highly mosaic. This mosaicism suggests ways in which the virion structural proteins might interact with each other. The Sf6 early operons are arranged like a typical lambdoid phage, with "boundary sequences" often found between functional modules in the "metabolic" genome domain. By virtue of high degree of similarity in the encoding genes and their DNA target sites, we predict that the integrase, early transcription anti-terminator, CI and Cro repressors, and CII protein of Sf6 have DNA binding specificities very similar to the homologous proteins encoded by phages HK620, lambda, 434 and P22, respectively. The late operon contains two tRNA genes. The Sf6 terminase genes are unusual. Analysis of in vivo initiation of the DNA packaging series showed that the Sf6 apparatus that recognizes DNA for packaging appears to cleave DNA for initiation of packaging series at many sites within a large region of about 1800 bp that includes a possible pac site. This is unlike previously characterized phage packaging mechanisms.

Bacteriophages↗
PubMed2003

A fluorescent method for detecting low-grade 11patUPD mosaicism in Beckwith-Wiedemann syndrome.

The quantitative evaluation of mosaicism for uniparental disomy (UPD) involving a restricted chromosomal region requires the availability of a sensitive and reproducible method that is capable of detecting even a small percentage of disomic cells and avoiding false positive and false negative results. The occurrence of UPD is usually monitored by means of the parent-proband segregation analysis of microsatellites mapping to the target region. We here describe the quantitative blood cell evaluation of segmental mosaic UPD11, a marker of Beckwith-Wiedemann syndrome, by means of the segregation analysis of 11p15 microsatellites using both radioactive and fluorescence-based techniques. As the greater amplification efficiency of the shorter allele in heterozygous subjects may bias the correct evaluation of disomy, the mean short/long allele ratio was established at three loci of each of 30 normal heterozygous subjects, as well as the peak As/Al area in the presence of 50% of each allele. The interval was defined using a 5% level of significance. The results show that the fluorescence-based technique is superior to radioactivity in detecting the subtle allelic imbalances present in low-grade mosaicism conditions.

Alleles↗
PubMed2005

Fetal and placental chromosomal mosaicism revealed by QF-PCR in severe IUGR pregnancies.

A number of genetic and environmental factors are taken into account as responsible for intrauterine growth restriction (IUGR); nevertheless, the relevance of genetic alteration in IUGR aetiology remains to be determined. The aim of this study was to investigate using a combined cytogenetic-molecular approach, improved by a new application of QF-PCR method, the presence of mosaic chromosomal changes in fetal/placental samples from 12 pregnancies with unexplained severe IUGR. This multiple approach allowed us to reveal and quantify subtle chromosomal mosaicisms with less than 5% of trisomic cells even in cases in which cytogenetic and FISH analyses failed to reveal them. These are three pregnancies with a mosaic trisomy for chromosomes 7, 2 and 14; the former case presented matUPD7 and was previously described in this journal (Placenta 22 (2001) 813) in association with pre- and postnatal growth restriction. It is intriguing that chromosomes 7, 2 and 14 are known or suspected to harbour imprinted genes, so that an unbalanced gene dosage in a subset of cells during embryonic development could lead to an early impairment of placental function. Our findings indicate that extensive molecular and cytogenetic studies of IUGR fetal and placental tissues are necessary to reveal at least part of the heterogeneous genetic lesions implicated in IUGR phenotypes.

Adult↗
PubMed2006

Bilateral temporal lobe epilepsy in a patient with Turner syndrome mosaicism.

Turner's syndrome (TS), resulting from deletion of one X chromosome in women, is associated with cerebral development abnormalities, particularly in the temporal lobes. Symptomatic epilepsy is described only in cases with extensive malformations. Here, we report the first case of bilateral temporal epilepsy without macroscopic cerebral malformation in a woman with TS mosaicism. Bitemporal dysfunction was confirmed by the ictal and interictal EEG, PET, MR-spectroscopy and the neuropsychological examination, other causes than TS mosaicism were excluded. In rare cases, TS mosaicism may underlie non-lesional temporal lobe epilepsy, probably in relation to microanatomic structural and functional cerebral abnormalities. Further studies are needed to determine the frequency of this association.

Adult↗
PubMed2006

Somatic mosaicism in a male with an exon skipping mutation in PDHA1 of the pyruvate dehydrogenase complex results in a milder phenotype.

Pyruvate dehydrogenase complex (PDC) deficiency is commonly due to mutations of PDHA1 on the X chromosome. Milder phenotypic manifestations occur in heterozygous females than in hemizygous males with the same mutation, and females are more likely to survive with severe mutations. The boy described here had hypotonia, moderate developmental delay, tremors, normal growth and brain MRI, and normal to slightly elevated lactate. PDC activity was low in skin fibroblasts and skeletal muscle (27-37%) but normal in lymphocytes. PDHA1 cDNA from cultured fibroblasts revealed two populations, one normal, the other lacking exon 6 (c.511-603 del). Genomic DNA from fibroblasts contained both normal and mutant (g.592G-->A) sequences within exon 6. Expression of minigene constructs containing exons 5, 6, and 7 with or without this mutation in 293T cells confirmed that the mutation alters splicing of exon 6. The mutant to wild-type DNA ratio varied substantially across tissues. Immunoblotting of fibroblast lysates detected only wild-type E1alpha protein. Immunocytochemistry of cultured skin fibroblasts showed a mosaic pattern with 60% of cells positive for E1alpha and 40% negative, consistent with PDC activity and DNA analysis. Karyotyping, FISH analyses, and genotyping revealed a 46XY male without chimerism. These data indicate somatic mosaicism for a mutation within exon 6 that causes exon skipping and production of a non-functional protein. The mutated 592G residue is conserved among all eukaryotes. Substituting A for G apparently alters normal splicing by creating a SRp40 exonic splice enhancer site. The milder phenotype in this male is accounted for by the mixture of normal cells and cells lacking E1alpha. Immunocytochemistry was a useful adjunct to molecular analysis for demonstrating mosaicism.

Base Sequence↗
PubMedDate not supplied

Hypomelanosis of ito and a 'mirror image' whole chromosome duplication resulting in trisomy 14 mosaicism.

We describe a female infant with multiple congenital anomalies including unusual hyperpigmentation, tetralogy of Fallot, absent corpus callosum and wide prominent nasal bridge. The infant was initially seen for genetic consultation on day one after birth. Chromosome analysis from cultured lymphocytes showed a normal 46,XX karyotype. However, cultured skin fibroblasts showed mosaicism with 46,XX,add(14)(q32).ish psu dic dup(14)(q32p13)(wcp14+)/46,XX complements. A review of the published report with chromosome mosaicism and hypomelanosis of Ito (HMI) is included. We suggest that the trisomy 14 mosaicism seen in fibroblast cultures has importance in the expression of pigmentation dysplasias in this patient. Pigmentary anomaly may be due to loss or gain of specific genes that influence pigmentation located on the long arm of chromosome 14 in this patient.

Abnormalities, Multiple↗
PubMed1998

Asymmetry in the occlusal morphology of first permanent molars in 45,X/46,XX mosaics.

The genetic control of dental morphology is affected by various chromosomal aberrations, and morphological changes familiar to specific aneuploidies can be distinguished in many cases. Asymmetry between bilateral teeth in the dental arch in laboratory animals shows increased expression after exposure to external stress during development. Bilateral asymmetry in occlusal cuspal morphology has not been widely used as a means of odontometric examination, partly because accurate and reliable methods are not commonly available. The aim here was to examine linear and angular variables of the occlusal morphology of maxillary and mandibular first permanent molars in three dimensions in individuals with 45,X/46,XX mosaicism and to find out if this aneuploidism causes deviations from normal development and increased asymmetry in bilateral variables of the occlusal surface. The participants were five females with 45,X/46,XX chromosome constitution, whose karyotypes were confirmed by cytogenetic tests of skin fibroblasts. The controls were 10 first-degree female relatives of the mosaic patients with normal 46,XX chromosome constitution. The method of measuring the three-dimensional morphology of occlusal surfaces was based on a machine-vision technique using a single video-imaging camera. An apparent increase in asymmetry of occlusal morphology in first permanent molars in 45,X/46,XX mosaics was found. As there was evidence of directional asymmetry, it is possible that different cell lines regulated by discrete genes cause the directionality.

Aneuploidy↗
PubMed2001

N-cadherin expression in motoneurons is directly regulated by androgens: a genetic mosaic analysis in rats.

We have recently reported that systemic androgens regulate adult N-cadherin (N-cad) expression in spinal motoneurons. However, the mechanism through which androgen mediates this effect remains undetermined. Androgen may act directly on motoneurons to regulate N-cad expression, or indirectly, via effects on androgen-sensitive afferent or efferent structures. Here, we describe a genetic mosaic investigation of this site-of-action indeterminacy. Following developmental random X chromosome inactivation, androgenized female rats heterozygous for the tfm androgen receptor mutation (X(WT)X(tfm)) are phenotypic mosaics of androgen-sensitive wild-type (WT) and androgen-insensitive (tfm) motoneurons. We compared steroid effects on WT and tfm cells in two sexually-dimorphic motoneuron pools, the spinal nucleus of the bulbocavernosus (SNB) and the dorsolateral nucleus (DLN), as well as a less steroid responsive motoneuron pool, the sexually monomorphic retrodorsolateral nucleus (RDLN). Independent of steroid treatment, a greater proportion of wild-type cells were N-cad immunoreactive (IR) in the DLN and RDLN. Following testosterone treatment, increased N-cad expression was observed in both cell types in the DLN, but in the SNB only the androgen-competent WT cells increased N-cad expression. Testosterone treatment did not significantly alter N-cad expression in the mosaic RDLN. The results indicate both cell autonomous and cell non-autonomous androgenic regulation of N-cad expression in spinal motoneurons.

Androgens↗
PubMed1989

Central projections of peripheral mechanosensory cells with increased excitability in Drosophila mosaics.

The formation and maintenance of the central projections of identified bristle mechanosensory neurons with altered excitability were examined in Drosophila mosaics. Two mutants, eag (ether à go-go) and Sh (Shaker), are known to increase excitability of both nerve and muscle cells and enhance synaptic transmission by affecting different types of K+ currents. The eag Sh double mutant produces a synergistic effect, resulting in a greatly increased level of spontaneous neuronal activity and extreme behavioral phenotypes. By constructing mosaic flies containing small patches of doubly mutant cuticle, it was possible to alter the excitability of only one or two identified sensory cells without affecting the surrounding tissue. In these mosaic flies, the doubly mutant sensory cells were more responsive to tactile stimulation. A CoCl2 backfilling technique was utilized in staining the sensory cell projections. Both qualitative and quantitative comparisons were made between projections of cells having normal and increased levels of excitability. The length, branching characteristics, and number of terminal varicosities were analyzed for each sensory cell projection. Results indicate that, at the light microscopy level, these characteristics were not obviously altered by an increased level of excitability.

Animals↗
PubMed2001

Successful pregnancy and delivery from frozen-thawed embryos after intracytoplasmic sperm injection using round-headed spermatozoa and assisted oocyte activation in a globozoospermic patient with mosaic Down syndrome.

OBJECTIVE: To describe a successful pregnancy and delivery from frozen-thawed embryos after intracytoplasmic sperm injection (ICSI) and assisted oocyte activation in a globozoospermic patient with mosaic Down syndrome. DESIGN: Controlled clinical study. SETTING: IVF Laboratory, PL Infertility Clinic, Seoul, Korea. PATIENT(S): A couple with infertility resulting from globozoospermia with mosaic Down syndrome: 47,XY,+21[7]/46,XY[33]. INTERVENTION(S): Semen analysis, karyotyping, ICSI, assisted oocyte activation, assisted hatching, and frozen-thawed ET. MAIN OUTCOME MEASURE(S): Fertilization rate, implantation, pregnancy, and delivery. RESULT(S): Thirty-eight oocytes were aspirated, and round-headed spermatozoa were injected into 35 oocytes in metaphase II. Assisted oocyte activation with calcium ionophore A23187 after ICSI resulted in a high fertilization rate (21 of 35, 60%; 2 pronuclei in 18 of 21; 3 pronuclei in 3 of 21) and good embryo development. At 3 days after ICSI, 5 embryos of good quality were surgically transferred to the endometrium after assisted hatching, but no pregnancy occurred. After 2 months, the surgical transfer of 4 frozen-thawed embryos after assisted hatching led to an ongoing pregnancy. A female infant weighing 3,000 g was delivered at 38 weeks of gestation by cesarean section. CONCLUSION(S): We report the first successful pregnancy and delivery from frozen-thawed embryos after ICSI and assisted oocyte activation in a globozoospermic patient with mosaic Down syndrome.

Adult↗
PubMed2001

Ambiguous genitalia, 45,X/46,XY mosaic karyotype, and Y chromosome microdeletions in a 17-year-old man.

OBJECTIVE: To describe clinical and laboratory features of a patient with 45,X/46,XY mosaic karyotype and Y chromosome microdeletions and to discuss the diagnostic problems in his management. DESIGN: Case report. SETTING: University department. PATIENT(S): A 17-year-old man with ambiguous genitalia, 45,X/46,XY mosaic karyotype, and Y chromosome microdeletions. INTERVENTION(S): Testicular ultrasonography, karyotype, open testicular biopsy, polymerase chain reaction (PCR) screening for cystic fibrosis, PCR screening for Y chromosome microdeletions in peripheral blood and testicular tissue, and reverse transcriptase PCR in testicular tissue for Y chromosome microdeletions. MAIN OUTCOME MEASURE(S): Avoidance of dissemination of testicular cancer. RESULT(S): The patient was referred for bilateral orchiectomy. CONCLUSION(S): 45,X/46,XY mosaic karyotype is associated with a broad spectrum of phenotypes that includes female with Turner syndrome, male with mixed gonadal dysgenesis, male pseudohermaphroditism, and apparently normal male. Microdeletions of the long arm of the Y chromosome may be associated with Y chromosomal instability, leading to formation of 45,X cell lines. 45,X/46,XY males carry an increased risk for gonadal tumors and must be followed closely.

Adolescent↗
PubMed2003

Successful triplet pregnancy and delivery after oocyte donation in an infertile female with chromosome mosaicism for monosomy X, partial trisomy X, and terminal Xp deletion.

OBJECTIVE: To present successful triplet pregnancy and delivery after oocyte donation and IVF in a female with chromosome mosaicism for monosomy X, partial trisomy X, and terminal Xp deletion. DESIGN: Descriptive case study. SETTING: Large tertiary care hospital. PATIENT(S): A 23-year-old infertile woman with primary amenorrhea, short stature, and a mosaic karyotype of 45,X[10]/46,X,idic(X)(qter-->p22.3::p22.3-->qter)[40]. Fluorescence in situ hybridization investigation of the isodicentric X chromosome revealed terminal Xp deletion. INTERVENTION(S): Ultrasound and laparoscopic examinations revealed streak ovaries and a hypoplastic uterus. Oocyte donation and IVF resulted in a triplet pregnancy without major maternal complications. MAIN OUTCOME MEASURE(S): Ultrasound and laparoscopy. RESULT(S): A cesarean section was performed at 32 weeks gestation because of preterm labor and malpresentation. Three babies were delivered with birth weights of 1,514 g, 1,686 g, and 1,968 g. All infants survived and were healthy at 3 years of age. CONCLUSION(S): With careful evaluation and counseling, assisted reproductive technology can be safely used in females with mosaic X chromosome abnormalities and gonadal dysgenesis.

Adult↗
PubMed1985

Two pregnancies and the loss of the 46,XX cell line in a 45,X/46,XX Turner mosaic patient.

Two successful pregnancies in a patient with a 45,X karyotype are reported. Twelve pregnancies have been reported in 9 monosomy X patients and 57 pregnancies in 24 patients with both a 45,X and a 46,XX cell line. The patient reported here was diagnosed at 10 years of age as a Turner mosaic (45,X/46,XX), but showed no evidence of a normal cell line in any of the four tissues analyzed 15 years later. The difficulty in detecting mosaicism as well as the stability of autosomal and sex chromosomal mosaicism are discussed. An argument is made for early cytogenetic evaluation, utilizing multiple tissues, and analyzing an adequate number of cells.

Adult↗
PubMed1998

Genetic counseling in a patient with XXY/XXXY/XY mosaic Klinefelter's syndrome: estimate of sex chromosome aberrations in sperm before intracytoplasmic sperm injection.

OBJECTIVE: To report the sex chromosome aberrations in the sperm of a patient with mosaic Klinefelter's syndrome before ICSI. DESIGN: Case report. SETTING: Institute of Human Genetics, University Hospital PATIENT(S): A patient with an XXY/XXXY/XY mosaic Klinefelter's syndrome and extreme oligozoospermia. INTERVENTION(S): Skin biopsy, buccal smear, hair root sampling, and semen sampling. MAIN OUTCOME MEASURE(S): The karyotypes of three additional somatic cell systems and the ratio of sex chromosome aberrations in sperm. RESULT(S): After two-color fluorescence in situ hybridization of 202 interphase sperm nuclei, both the proportion of hyperhaploid 24, XY and 25, XXY sperm (5.0% and 0.5%, respectively) and of hyperhaploid 24, XX sperm (2.0%) were elevated. In contrast with peripheral lymphocytes, 93.9% of which showed sex chromosome aberrations, in the present patient only 7.5% of sperm proved to be hyperhaploid with an extra sex chromosome. CONCLUSION(S): The determination of sex chromosome aberrations in the sperm of a patient with mosaic Klinefelter's syndrome may provide additional information to estimate the transmission risk to his offspring.

Adult↗
PubMed1997

Paternal somatic and germ-line mosaicism for a sex-determining region on Y (SRY) missense mutation leading to recurrent 46,XY sex reversal.

OBJECTIVE: To determine the etiology for recurrent 46,XY sex reversal in a family with two Swyer siblings. DESIGN: Deoxyribonucleic acid (DNA) from peripheral lymphocytes and sperm were analyzed for duplication of the dosage sensitive sex locus (DSS) and for mutations in sex-determining region on Y (SRY). SETTING: An academic teaching hospital. PATIENTS: A family consisting of mother, father, and five phenotypic daughters, of which two were 46,XY sex-reversed females. INTERVENTION: Deoxyribonucleic acid (DNA) extraction, polymerase chain reaction (PCR), Southern blotting, dosage densitometry, single-strand conformation polymorphism (SSCP), and sequencing. MAIN OUTCOME MEASURE: Comparison of control and subject DNA. RESULTS: Deoxyribonucleic acid (DNA) analysis of SRY in genomic DNA from the 46,XY sex-reversed siblings revealed identical missense mutations (T-->G) in both sisters. Analysis of the SRY gene in paternal lymphocyte and sperm DNA revealed mosaicism for wild and mutant (T-->G) SRY sequences. SRY analysis of sperm DNA also demonstrated the same mosaicism for the T-->G missense mutation. CONCLUSION: A postembryonic SRY mutation gave rise to paternal mosaicism for two distinct cell populations (SRY+/SRY-). The presence of a wild type SRY in the somatic cell line may account for a normal pattern of male sexual differentiation, whereas the presence of a mutated SRY in the germ line resulted in two 46,XY sex-reversed offspring. These results confirm a proposed mechanism for the condition of recurrent 46,XY sex-reversed females.

Adolescent↗